Citations

Abstract Background: SG was approved in 2020 for the treatment of metastatic triple negative breast cancer (TNBC). The most common grade 3/4 adverse event in the ASCENT trial was neutropenia (51.2%) with a 6% incidence of febrile neutropenia. 1 Package insert recommendations do not endorse primary prophylactic growth factor support, rather only initiating if severe neutropenia occurs on treatment.2 Objective: This study retrospectively reviewed the utilization of growth factor support in patients (pts) with metastatic TNBC initiated on SG at each Mayo Clinic Enterprise site. Methods: We performed a multi-center, retrospective review of all pts with TNBC who received SG from January 2021 to December 2021 at Mayo Clinic sites in Minnesota, Florida, Arizona, and its community-based health system network. Data collected included history of neutropenia with previous cycles of SG resulting in a treatment delay, number of cycles, grade of neutropenia and cycle/day of treatment plan when growth factor added. Pts who received only one dose of SG were excluded. The Fisher’s exact test was utilized to compare the difference in the use of primary prophylaxis between sites. Results: 67 pts received at least two doses of SG. Within this cohort, 42 pts (63%) received growth factor support during treatment with SG. Growth factor support was most often added during the first two cycles (59.5%). A total of 12 patients initiated growth factor with no history of delays related to neutropenia and without neutropenia at the time of administration. Eleven of these pts had growth factor support added on Cycle 1 as primary prophylaxis. Primary prophylaxis was most common at Mayo Clinic – Rochester compared to the other sites (Table 1), however there was not a statistically significant difference (p=0.27). There were 26 pts (39%) with a treatment delay due to neutropenia while receiving SG, of which 21 (81%) were managed with the addition of growth factor (13 pegfilgrastim, 8 filgrastim). The median number of cycles for all pts was 5 (range: 1-25). Pts who received growth factor were treated with a median of 5 cycles (range: 1-25) and pts who did not receive growth factor were treated with a median of 4 cycles (range: 1-19) (p=0.10). Conclusions: We observed wide variability in the use of prophylactic growth factor between Mayo Clinic sites with SG. The optimal practice of growth factor use with SG warrants further exploration. References: 1. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541 2. Immunomedics, Inc. Trodelvy (sacituzumab govitecan-hziy) [package insert]. Foster City, CA: Gilead Sciences; 2020. Table 1: Grade of neutropenia for patients receiving SG when growth factor initiated Citation Format: Kaylee Clark, Jamie L. Carroll, Alvaro Moreno-Aspitia, Brenda Ernst, Farah Raheem, Ashley Heil, Beth Boyer, Kristin Mara, Matthew P. Goetz, Roberto A. Leon-Ferre, Karthik V. Giridhar, Jodi Taraba. Mayo Clinic Enterprise patterns of growth-factor utilization for sacituzumab govitecan (SG)-induced neutropenia among patients with metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-56.

Abstract Erdheim-Chester disease (ECD) and Rosai-Dorfman disease (RDD) are rare non-Langerhans cell histiocytoses (non-LCHs), for which therapeutic options are limited. MAPK pathway activation through BRAFV600E mutation or other genomic alterations is a histiocytosis hallmark and correlates with a favorable response to BRAF inhibitors and the MEK inhibitor cobimetinib. However, there has been no systematic evaluation of alternative MEK inhibitors. To assess the efficacy and safety of the MEK inhibitor trametinib, we retrospectively analyzed the outcomes of 26 adult patients (17 with ECD, 5 with ECD/RDD, 3 with RDD, and 1 with ECD/LCH) treated with orally administered trametinib at 4 major US care centers. The most common treatment-related toxicity was rash (27% of patients). In most patients, the disease was effectively managed at low doses (0.5-1.0 mg trametinib daily). The response rate of the 17 evaluable patients was 71% (73% [8/11] without a detectable BRAFV600E achieving response). At a median follow-up of 23 months, treatment effects were durable, with a median time-to-treatment failure of 37 months, whereas the median progression-free and overall survival were not reached (at 3 years, 90.1% of patients were alive). Most patients harbored mutations in BRAF (either classic BRAFV600E or other BRAF alterations) or alterations in other genes involved in the MAPK pathway, eg, MAP2K, NF1, GNAS, or RAS. Most patients required lower than standard doses of trametinib but were responsive to lower doses. Our data suggest that the MEK inhibitor trametinib is an effective treatment for ECD and RDD, including those without the BRAFV600E mutation.

