Citations

Abstract Title: Real-world analysis of adverse events in patients with triple-negative breast cancer receiving therapy per KEYNOTE-522 Background: KEYNOTE-522 was a randomized, double-blind, placebo-controlled phase 3 trial which resulted in the FDA approval of pembrolizumab with neoadjuvant chemotherapy for patients (pts) with newly diagnosed, high-risk, early-stage triple-negative breast cancer (TNBC). Given the improvement in pathological complete response (pCR) and event-free survival rates, this regimen has emerged as standard-of-care (SOC) therapy. To date, real world outcome analyses are limited. Methods: In this retrospective, multicenter study, we examined pts with early-stage TNBC who received planned treatment per KEYNOTE-522 as SOC. 16 sites were included in the analysis. IRB approval was obtained from each participating site. Number and length of treatment delays, treatment related toxicities (both chemotherapy and immune-related) of all grades, and pCR rate were collected from the electronic medical record of each participating site, and deidentified data were shared for central analysis. Results: 577 pts were included in this analysis. The median age of the cohort was 52 [range 27-77]. 457 pts had T1-2 disease and 139 had T3-4 disease. 316 pts had N0 disease and 261 had N1-3 disease. 506 pts had baseline ECOG 0, 62 had ECOG 1, and 9 had ECOG 2-3. Of the 482 patients who had surgery at the time of this analysis, 219 patients had pCR (54.5%) and 192 pts were still receiving treatment. 217 patients (37%) had an adverse drug event (ADE) causing dose reductions and 228 patients (39.5%) had to discontinue treatment early. There were 360 unplanned care visits, with 91 patients having 2+ visits. 66 patients had hospitalizations due to the regimen with 102 total hospitalizations. 179 (31%) of patients had grade 3+ immune related adverse events (irAEs), including many that are rare and potentially serious. 317 (54%) had an immune related adverse effect (see Table 1). There was no significant difference in the frequency of grade 3+ irAE based on age or body mass index. We observed no difference in residual disease between patients who discontinued treatment early and those who did not. However, if patients had an ADR causing a dose reduction, pts were significantly more likely to have residual disease (P=0.039) Conclusions: In a multicenter real-world analysis, the KEYNOTE-522 regimen was associated with a high frequency of dose reductions, early treatment discontinuations, ER visits, and hospitalizations. This may have accounted for a lower pCR rate than observed in the landmark clinical trial. Most grade 3+ irAEs occurred at greater frequency in our real-world analysis. Providers should carefully monitor for toxicity to ensure optimal patient outcomes. Table 1 Citation Format: Mara Hofherr, Katherine Clifton, Spenser January, Emily Owen, Farah Raheem, Lida A. Mina, Suganya Arunachalam Karikalan, Lauren Lyons, Meredith Watson Rose, Katherine Madden, Jerline Hsin, Aimee Keegan, Wai Yu, Shawna Kraft, Allison Schepers, Emily Armgardt, Douglas Mazewski, Alison Svoboda, Kayla Harwood, Jodi Taraba, Yonatan Resnick, Shelly Hummert, Lisa Grate, Sidney Keisner, Jacob Hobbs, Todd Davis, Kristin Bastian, Dawn Minikel, Traci White, William Adler, Avneek Singh Sandu, Fouad Boulbol, Kelsey Finch, Andrew Davis. Real-World Analysis of Adverse Events in Patients with Triple Negative Breast Cancer Receiving Therapy per KEYNOTE-522 [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 PS14-06.

ObjectivesTo evaluate the effect of Alzheimer's disease (AD) ‐related biomarker change on clinical features, brain atrophy and functional connectivity of patients with corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP).MethodsData from patients with a clinical diagnosis of CBS, PSP, and AD and healthy controls were obtained from the 4‐R‐Tauopathy Neuroimaging Initiative 1 and 2, the Alzheimer's Disease Neuroimaging Initiative, and a local cohort from the Toronto Western Hospital. Patients with CBS and PSP were divided into AD‐positive (CBS/PSP‐AD) and AD‐negative (CBS/PSP‐noAD) groups based on fluid biomarkers and amyloid PET scans. Cognitive, motor, and depression scores; AD fluid biomarkers (cerebrospinal p‐tau, t‐tau, and amyloid‐beta, and plasma ptau‐217); and neuroimaging data (amyloid PET, MRI and fMRI) were collected. Clinical features, whole‐brain gray matter volume and functional networks connectivity were compared across groups.ResultsData were analyzed from 87 CBS/PSP‐noAD and 23 CBS/PSP‐AD, 18 AD, and 30 healthy controls. CBS/PSP‐noAD showed worse performance in comparison to CBS/PSP‐AD in the PSPRS [mean(SD): 34.8(15.8) vs 23.3(11.6)] and the UPDRS scores [mean(SD): 34.2(17.0) vs 21.8(13.3)]. CBS/PSP‐AD demonstrated atrophy in AD signature areas and brainstem, while CBS/PSP‐noAD patients displayed atrophy in frontal and temporal areas, globus pallidus, and brainstem compared to healthy controls. The default mode network showed greatest disconnection in CBS/PSP‐AD compared with CBS/PSP‐no AD and controls. The thalamic network connectivity was most affected in CBS/PSP‐noAD.InterpretationAD biomarker positivity may modulate the clinical presentation of CBS/PSP, with evidence of distinctive structural and functional brain changes associated with the AD pathology/co‐pathology. ANN NEUROL 2024;96:99–109

