Citations

Summary: Lymphedema following oncologic intervention can cause significant lifelong morbidity for patients in whom conservative management fails. The associated swelling, discomfort, pain, and recurrent cellulitis greatly diminish quality of life. Surgical procedures, including suction-assisted lipectomy, lymphovenous anastomosis (LVA), and vascularized lymph node transfers, show effectiveness in both volume reduction in affected extremities and symptom relief. However, the success of procedures like LVA is dependent on effective preoperative lymphatic mapping to identify suitable vessels for anastomosis. Traditional superficial lymphatic mapping uses near infrared fluorescence indocyanine green (ICG) imaging. Moreover, recent advances in contrast-enhanced ultrasound (CEUS) lymphography increased lymphovenous bypass target identification for LVA in the extremities.7 CEUS lymphography uses microbubbles as a contrast-enhancing agent injected intradermally into the affected extremity with subsequent identification of superficial collecting lymphatic vessels using ultrasound. Although a recent report noted an uptick in severe and critical adverse drug reactions to an ultrasound contrast agent injected intravenously in stress echocardiography, adverse drug reactions associated with ultrasound contrast-enhancing agents in body ultrasound are rare. The safety profile and potential complications from CEUS lymphography in the lymphedema population have yet to be fully characterized. In this case report, the authors present the first cutaneous adverse drug event following a secondary exposure to the contrast used for CEUS imaging. Mechanisms and justifications for an immune-mediated process are explored, and a review of similar manifestations in other related contrast applications is discussed.

AbstractIntroductionSurgical techniques for sellar reconstruction include no reconstruction, use of synthetic materials, autologous grafts, and/or vascularized flaps. The aim of this study was to conduct a multi‐center study comparing the efficacy and postoperative morbidity associated with different sellar reconstruction techniques.MethodsA retrospective chart review of patients who underwent endoscopic transsphenoidal surgery for pituitary tumors from five participating sites between January 2021 and March 2023 was performed. The variables included demographics, tumor characteristics, reconstruction technique, postoperative cerebrospinal fluid leak (CSF) leak, and 22‐item Sino‐Nasal Outcome Test (SNOT‐22) scores. Comparisons of postoperative complications, SNOT‐22 scores, and duration of surgery by type of onlay reconstruction were evaluated using Fisher's exact test, analysis of variance, and Kruskal‒Wallis test.ResultsFive hundred and one patients were identified. The median tumor size was 2.1 cm, and 64% were non‐functioning. Intraoperative CSF leak was identified in 38% of patients. A total of 89% of patients underwent onlay reconstruction: 49% were reconstructed with mucosal grafts, 35% with nasoseptal flaps, and 5% with other onlay techniques. Nasoseptal flaps were utilized more frequently in the setting of giant pituitary adenomas (>3 cm), medial cavernous sinus wall resection, and high‐flow intraoperative CSF leaks. Cases who utilized mucosal grafts had an overall shorter operating time (median: 183 min vs. 240 min; p < 0.001). Five postoperative CSF leaks were identified, and therefore, statistical analysis could not be performed for this complication.ConclusionThe effectiveness and morbidity of different sellar reconstruction techniques are comparable. Vascularized flaps were utilized more frequently in the setting of larger tumors and high‐flow intraoperative CSF leaks.

AbstractA 3D‐printed array of hollow microneedles (HMNs) is designed and fabricated using a high‐resolution stereolithography 3D printer and assembled with a 3D‐printed reservoir that incorporates a Luer lock mechanism, ensuring standard and secure connection to syringes. The proof‐of‐concept needle designs consist of half‐eccentric and concentric conical tip shapes, each arrayed with two different interspacing values. After the geometrical features of the devices are characterized, the devices are tested ex vivo in porcine skin to evaluate the impact of tip shape and interspacing on the depth of penetration and the efficacy of the devices in delivering fluids (such as tattoo ink) into the dermis. Overall, the 3D‐printed HMNs can deliver fluids into the target layer of skin. Refinement of the design is ongoing with the ultimate aim to provide alternatives for intradermal drug delivery and diagnostic imaging, such as superficial lymphography.

