Citations

TPS766 Background: Imatinib is the worldwide standard for first-line therapy of advanced KIT-mutant GIST. However, secondary resistance mutations in the KIT ATP-binding domain (exons 13, 14), activation loop (exons 17, 18), or both develop and result in loss of imatinib-sensitivity. While no single tyrosine kinase inhibitor (TKI) inhibits all KIT mutations, the combination of bezuclastinib + sunitinib targets commonly occurring primary (exons 9, 11) and secondary (exons 13, 14, 17, and 18) KIT mutations. In a Phase 1/2 clinical study, pts with relapsed and/or refractory GIST and a median of 3 prior lines of therapy treated with bezuclastinib + sunitinib (n=15) experienced clinical benefit and an acceptable safety profile, warranting further evaluation in a randomized trial. Methods: Peak (NCT05208047) is a global, randomized, open-label, multi-part Phase 3 study evaluating the efficacy and safety of bezuclastinib + sunitinib versus sunitinib as second-line treatment in adult pts who were intolerant to imatinib or whose tumors had imatinib-resistance. The lead-in portion, to test a new formulation of bezuclastinib, (Part 1) has completed enrollment. Based upon PK and safety, a dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD has been determined for Part 2 of the Peak study. Part 2 will enroll ~388 pts to be randomized (1:1) to bezuclastinib 600 mg QD + sunitinib 37.5 mg QD or sunitinib 37.5 mg QD alone. Key inclusion: >1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, Eastern Cooperative Oncology Group Performance Status 0-2, adequate organ function, and prior imatinib therapy (no other prior therapy). Key exclusion: PDGFR mutations or succinate dehydrogenase deficiency, clinically significant cardiac disease, and use of strong CYP3A4 inhibitors or inducers. The primary endpoint is progression-free survival (PFS) confirmed by blinded independent central review per mRECIST v1.1. Additional efficacy (including overall survival and objective response rate) and safety endpoints will be evaluated. Clinical trial information: NCT05208047 .

748 Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with 3 or more kinase inhibitors, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. In the second interim analysis of overall survival (OS) from the phase 3 INTRIGUE study, the OS event rate was 41% in the all-patient (AP) intent-to-treat (ITT) population, and OS was similar between treatment arms in both the KIT exon 11 ITT and AP ITT populations. Here, we present the final OS and updated safety from INTRIGUE. Methods: INTRIGUE (NCT03673501) is an open-label, phase 3 study of adults with advanced GIST who had disease progression on or intolerance to imatinib. Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 weeks on/2 weeks off) and was stratified by KIT mutational status and imatinib intolerance. OS was a key secondary endpoint (the primary endpoint of progression-free survival was reported previously); final OS analysis was prespecified to occur with ≥200 and ≥145 events in the AP ITT and KIT exon 11 ITT populations, respectively. Data cutoff was March 15, 2023. Results: Of 453 pts, 444 received treatment; 40 remain on treatment (ripretinib, 28/223 [13%]; sunitinib, 12/221 [5%]). Treatment discontinuation was due to progressive disease (PD) by independent radiologic review (56%), PD by investigator (11%), clinical PD (6%), withdrawal of consent (6%), and adverse events (AEs; 5%). Fewer pts discontinued treatment due to AEs with ripretinib vs sunitinib (3% vs 6%). There were 211 OS events (47%) in the AP ITT population and 151 OS events (46%) in the KIT exon 11 ITT population. OS was similar with ripretinib vs sunitinib in the 2 ITT populations (Table). Fewer pts had grade 3/4 treatment-emergent AEs with ripretinib vs sunitinib (43% vs 67%). Dose interruptions and reductions were lower with ripretinib vs sunitinib. Median treatment duration for ripretinib vs sunitinib was 7.9 vs 6.5 months. Conclusions: In the finalOS analysis from the INTRIGUE study, OS was similar between treatment arms. The safety profile remained consistent and more favorable for ripretinib vs sunitinib in pts with advanced GIST previously treated with imatinib. Clinical trial information: NCT03673501 . [Table: see text]