Abstract Introduction This is a case of a revision of a three-piece penile prosthesis in a 53-year-old gentleman who had received an infrapubic implantable penile prosthesis (IPP) in Turkey over 12 months ago. He complained of an unsupported floppy shaft when the prosthesis was inflated, as well as a right hemi scrotal bulging which was exacerbated by activity but showed no signs of infection. A hydrocele had occurred 2 months following the IPP insertion and was confirmed on imaging. The MRI showed the pump within the hydrocele. He had previously had a laparoscopy gastric banding and a bilateral inguinal hernia repair with mesh. Objective Video to demonstrate the surgical case Methods This is a video demonstrating the steps of this operation. The procedure started with a transverse penoscrotal incision and dissection through the dartos muscle. The initial corporotomy allowed removal of the first cylinder of the prosthesis. Upon removing the right cylinder, the hydrocele was opened to reveal the presence of turbid fluid, 150ml of fluid was aspirated and sent for microbiology investigations. The next stage involved removal of the left cylinder and 7.5cm of rear-tip extenders (RTE) were subsequently removed intact, with further RTE from the right removed separately using a nasal speculum. Therefore, a 20cm IPP was removed with 7.5cm RTE on each side. An antibiotic salvage wash (Rifampicin/Gentamicin) was performed several times. At this point a 26cm + 1cm (13mm) malleable prosthesis was inserted as a spacer. The previous infrapubic wound was opened to remove the reservoir, 75ml of fluid was aspirated from around the reservoir prior to removal. Attempts are made to identify a possible fistula with flexible cystoscopy, but normal urethra, bladder neck and bladder are seen. Giving no evidence of any fistula into the abdominal cavity or urethral injury to explain fluid in the corporal cavities or around the components of the prosthesis. Methylene blue and distention were also used to attempt to identify a bladder leak, however this was also unremarkable. A suprapubic catheter was inserted to ensure the decompression of the urinary system to allow any small/undetected leaks to heal. This was done under direct vision using a cystoscope prior to being secured. Results The patient had a replacement of the inflatable penile prosthesis to a malleable prosthesis, a suprapubic catheter inserted and a drainage of his hydrocele. The patient recovered well from surgery and on examination the prosthesis tips were seated nicely in the glans. The fluid microbiology culture did not grow any organism. A subsequent cystogram showed no signs of any bladder leak. The patient was happy with the outcome and underwent a trial without catheter. He has a planned review and will be considered for an exchange to an inflatable device at this time. Conclusions This is an unusual presentation of a hydrocele, in the absence of any infective symptoms which is suggestive of a contained urine leak and even a missed bladder injury from the first prosthesis surgery. However, no fistula was found during the surgery or the post-operative cystogram. Disclosure No.

Background: Following the adoption of new nomenclature for steatotic liver disease, we aimed to build consensus on the use of International Classification of Diseases codes and recommendations for future research and advocacy. Methods: Through a two-stage Delphi process, a core group (n = 20) reviewed draft statements and recommendations (n = 6), indicating levels of agreement. Following revisions, this process was repeated with a large expert panel (n = 243) from 73 countries. Results: Consensus ranged from 88.8% to 96.9% (mean = 92.3%). Conclusions: This global consensus statement provides guidance on harmonizing the International Classification of Diseases coding for steatotic liver disease and future directions to advance the field.

