Citations

Abstract We investigated the extent of access to Meckel's cave (MC) and the middle cranial fossa (MCF) protecting the internal carotid artery (ICA) using the retrosigmoid approach with endoscopic-assisted reverse anterior petrosectomy (EA-RAP). Five specimens were dissected using the limited and extended EA-RAP. Based on the bone removal of the internal acoustic meatus (IAM) and subarcuate fossa, exposure of the MC and ICA were statistically compared. The limited and extended EA-RAP allowed access to the medial and anterior MC (4 mm posterior to the first genu of the cavernous ICA, and 20 mm posterior to foramen rotundum [FR]). The access to the lateral MC varied with distance of 12 and 8 mm medial to the foramen ovale for the limited and extended EA-RAP, respectively. In the extended EA-RAP, the exposure of the ICA was gained by drilling with the 0-degree endoscope (3 mm) versus 45-degree endoscope (9 mm). The working distances from the midpoint of the IAM to the most medial point of the exposed ICA was 24 mm. The most lateral point of the exposed ICA varied between 0- and 45-degree endoscopes with a distance of 21 and 13 mm, respectively. A coronal plane from the posterior genu of the cavernous ICA and a sagittal plane to the common crus of the semicircular canals can define the area of MCF accessed by the EA-RAP. Drilling of the temporal bone should be carefully customized according to the patient and can be aided by endoscopic assistance for direct visualization to minimize the risk of injuries to ICA.

BACKGROUND AND OBJECTIVE: Endoscopic endonasal approaches to treat cavernous sinus lesions require detailed knowledge of the origin, course, and anatomic variations of the branches of the cavernous internal carotid artery (cICA) because inadvertent avulsion can cause intraoperative ICA injury. We aim to study the origin and course of the branches of the cICA from an endoscopic endonasal perspective and relate these branches to surgically relevant anatomic references. METHODS: Sixty sides of 30 formalin-fixed specimens were dissected to identify the origin and course of cICA branches, including the inferolateral trunk (ILT), the meningohypophyseal trunk (MHT), anterior and inferior McConnell's capsular arteries (MCAs), and the superolateral trunk (SLT). RESULTS: The ILT and MHT were bilaterally in all specimens, whereas the anterior and inferior MCAs were identified in 28% and 25% of dissected sides, respectively. The SLT was only found in 3% of sides dissected. The MHT was the most proximal branch of the cICA, and its origin was an average of 8.9 mm anterior to the foramen lacerum and 3.8 mm superior to the sellar floor. The ILT was the second most proximal branch of the cICA, which originated 6.4 mm from the MHT on average. The anterior and inferior MCAs were present in 28% and 25% of specimens, respectively. The SLT, when present, was the second most proximal branch of the cICA, which originated at a mean height of 2.7 mm from the sellar floor. Overall, complete ILT and MHT were identified in 68% and 77% of cases, respectively. CONCLUSION: The MHT and ILT are constant branches of the cICA, with the MHT originating from the medial cICA posterior bend 4 mm superior to the sellar floor and 9 mm anterior to the foramen lacerum, whereas the ILT arises from the lateral horizontal cICA, 2.3 mm superior to the sellar floor and 6 mm anterior to the MHT.

Abstract Purpose: Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor signaling inhibitors (ARSI) is often lethal. Liquid biopsy biomarkers for this deadly form of disease remain under investigation, and underpinning mechanisms remain ill-understood. Experimental Design: We applied targeted cell-free DNA (cfDNA) sequencing to 126 patients with mCRPC from three academic cancer centers and separately performed genome-wide cfDNA methylation sequencing on 43 plasma samples collected prior to the initiation of first-line ARSI treatment. To analyze the genome-wide sequencing data, we performed nucleosome positioning and differential methylated region analysis. We additionally analyzed single-cell and bulk RNA sequencing data from 14 and 80 patients with mCRPC, respectively, to develop and validate a stem-like signature, which we inferred from cfDNA. Results: Targeted cfDNA sequencing detected AR/enhancer alterations prior to first-line ARSIs that correlated with significantly worse progression-free survival (P = 0.01; HR = 2.12) and overall survival (P = 0.02; HR = 2.48). Plasma methylome analysis revealed that AR/enhancer lethal mCRPC patients have significantly higher promoter-level hypomethylation than AR/enhancer wild-type mCRPC patients (P < 0.0001). Moreover, gene ontology and CytoTRACE analysis of nucleosomally more accessible transcription factors in cfDNA revealed enrichment for stemness-associated transcription factors in patients with lethal mCRPC. The resulting stemness signature was then validated in a completely held-out cohort of 80 patients with mCRPC profiled by tumor RNA sequencing. Conclusions: We analyzed a total of 220 patients with mCRPC, validated the importance of cell-free AR/enhancer alterations as a prognostic biomarker in lethal mCRPC, and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness. See related commentary by Nawfal et al., p. 7