55 Background: Nearly one-half of deficient mismatch repair (d-MMR) metastatic colorectal cancers (mCRC) demonstrate durable responses to immune checkpoint inhibitors (ICIs). Given preclinical data indicating that liver metastases sequester activated CD8+ T cells from systemic circulation, we examined clinical outcome by metastatic site. Methods: In a retrospective cohort of patients with d-MMR mCRCs treated at multiple centers in France (n=66), we sought to validate data from a U.S. cohort, and then performed pooled analysis (n=104). All patients received first-line ICI monotherapy. Metastatic site was analyzed in relationship to tumor response (RECIST version 1.1), and progression-free survival (PFS) by multivariable stratified Cox regression after adjustment for covariates. Results: Objective responses were achieved in 38/66 (58%) patients in the validation cohort. Best tumor response included 13 (20%) complete responses (CR), 25 (38%) partial responses (PR), 16 (25%) stable disease, and 11 (17%) progressive disease (PD). One-year and 5-year PFS rates were 73% and 67%, respectively; 18 (27%) patients progressed during immunotherapy. Best tumor response was attenuated in patients with liver metastasis ( P=0.03). Presence of liver metastasis, but not other sites, was associated with significantly poorer PFS after adjustment for covariates (HRadj 2.82; 95%CI, 1.08-7.39; Padj=0.03). In a pooled analysis, liver metastasis remained significantly and independently associated with poorer PFS (HRadj 3.18; 95%CI, 1.52-6.67; Padj=0.002) and with attenuated tumor best response (P=0.01). Conclusions: Metastasis to the liver, but not other sites, was validated as an independent factor associated with poorer response and survival after ICI treatment in d-MMR mCRCs. These data underscore the need for novel therapeutic strategies in these patients. [Table: see text]

Abstract Background: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors’ association with colorectal cancer risk and survival differs by SBS88. Methods: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer–specific survival using Cox proportional hazards regression (N = 3,465 cases). Results: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66–0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer–specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47–7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78–1.21, Pheterogeneity = 0.066). Conclusions: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer–specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available. Impact: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival.

Background: Irreparable rotator cuff tears represent approximately 12% of all presenting cuff tears, and multiple surgical techniques have been described for treatment, including allograft/bridge augmentation, debridement, partial repair, subacromial balloon, tendon transfer, and superior capsule reconstruction (SCR). SCR has demonstrated durable improvement in range of motion (ROM) and outcome scores at 2 and 5 years. Indications: Surgical indications for SCR include an irreparable tear of the supraspinatus and/or infraspinatus with a preserved or reparable subscapularis and preserved glenohumeral joint cartilage. Technique Description: Diagnostic arthroscopy is performed to identify and characterize the rotator cuff tear. Thorough debridement of the greater tuberosity is performed. Two all-suture FiberTak anchors are placed in the superior aspect of the glenoid. Two 2.6-mm FiberTak suture anchors are placed in the humeral head at the chondral margin. After measuring, the dermal allograft is cut to size with 15-mm overhang left on the far lateral edge. A 12-mm passport cannula is inserted laterally and the sutures from the glenoid and humeral head anchors are brought out through the cannula maintaining their position and orientation. The sutures are passed through the graft outside the cannula. The graft is introduced into the shoulder via the passport cannula with a back grasper. A cannula-in-cannula technique is used to tie the glenoid anchors first and then the medial row anchors. Two lateral row swivel lock anchors are used to complete a standard double row repair. Margin convergence is performed between the dermal allograft and remaining rotator cuff anterior and posterior. Postoperatively, patients are kept in a sling for 6 weeks, with no shoulder ROM. From weeks 6 to 12, patients discontinue sling and begin passive progression to active ROM. Strengthening is initiated at 12 weeks, and return-to-sport or work is at approximately 6 months. Results: Irreparable rotator cuff tears treated with arthroscopic rotator cuff repair and SCR show durable improvement in patient-reported outcomes at 2 and 5 years. Re-tear rates did not differ between athletes and non-athletes. Discussion/Conclusion: Arthroscopic rotator cuff repair with SCR is a durable and reliable surgical option for patients presenting with preserved glenohumeral joint and irreparable supraspinatus and/or infraspinatus tear. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

Abstract Tumor-associated vasogenic brain edema is a well-known contributor of morbidity and mortality in patients with metastatic disease to the brain. It is widely accepted that brain metastases (BM) is associated with extensive edema and can cause increased symptomatology such as pain, neurologic deficit, and elevated intracranial pressure depending on extent and location. We present a proof-of-concept retrospective analysis utilizing DLBAI to segment and detect radiological and topographical patterns of peritumoral edema and assess for clinicopathological correlates in 84 patients with NSCLC and BM who underwent surgical resection and were not previously on steroids. We found that overall, tumors in all locations demonstrated a mean 10:1 edema to tumor ratio (ETR) and an occipital tumor location was associated with a significantly elevated ETR. Within our cohort there were no other factors that were significantly associated with ETR. This study demonstrates a proof-of-concept that DLBAI is an efficient and accurate method of radiographic analysis that can be applied to detect and potentially predict clinicopathological data and prognostic determinants. Clinically, we demonstrate that NSCLC is associated with significant peritumoral edema and that topographical factors may be associated with increased extent of edema.