Abstract Oligodendroglioma is characterized by oligodendrocyte-like histology, mutation in the IDH genes, along with codeletion of chromosome arms 1p and 19q. Treatment for oligodendrogliomas combines surgery, followed by observation, and chemotherapy and/or radiotherapy when tumors progress. Most oligodendrogliomas eventually recur with a more aggressive phenotype, leading to patient mortality but molecular mechanisms remain poorly understood. To investigate the molecular trajectory of oligodendroglioma, we collected more than 270 longitudinal samples from over 130 oligodendroglioma patients, to perform whole genome or whole exome sequencing, bulk RNA, and single-nucleus RNA sequencing (n = 30 samples). Common mutations in IDH1/2, TERT promoter, CIC, and FUBP1 were observed. About half of the CIC and FUBP1 mutations occurred in the initial sample and persisted stably throughout recurrence. The majority of PIK3CA and PIK3R1 mutations were either shared or present in recurrences only implicating the PI3K pathway in oligodendroglioma recurrence. Mutational signature analysis revealed 34.5% of tumors treated with alkylating agents acquired SBS11/SBS31 associated hypermutation. By integrating signatures with clonality estimates, we approximated the timing of mutational processes and found that clonal timings of treatment related mutations correlate with the treatment administration date. We found that aging signature-related mutations were mostly clonal, and treatment signature-related mutations were more likely to be sub-clonal, supporting the late emergence of these mutations following treatment. We observed increased somatic copy number alterations in oligodendroglioma recurrences, reflected in notable chromosome 4 losses. Associating treatment with snRNAseq derived cellular states, we observed a significant increase in the fraction of proliferating stem-like cells in the hypermutator versus non-hypermutator recurrent samples. These findings shed light on the molecular changes occurring in oligodendrogliomas following treatment and provide insights that may aid in targeting treatment resistance.

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Background and Aims: Aldafermin, an engineered analog of the human hormone FGF19, improves liver histology in patients with noncirrhotic NASH; however, its efficacy and safety in compensated cirrhosis is unknown. No drug has yet to demonstrate benefit in the compensated NASH population. Approach and Results: In this multicenter, double-blind, placebo-controlled, phase 2b trial, 160 patients with compensated NASH cirrhosis were randomized to aldafermin 0.3 mg (n = 7), 1 mg (n = 42), 3 mg (n = 55), or placebo (n = 56) for 48 weeks. The 0.3 mg group was discontinued to limit exposure to suboptimal doses. The primary end point was a change in Enhanced Liver Fibrosis from baseline to week 48. The analyses were performed in the intention-to-treat population. At week 48, the least-squares mean difference in the change in Enhanced Liver Fibrosis was −0.5 (95% CI, −0.7 to −0.2; p = 0.0003) between the 3 mg group and the placebo group. 15%, 21%, and 23% of patients in the placebo, 1 mg, and 3 mg group, respectively, achieved fibrosis improvement ≥ 1 stage; and 13%, 16%, and 20% achieved fibrosis improvement ≥ 1 stage without NASH worsening. Improvement in alanine aminotransferase, aspartate aminotransferase, neoepitope-specific N-terminal pro-peptide of type III collagen, and liver stiffness favored aldefermin groups over placebo. Diarrhea was the most frequent adverse event, occurring at 26% and 40% in the 1 mg and 3 mg groups, respectively, compared to 18% in the placebo group. Overall, 0%, 2%, and 9% of patients in the placebo, 1 mg, and 3 mg group, respectively, discontinued due to treatment-related adverse events. Conclusions: Aldafermin 3 mg resulted in a significant reduction in Enhanced Liver Fibrosis in patients with compensated NASH cirrhosis.

AbstractINTRODUCTIONDelay in diagnosis of posterior cortical atrophy (PCA) syndrome is common, and the lack of familiarity with assessment tools for identifying visual cortical dysfunction is a contributing factor. We propose recommendations for the approach to the evaluation of PCA clinical features during the office visit, the neuropsychological evaluation, and the research setting. A recommended screening battery for eye clinics is also proposed.METHODSRecommendations were developed using results from a web‐based survey of members of Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) Atypical Alzheimer's Disease Professional Interest Area (PIA), literature review, and consensus by the PCA assessment working party of the Atypical Alzheimer's Disease PIA.RESULTSSurvey results revealed robust agreement for assessment tool preferences for PCA features, and many respondents indicated that they reserve assessment tools for use only when PCA is suspected. For some PCA features, curated tools were preferred over validated battery tools, particularly for the office visit. Consensus recommendations superseded survey preferences for two core cognitive features within the 2017 PCA diagnostic criteria.DISCUSSIONThese consensus recommendations provide an evaluation framework for PCA clinical features and can facilitate timely and accurate recognition and diagnosis of PCA. Broader use of these tools should be sought, and development and validation of novel PCA clinical outcome assessments are needed to improve our understanding of atypical AD and other dementias and support the inclusion of those with PCA in treatment trials.