Abstract We conducted this systematic review and meta-analysis to clarify the trend of precocious puberty (PP) incidence after the COVID-19 outbreak and explore potential contributing factors, such as age at presentation and body mass index (BMI) SD score (SDS). Children visiting pediatric endocrinology clinics for the first time for suspected PP were included. We searched databases until February 28, 2023, for studies reporting various indicators of PP incidence before and during the pandemic. Total numbers of events and observations were recorded. A meta-analysis was performed to compare the odds of PP, BMI SDS, and age at presentation between the 2 periods. The dose-response relationships between time points (by number of years away from the pandemic) and PP risk were explored. In summary, a total of 32 studies including 24 200 participants were recruited. The COVID-19 pandemic was associated with the increasing odds of PP among children referred for a suspicious condition (odds ratio = 1.96; 95% CI, 1.56-2.47; I2 = 54%; P < .001). Sensitivity analysis confirmed the robustness of the findings. The BMI SDS did not vary between the 2 periods, whereas age at presentation was lower after the pandemic. Precocious puberty incidence increased more rapidly during the pandemic period than during the prepandemic period. Trial registration: International Prospective Register of Systematic Reviews (PROSPERO; identifier: CRD42023402212)

AbstractMulti‐energy computed tomography (MECT) offers the opportunity for advanced visualization, detection, and quantification of select elements (e.g., iodine) or materials (e.g., fat) beyond the capability of standard single‐energy computed tomography (CT). However, the use of MECT requires careful consideration as substantially different hardware and software approaches have been used by manufacturers, including different sets of user‐selected or hidden parameters that affect the performance and radiation dose of MECT. Another important consideration when designing MECT protocols is appreciation of the specific tasks being performed; for instance, differentiating between two different materials or quantifying a specific element. For a given task, it is imperative to consider both the radiation dose and task‐specific image quality requirements. Development of a quality control (QC) program is essential to ensure the accuracy and reproducibility of these MECT applications. Although standard QC procedures have been well established for conventional single‐energy CT, the substantial differences between single‐energy CT and MECT in terms of system implementations, imaging protocols, and clinical tasks warrant QC tests specific to MECT. This task group was therefore charged with developing a systematic QC program designed to meet the needs of MECT applications. In this report, we review the various MECT approaches that are commercially available, including information about hardware implementation, MECT image types, image reconstruction, and postprocessing techniques that are unique to MECT. We address the requirements for MECT phantoms, review representative commercial MECT phantoms, and offer guidance regarding homemade MECT phantoms. We discuss the development of MECT protocols, which must be designed carefully with proper consideration of MECT technology, imaging task, and radiation dose. We then outline specific recommended QC tests in terms of general image quality, radiation dose, differentiation and quantification tasks, and diagnostic and therapeutic applications.

Breast cancer is treated with a multidisciplinary approach involving surgical oncology, radiation oncology, and medical oncology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget’s disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of systemic therapy (preoperative and adjuvant) options for nonmetastatic breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org .

PURPOSE Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)–positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need. METHODS In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia. RESULTS After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively. CONCLUSION Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.

Abstract Objectives Precise literature recommendation and summarization are crucial for biomedical professionals. While the latest iteration of generative pretrained transformer (GPT) incorporates 2 distinct modes—real-time search and pretrained model utilization—it encounters challenges in dealing with these tasks. Specifically, the real-time search can pinpoint some relevant articles but occasionally provides fabricated papers, whereas the pretrained model excels in generating well-structured summaries but struggles to cite specific sources. In response, this study introduces RefAI, an innovative retrieval-augmented generative tool designed to synergize the strengths of large language models (LLMs) while overcoming their limitations. Materials and Methods RefAI utilized PubMed for systematic literature retrieval, employed a novel multivariable algorithm for article recommendation, and leveraged GPT-4 turbo for summarization. Ten queries under 2 prevalent topics (“cancer immunotherapy and target therapy” and “LLMs in medicine”) were chosen as use cases and 3 established counterparts (ChatGPT-4, ScholarAI, and Gemini) as our baselines. The evaluation was conducted by 10 domain experts through standard statistical analyses for performance comparison. Results The overall performance of RefAI surpassed that of the baselines across 5 evaluated dimensions—relevance and quality for literature recommendation, accuracy, comprehensiveness, and reference integration for summarization, with the majority exhibiting statistically significant improvements (P-values <.05). Discussion RefAI demonstrated substantial improvements in literature recommendation and summarization over existing tools, addressing issues like fabricated papers, metadata inaccuracies, restricted recommendations, and poor reference integration. Conclusion By augmenting LLM with external resources and a novel ranking algorithm, RefAI is uniquely capable of recommending high-quality literature and generating well-structured summaries, holding the potential to meet the critical needs of biomedical professionals in navigating and synthesizing vast amounts of scientific literature.