Abstract Background and Purpose Artifact from cochlear implant electrodes degrades image resolution on CT. Here, we describe the use of coregistered pre‐ and postoperative CT images to reduce metallic artifact from the electrodes to assess its position more accurately within the cochlear lumen. Methods Pre‐ and postoperative CTs were reviewed after coregistration/overlay of both exams. Images were evaluated by two neuroradiologists for scalar location of electrodes tip (± scalar translocation), tip fold over, and angular depth of insertion. Results Thirty‐four patients were included in the final cohort. Transscalar migration was present in three (8.8%) cases (one case demonstrated tip fold over), with initial disagreement regarding transscalar migration in 1 out of 34 patients (2.9%). Agreement regarding depth of insertion was present in 31 (91.1%) cases. Five‐point Likert scales were used to compare the ability to resolve the proximity of electrodes to the lateral/outer cochlear wall without and with overlay, which is a qualitative measure of artifact from the array. Likert scores showed definitive benefit of metal artifact reduction using overlayed images with an average score of 4.34. Conclusion This study demonstrates a novel technique of using fused coregistration of pre‐ and postoperative CTs for the purpose of artifact reduction/electrode localization. It is anticipated that this technique will permit more accurate localization of the electrodes for improvement in surgical technique and electrode array design.

AbstractPurposeAnterior cruciate ligament tears and anterior cruciate ligament reconstruction (ACLR) are common in young athletes. The modifiable and non‐modifiable factors contributing to ACLR failure and reoperation are incompletely understood. The purpose of this study was to determine ACLR failure rates in a physically high‐demand population and identify the patient‐specific risk factors, including prolonged time between diagnosis and surgical correction, that portend failure.MethodsA consecutive series of military service members with ACLR with and without concomitant procedures (meniscus [M] and/or cartilage [C]) done at military facilities between 2008 and 2011 was completed via the Military Health System Data Repository. This was a consecutive series of patients without a history of knee surgery for two years prior to the primary ACLR. Kaplan–Meier survival curves were estimated and evaluated with Wilcoxon test. Cox proportional hazard models calculated hazard ratios (HR) with 95% confidence intervals (95% CI) to identify demographic and surgical factors that influenced ACLR failure.ResultsOf the 2735 primary ACLRs included in the study, 484/2,735 (18%) experienced ACLR failure within four years, including (261/2,735) (10%) undergoing revision ACLR and (224/2,735) (8%) due to medical separation. The factors that increased failure include Army Service (HR 2.19, 95% CI 1.67, 2.87), > 180 days from injury to ACLR (HR 1.550, 95% CI 1.157, 2.076), tobacco use (HR 1.429 95% CI 1.174, 1.738), and younger patient age (HR 1.024, 95% CI 1.004, 1.044).ConclusionThe overall clinical failure rate of service members with ACLR is 17.7% with minimum four‐year follow‐up, where more patients are likely to fail due to revision surgery than medical separation. The cumulative probability of survival at 4 years was 78.5%. Smoking cessation and treating ACLR patients promptly are modifiable risk factors impacting either graft failure or medical separation.Level of evidenceLevel III.

This review article summarizes the basic principles of vascular anatomy, physiology, diagnostic work-up and treatment for patients with nontraumatic upper extremity vascular disorders. Vascular disorders can be considered vasospastic or occlusive. The most commonly encountered vasospastic condition is Raynaud’s Phenomenon secondary to scleroderma. While historically this has been managed medically with vasodilators, more advanced cases can benefit from surgical treatment to improve blood flow and minimize tissue loss, with compelling evidence that earlier surgical intervention can modify disease process and should be considered. Occlusive disease can present as aneurysm or thrombosis and often requires surgical treatment with resection of the occluded segment with or without vascular reconstruction. In advanced atherosclerotic disease or end stage ischemia, arterialization of the venous system can be considered to avoid more proximal amputations.