7532 Background: ABBV-383 is a BCMA x CD3 bispecific antibody with 2 high-affinity BCMA-binding domains and a low-affinity CD3 engaging arm that has been shown to decrease the negative impact of soluble BCMA (sBCMA) and drive sustained T-cell activation with reduced cytokine release in preclinical models of MM. Here, we describe correlative biomarker results of baseline and longitudinal sBCMA levels and immune profiles in the ongoing first-in-human trial that supports 60 mg Q4W as the optimal therapeutic dose of ABBV-383 monotherapy. Methods: Peripheral blood and serum samples from patients with RRMM enrolled in the phase 1 open-label, dose-expansion study (NCT03933735) who received ABBV-383 at 20, 40, or 60 mg Q3W or 60 mg Q4W were collected at baseline (post-dexamethasone, pre–ABBV-383), on treatment, and at disease progression. Samples were analyzed by flow cytometry for immune cell populations, Luminex for cytokines, and electrochemiluminescence ligand binding for sBCMA. Results: Median sBCMA levels at baseline were highly variable among patients, but did not associate with clinical response (≥ partial response [PR]) to ABBV-383 at the selected optimal dose level of 60 mg Q4W (<PR: 244.7 ng/mL; ≥PR: 52.2 ng/mL; P=0.13). Reduction in sBCMA levels over time associated with clinical response (Cmin at cycle 5: <PR, 244.7 ng/mL; ≥PR, 4.7 ng/mL; P=0.04). ABBV-383 treatment led to a rapid and transient increase of proinflammatory cytokines, including IL-6, IL-8, IL-10, TNF-α (Cmax within cycle 1: 29, 349.5, 1375, 456.5 pg/mL, respectively), and promoted T-cell redistribution (89% reduction of CD8+ T cells from periphery), activation (1.9-fold increase in CD69+CD8+ T cells), and proliferation (2-fold increase in Ki67+CD8+ T cells) within cycle 1 in 60-mg Q4W-treated patients. The frequency of baseline CD8+ T-cell exhaustion (PD-1/TIM3) did not impact clinical response at the optimal dose level of 60 mg Q4W ABBV-383 (<PR: 3.5%; ≥PR: 3.9%; P=0.9). Peak induction levels of proinflammatory cytokines during cycle 1 correlated with occurrence of cytokine release syndrome (≥G1) as well as clinical response across dose levels. Conclusions: High-avidity BCMA binding coupled to low-affinity T-cell engagement distinguishes the resulting mechanism of action for ABBV-383. Responses to 60 mg Q4W ABBV-383 were independent of baseline sBCMA levels and resulted in rapid and transient proinflammatory cytokine production that promoted robust T-cell redistribution, activation, and proliferation, indicating that the optimal dose of ABBV-383 maximizes its clinical potential as a convenient, safe, and effective therapy for MM. Clinical trial information: NCT03933735 .

PURPOSE Telisotuzumab vedotin (Teliso-V) is a c-Met–directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536 ) aimed to identify the optimal c-Met protein–overexpressing non–small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor ( EGFR )-wildtype NSCLC. METHODS Eligible patients had locally advanced/metastatic c-Met protein–overexpressing NSCLC and ≤2 previous lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous EGFR -wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%–<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review. RESULTS In total, 172 patients with nonsquamous EGFR -wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 AE was peripheral sensory neuropathy (7%). CONCLUSION Teliso-V was associated with durable responses in c-Met protein–overexpressing nonsquamous EGFR -wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

LBA507 Background: In monarchE (NCT03155997), 2 years of adjuvant abemaciclib + ET resulted in sustained improvement in invasive disease-free survival (IDFS; HR=0.680, 7.6% absolute benefit at 5 years) in patients (pts) with HR+, HER2-, node-positive, high-risk EBC. Here, we investigate the prognostic value of ctDNA detection and dynamics in pts from monarchE. Methods: Samples were analyzed from a selected pt subset (n=1397; abemaciclib + ET arm, n=685; ET arm, n=712), enriched for overall IDFS events compared to the total monarchE study population (IDFS event rate: 31% [433/1397] vs 18% [992/5637]). Pts had blood collected pre-study treatment (baseline) and at 3, 6, or 24 months. ctDNA detection was performed using the personalized, tumor informed Signatera ctDNA assay (Natera, Inc) and whole exome sequencing (WES) of matched primary tumor and normal required for assay design was performed. Results: Among 1397 pts, 65% (n=910) had sufficient plasma samples and WES performed, and all 910 had successful ctDNA assay testing. Among these 910 pts, the IDFS event rate was 27% (abemaciclib + ET, 23% [101/438]; ET alone, 31% [146/472]). Rates of ctDNA positivity (at baseline and any change from baseline) and associated IDFS events are shown in Table. Among pts with ctDNA positivity, 87% had an IDFS event in comparison to 15% with persistent ctDNA negative (-) status during the study. Conclusions: In a pt subset from monarchE enriched for IDFS events, ctDNA detection was relatively infrequent (<20%); however, its detection at any time during the 24 months of study therapy was adversely prognostic. As compared to pts who had remaining ctDNA positive (+), pts who had clearance of ctDNA on therapy had lower risk of IDFS events, but the event risk still remained clinically meaningful in these pts. Clinical trial information: NCT03155997 . [Table: see text]