Abstract BACKGROUND: Anti-HER2 therapies have transformed the trajectory for patients with HER2-positive (HER2+) MBC. A subset of patients with HER2+ MBC do exceptionally well and remain on maintenance anti-HER2 therapy for many years. However, current therapy is non-curative and patients are treated indefinitely. While these therapies often are well-tolerated, they may cause significant toxicities, are expensive, and typically require frequent infusion and provider visits. Case reports and retrospective series demonstrate that some patients may do well after stopping anti-HER2 treatment. We currently lack prospective data on the likelihood of clinical impact of successful treatment discontinuation, outcomes among patients who progress and restart HER2-directed therapy, and tools to predict who may safely stop therapy. In this study, we will enroll pts with an exceptional response to anti-HER2 therapy. Pts may elect to either continue or stop anti-HER2 therapy and will be followed clinically and radiographically on a protocol-specified schedule. Considering the central role of patients in choosing the study intervention arm, and the unique nature of stopping therapy as a treatment intervention, patient advocates have been deeply involved in the study design to ensure patient concerns are being heard and addressed. We will retrospectively assess minimal residual disease (MRD), measured in plasma, as a biomarker of ongoing response, in a step toward shifting the treatment paradigm for pts with HER2+ MBC. METHODS: STOP-HER2 is a prospective, non-randomized, phase II, multicenter study of either continuation (cohort 1) or cessation (cohort 2) of anti-HER2 therapy in exceptional responders with HER2+ MBC. Eligible patients must have biopsy-proven HER2+ MBC by ASCO/CAP guidelines and must have been receiving first-line anti-HER2 therapy for MBC for at least 3 years without evidence of progressive disease (PD) as determined by the treating investigator. Patients with prior brain-only PD or oligo-PD outside the brain are eligible at least 2 years after local treatment to the central nervous system (CNS) and in absence of subsequent PD. Up to fifty-two participants will be enrolled into cohort 2, and an additional thirty participants enrolled into the cohort 1, at 10 US sites within the Translational Breast Cancer Research Consortium. Co-primary endpoints are the 1-year progression-free survival (PFS) in cohorts 2 and 1, separately. Secondary endpoints include the clinical benefit rate upon re-initiation of anti-HER2 therapy for patients in cohort 2 experiencing PD after treatment discontinuation; and 3-year overall survival in both cohorts. Correlative endpoints include MRD status at baseline and the correlation between MRD dynamics and outcomes. Patient-reported outcomes will be collected and analyzed, including quality of life, illness intrusiveness, financial toxicity, anxiety, and decision regret. The study will use a two-stage design to assess the primary objective of estimating the rate of participants who are free of progression at one year after discontinuing anti-HER2 therapy. If 50% or less are free of progression at one year, stopping HER2 therapy would not be considered a viable treatment plan (null hypothesis). The study is designed to have 80% power to reject the null hypothesis at the 10% type I error rate when 68% of exceptional responders are free of progression at one year after stopping HER2 therapy. STOP-HER2 began enrollment in Q2 2023 (NCT05721248). Citation Format: Heather Parsons, Kathryn Ruddy, Stefania Morganti, Karen Smith, Victoria Attaya, Eliza Kallfelz, Michelle DeMeo, Jamie LaScala, Shirley Mertz, Teri Pollastro, Patricia Spears, Adam Brufsky, Chau Dang, Susan Dent, Ahmed Elkhanany, WIlliam Gwin, Ciara O'Sullivan, Kathy Miller, Sara Nunnery, Elaine Walsh, Anna Maria Storniolo, Sara Tolaney, Nabihah Tayob, Antonio Wolff, Eric Winer, Mothaffar Rimawi, Ian Krop, Nancy Lin. The STOP-HER2 Trial: A Phase 2 Study of Stopping Trastuzumab - Outcomes in Patients with HER2+ Metastatic Breast Cancer (TBCRC 062) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-01.

Introduction: In the current study, we examined the temporal trends in mortality across gender, race, and 10-year age groups over last two-decades. Methods: We conducted a retrospective population-based study using Centers for Disease Control and Prevention database. Subjects with underlying cause of death from AMI were identified using validated ICD10 codes. Age adjusted mortality rates were calculated for gender and race whereas crude rates were calculated for 10-year age group. Using Poisson regression, we estimated the rate ratio between race/ethnicity pairs adjusting for age and sex in order to analyze temporal trend. Results: We identified 2,709,173 subjects with reported underlying cause of death as AMI between January-2000 to December-2019 of which 54.7% were males (n=1,483,163). The age adjusted mortality rate per 100,000 was higher in males compared to females (52.4% vs 30.7%, OR: 1.66 [1.45-1.89]). Among ethnicities African American (AA) population had the highest age adjusted mortality rate per 100,000 [Table 1]. As expected, age group >85 years had the highest mortality rate per 100,000 constituting 30% of total deaths (78% of total deaths were noted in >65yr age group). AMI age adjusted mortality rates/100,000 showed significant decline across gender and race with highest decline in female population (66.5% decline). Highest percentage decline in mortality was noted in AA female population (68.2%) whereas in males it was the white population (62%). In females, highest percentage decline in mortality was noted in 75-84 age-group (70%) while it was >85 age-group (67%) in males. Conclusion: Over last two decades there has been a significant decline in AMI mortality rates across gender and race. AA continue to have higher age adjusted mortality rate among both male and female population (38% and 22% respectively). Further studies are needed to identify and provide targeted prevention and intervention strategies in high-risk populations.