Abstract Objective To assess preferences among adults with migraine for differentiating attributes of injected or infused preventive treatment options and evaluate their importance in determining a treatment choice. Background Adults with migraine and health‐care providers consider many factors when making treatment decisions. Injected or infused preventive migraine treatment options differ in several attributes, including mode of administration and dosing frequency, which may be preferentially selected or avoided by patients. Understanding a patient's preference is important for clinicians as they advise on various treatment options. Methods A total of 604 US adults diagnosed with migraine participated in an online survey that captured information on demographics, migraine history, and treatment preferences. A discrete choice experiment (DCE) was used to evaluate participants’ preferences for specific attributes of injected/infused preventive migraine therapies. The DCE data were utilized to estimate attribute importance (expressed as a percentage) and identify subgroups that had different distributions of preferences. Results In the overall migraine population, mode of administration (28.8%), durability of effectiveness (27.0%), and speed of onset (25.5%) had the highest relative importance, whereas administration setting (9.9%) and dosing frequency (8.8%) had the lowest. Four distinct subgroups were identified: Group 1 ( n = 128) preferred self‐injection administration and durability of effectiveness; Group 2 ( n = 189) expressed aversion to cranial injections; Group 3 ( n = 158) prioritized rapid speed of onset; and Group 4 ( n = 129) favored health‐care provider administration and durability of effectiveness. Conclusions Speed of onset, durability of effectiveness, and mode of administration are key moderators of treatment preference among US adults with migraine. Certain segments of the migraine population prioritize specific treatment attributes over others, with intravenous infusion not considered a barrier in three of four identified segments. Clinicians can best help their patients find the right medication if they understand which medication attributes are most and least important to them.

Carcinoma-associated fibroblasts (CAFs) play an important role in the progression of multiple malignancies. Secretion of cytokines and growth factors underlies the pro-tumoral effect of CAFs. Although this paracrine function has been extensively documented, the molecular mechanisms controlling the expression of these factors remain elusive. In this study, we provide evidence of a novel CAF transcriptional axis regulating the expression of SDF1, a major driver of cancer cell migration, involving the transcription factor GLI1 and histone acetyltransferase p300. We demonstrate that conditioned media from CAFs overexpressing GLI1 induce the migration of pancreatic cancer cells, and this effect is impaired by an SDF1-neutralizing antibody. Using a combination of co-immunoprecipitation, proximity ligation assay and chromatin immunoprecipitation assay, we further demonstrate that GLI1 and p300 physically interact in CAFs to co-occupy and drive SDF1 promoter activity. Mapping experiments highlight the requirement of GLI1 N-terminal for the interaction with p300. Importantly, knockdowns of both GLI1 and p300 reduce SDF1 expression. Further analysis shows that knockdown of GLI1 decreases SDF1 promoter activity, p300 recruitment, and levels of its associated histone marks (H4ac, H3K27ac, and H3K14ac). Finally, we show that the integrity of two GLI binding sites in the SDF1 promoter is required for p300 recruitment. Our findings define a new role for the p300–GLI1 complex in the regulation of SDF1, providing new mechanistic insight into the molecular events controlling pancreatic cancer cells migration.

Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in TMEM161B , which encodes a multi-pass transmembrane protein of unknown function. Tmem161b null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. Tmem161b depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret models, including leading to abnormal gyration in the ferret model. Tmem161b localizes non-exclusively to the primary cilium, and scanning electron microscopy revealed shortened, dysmorphic, and ballooned ventricular zone cilia in the Tmem161b null mouse, suggesting that the Shh-related phenotypes may reflect ciliary dysfunction. Our data identify TMEM161B as a regulator of cerebral cortical gyration, as involved in primary ciliary structure, as a regulator of Shh signaling, and further implicate Shh signaling in human gyral development.