Abstract Aims Patients with pulmonary hypertension (PH) are grouped based upon clinical and haemodynamic characteristics. Groups 2 (G2, left heart disease [LHD]) and 3 (G3, lung disease or hypoxaemia) are most common. Many patients display overlapping characteristics of heart and lung disease (G2–3), but this group is not well-characterized. Methods and results Patients with PH enrolled in the prospective, NHLBI-sponsored PVDOMICS network underwent intensive clinical, biomarker, imaging, gas exchange and exercise phenotyping. Patients with pure G2, pure G3, or overlapping G2–3 PH were compared across multiple phenotypic domains. Of all patients with predominant G2 (n = 136), 66 (49%) were deemed to have secondary lung disease/hypoxaemia contributors (G2/3), and of all patients categorized as predominant G3 (n = 172), 41 (24%) were judged to have a component of secondary LHD (G3/2), such that 107 had G2–3 (combined G2/3 and G3/2). As compared with G3, patients with G2 and G2–3 were more obese and had greater prevalence of hypertension, atrial fibrillation, and coronary disease. Patients with G2 and G2–3 were more anaemic, with poorer kidney function, more cardiac dysfunction, and higher N-terminal pro-B-type natriuretic peptide than G3. Lung diffusion was more impaired in G3 and G2–3, but commonly abnormal even in G2. Exercise capacity was severely and similarly impaired across all groups, with no differences in 6-min walk distance or peak oxygen consumption, and pulmonary vasoreactivity to nitric oxide did not differ. In a multivariable Cox regression model, patients with G2 had lower risk of death or transplant compared with G3 (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.30–0.86), and patients with G2–3 also displayed lower risk compared with G3 (HR 0.57, 95% CI 0.38–0.86). Conclusions Overlap is common in patients with a pulmonary or cardiac basis for PH. While lung structure/function is clearly more impaired in G3 and G2–3 than G2, pulmonary abnormalities are common in G2, even when clinically judged as isolated LHD. Further study is required to identify optimal systematic evaluations to guide therapeutic innovation for PH associated with combined heart and lung disease. Clinical Trial Registration: ClinicalTrials.gov NCT02980887.

10015 Background: The Children’s Oncology Group developed and implemented a unified method of dosing anticancer drugs in infants and small children with a BSA < 0.6 m2. The dosing tables use BSA-based dose banding and account for deliverable doses/volumes of the drugs. We studied the PK of VCR (1.5 mg/m2 dose level) in infants and children to determine whether this new infant dosing method achieves uniform drug exposures across the pediatric age span. Methods: We designed a sampling strategy to limit the blood volume required by focusing on the elimination (β) phase of the VCR concentration-time curve, which accounts for > 80% of the total area-under the curve (AUC). Duplicate samples to detect contamination were drawn at 3 post-infusion time points (2, 6-8 and 18-24 hr) through a central venous catheter (CVC) after a 90 min flush. VCR concentrations were measured at the Children’s Hospital of Philadelphia using a validated high-pressure liquid chromatography/tandem mass spectrometry method with a lower limit of quantitation (LLQ) of 0.25 ng/mL. A one-compartment model was fit to the concentration-time data using population PK methods (Phoenix NLME). The AUCβ was derived from the dose and clearance for each patient. Patients were accrued in 4 age groups (≤6 mo, goal n = 20); > 6 mo to ≤12 mo, goal n = 10; > 12 mo to ≤36 mo, goal n = 10; and > 36 mo to ≤12 yr, goal n = 10) to focus on infants and ensure representation across the pediatric age range. Results: 52 eligible patients have been enrolled and 39 are evaluable for PK analysis, including 9 ≤6 mo, 8 > 6 mo and ≤12 mo, 12 > 12 mo and ≤36 mo, and 10 > 36 mo and ≤12 y,. The median (range) age is 13.5 mo (1.15-112 mo). VCR was quantifiable in all samples, and there was no evidence of contamination in the duplicate samples drawn through the CVC. The mean ± SD AUCβ in the 39 evaluable patients was 54.7 ± 19.8 ng⋅h/mL. As shown in the Table, the AUCβ is similar in patients with a BSA < 0.6 m2 dosed according to the BSA-banded infant dosing table and patients with a BSA ≥0.6 m2 dosed by multiplying their BSA times 1.5 mg/m2 (p = 0.53, Mann Whitney test). Conclusions: The VCR BSA-banded infant dosing table appears to provide uniform VCR exposure for infants and young children compared to conventional BSA-based dosing in older children. The study design and sampling strategy facilitated rapid accrual of a young population and generated more VCR PK data in infants within a year than has been published since the drug was approved in 1963. This study demonstrates the feasibility of systematically studying other anticancer drugs in infants and other special populations to ensure they are receiving safe and effective doses. VCR AUCβ by dosing method. Clinical trial information: NCT05359237 . [Table: see text]