Background: Medial-sided elbow injuries are becoming increasingly common among throwing athletes due to overuse and increased specialization at early ages. High valgus stress and repetitive elbow flexion/extension during throwing not only affects the ligaments and dynamic support of the elbow, but commonly affects the ulnar nerve. Indications: Management of cubital tunnel syndrome is initially rest, therapy, and functional training; however, if conservative measures do not appropriately address the ulnar neuropathy, surgical decompression with subcutaneous transposition is a reliable treatment option. Technique Description: An incision is created over the medial epicondyle. The medial antebrachial cutaneous nerve is identified and protected. The ulnar nerve is identified and tagged with a vessel loop to allow for appropriate handling of the nerve. Decompression of the ulnar nerve begins proximally by spreading the tissues superficial to the ulnar nerve and splitting the fascia overlying it. Then, dissection deep to the nerve is performed. A small strip of the medial intermuscular septum will be used as a sling to hold the nerve securely in the transposed position. This is released proximally and the distal attachment to the medial epicondyle is left in place. Decompression is then continued distally by releasing the superficial fascia over the flexor carpi ulnaris (FCU) and a portion of the deep FCU muscle belly and fascia. The nerve is decompressed circumferentially, while preserving penetrating branches to the FCU as able. Ultimately, the ulnar nerve is decompressed 10 cm proximal and 10 cm distal to the medial epicondyle. The intermuscular septum is then pulled over the nerve, checked for appropriate length, and sutured in place both posterior and anterior to the ulnar nerve. Results: Symptom improvement after decompression and transposition is high (>90%); however, performance outcomes in overhead and throwing athletes is variable, and return to previous or higher level of play ranges from 60% to 90%. Discussion/Conclusion: Ulnar nerve decompression and transposition can reliably address underlying symptoms, but results are mixed for return to sport outcomes in overhead and throwing athletes. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

AbstractTo address the current and long‐term unmet health needs of the growing population of non‐Hodgkin lymphoma (NHL) patients, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/). A total of 7735 newly diagnosed patients aged 18 years and older with NHL were prospectively enrolled from 7/1/2015 to 5/31/2020 at 8 academic centers in the United States. The median age at diagnosis was 62 years (range, 18–99). Participants came from 49 US states and included 538 Black/African‐Americans (AA), 822 Hispanics (regardless of race), 3386 women, 716 age <40 years, and 1513 rural residents. At study baseline, we abstracted clinical, pathology, and treatment data; banked serum/plasma (N = 5883, 76.0%) and germline DNA (N = 5465, 70.7%); constructed tissue microarrays for four major NHL subtypes (N = 1189); and collected quality of life (N = 5281, 68.3%) and epidemiologic risk factor (N = 4489, 58.0%) data. Through August 2022, there were 1492 deaths. Compared to population‐based SEER data (2015–2019), LEO participants had a similar distribution of gender, AA race, Hispanic ethnicity, and NHL subtype, while LEO was underrepresented for patients who were Asian and aged 80 years and above. Observed overall survival rates for LEO at 1 and 2 years were similar to population‐based SEER rates for indolent B‐cell (follicular and marginal zone) and T‐cell lymphomas, but were 10%–15% higher than SEER rates for aggressive B‐cell subtypes (diffuse large B‐cell and mantle cell). The LEO cohort is a robust and comprehensive national resource to address the role of clinical, tumor, host genetic, epidemiologic, and other biologic factors in NHL prognosis and survivorship.

The role of informatics in public health has increased over the past few decades, and the coronavirus disease 2019 (COVID-19) pandemic has underscored the critical importance of aggregated, multicenter, high-quality, near-real-time data to inform decision-making by physicians, hospital systems, and governments. Given the impact of the pandemic on perioperative and critical care services (eg, elective procedure delays; information sharing related to interventions in critically ill patients; regional bed-management under crisis conditions), anesthesiologists must recognize and advocate for improved informatic frameworks in their local environments. Most anesthesiologists receive little formal training in public health informatics (PHI) during clinical residency or through continuing medical education. The COVID-19 pandemic demonstrated that this knowledge gap represents a missed opportunity for our specialty to participate in informatics-related, public health-oriented clinical care and policy decision-making. This article briefly outlines the background of PHI, its relevance to perioperative care, and conceives intersections with PHI that could evolve over the next quarter century.