Citations

AbstractINTRODUCTIONThis study examined lucid episodes among people living with late‐stage Alzheimer's disease and related dementias (PLWD) and then developed a typology of these episodes to help characterize them.METHODSFamily caregivers of PLWD provided information about witnessed episodes, including proximity to death, cognitive status, duration, communication quality, and circumstances prior to lucid episodes on up to two episodes (caregiver N = 151; episode N = 279). Latent class analysis was used to classify and characterize empirically distinct clusters of lucid episodes.RESULTSFour lucid episode types were identified. The most common type occurred during visits with family and among PLWD who lived > 6 months after the episode. The least common type coincided with family visits and occurred within 7 days of the PLWD's death.DISCUSSIONFindings suggest that multiple types of lucid episodes exist; not all signal impending death; and some, but not all, are precipitated by external stimuli.

320 Background: sRT is used in men with prostate cancer (PC) recurrence following radical prostatectomy (RP) signaled by a persistent or delayed elevation in PSA. It was previously reported that the use of AAT with RT improved cancer control and overall survival (OS). Long-term follow-up (FU) results are presented here. Methods: From 1998to 2003, 760 eligible post-RP patients with Stage pT3N0 or with pT2N0 and positive margins and PSA from 0.2 to 4.0 ng/mL were randomly assigned on a double-blinded, placebo-controlled trial of RT + placebo vs. RT + anti-androgen therapy (AAT) (24 months of bicalutamide, 150mg daily) during and after RT (64.8 Gy in 36 fractions prostate bed). The primary endpoint was OS estimated using Kaplan-Meier method. Time to PC death and metastatic PC (competing risk of death without an event) was estimated using cumulative incidence. The hazard ratio (HR) was obtained using Cox models (OS) and subdistribution HRs (sHRs) used the Fine-Gray model (time to PC death and metastatic PC). All tests are one-sided based on study design. Results: Median FU for surviving patients was 19 years. OS at 18 years was 53% [95% confidence interval (CI): 47-58%] for RT + AAT and 43% [95% CI: 38-48%] for RT + placebo (adjusted HR 0.82 [95% CI: 0.67-1.00], p = 0.025). The 18-year incidence of centrally reviewed PC deaths were 18% [95% CI: 14-22%] RT + AAT and 28% [95% CI: 23-32%] RT + placebo (adjusted sHR = 0.57 [95% CI: 0.42-0.78], p<0.001). The 18-year incidence of metastatic PC was 22% [95% CI: 18-26%] and 31% [95% CI: 26-35%] for AAT and placebo arms respectively with adjusted sHR = 0.59 [95% CI: 0.44-0.80, p<0.001]. Subgroup analyses is shown in the Table. Conclusions: Long term results of 24-month duration AAT during and after sRT are consistent with the primary report with significantly improved long-term OS, reduced incidence of metastatic PC and PC death for RT+AAT. Statistically significant metastatic PC was noted for Gleason score 8-10, study entry PSA>1.5 and margin positive patients and borderline significance was observed in patients with study entry PSA 0.7-1.5. Clinical trial information: NCT00002874 . [Table: see text]

Background: Cenicriviroc (CVC) is a novel, orally administered antagonist of chemokine receptor types 2/5 that has demonstrated antifibrotic activity in a phase 2b study of patients with NASH. This phase 2, open-label, rollover study investigated the long-term safety and tolerability of CVC in patients with NASH and stage 0–4 liver fibrosis. Methods: Eligible patients who completed the phase 2 CENTAUR study or reached a predefined endpoint in the phase 3 AURORA study were rolled over and received open-label CVC 150 mg once daily. Safety assessments were conducted at the start of the study, and patients were seen in the clinic every 3 months until the study sponsor terminated CVC development. Safety endpoints included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, adverse event severity, and clinical laboratory assessments. Results: A total of 167 patients were enrolled, with a median treatment duration of 33.6 months. Before study termination, 36 patients (21.6%) prematurely discontinued the study. Treatment-related TEAEs were reported in 28 patients (16.8%). The most common treatment-related TEAEs were 4 cases of diarrhea (2.4%) and 2 cases each (1.2%) of abdominal pain, nausea, alanine aminotransferase increased, aspartate aminotransferase increased, hypertriglyceridemia, myalgia, pruritus, and rash. The majority of these treatment-related events were mild in intensity, and none were life-threatening. There were no clinically meaningful changes in hepatic function, chemistry, or liver parameters from baseline to the end of the study. Conclusions: In this rollover study, CVC 150 mg once daily was well tolerated in patients with NASH and stage 0–4 liver fibrosis. No new safety signals were reported, and these data further support the safety and tolerability of CVC.

Sickle cell disease (SCD) is a chronic hematologic disorder which causes progressive cerebral arteriopathy beginning in childhood. As a result, arterial ischemic stroke is a major cause of morbidity and mortality in SCD, and SCD is a leading cause of childhood stroke worldwide. Allogenic hematopoietic stem cell transplant (HSCT) may be curative for individuals with SCD. Long-term outcomes and effects are currently being studied. In this report, we describe a child with SCD who presented with arterial ischemic stroke at 6 years of age and was found to have a severe form of cerebral large vessel arteriopathy by catheter-directed angiography. The patient initially underwent revascularization surgery by indirect superficial temporal artery to middle cerebral artery bypass, and 1 year later, he underwent curative HSCT. Approximately 3 years after HSCT, repeat catheter-directed angiography revealed a striking reversal of cerebral large vessel arteriopathy. This article reveals a previously unrecognized and potentially beneficial effect of HSCT that may ameliorate cerebral large vessel arteriopathy and improve cerebrovascular health for children with SCD.

LBA588 Background: Currently, there is no universally accepted first line (1L) therapy for higher grade, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and an unmet medical need remains in these patients (pts). Radioligand therapy (RLT) is an innovative cancer treatment that crosses the traditional domains of systemic, radiation or surgical therapies. The Phase 3 NETTER-2 study (NCT03972488) evaluated [177Lu]Lu-DOTA-TATE (hereafter 177Lu-DOTATATE) as 1L treatment in pts with Grade (G) 2 and G3 advanced GEP-NETs. This is the first trial to assess 1L RLT in any solid tumor. Methods: Eligible pts were newly diagnosed with somatostatin receptor-positive high G2 or G3 (Ki-67 ≥10% and ≤55%) advanced GEP-NETs within the last 6 months prior to enrollment. Pts were randomized (2:1) to receive 4 cycles of 177Lu-DOTATATE (4 × 7.4 GBq) plus 30 mg octreotide long-acting release (LAR) at 8-weekly intervals during 177Lu-DOTATATE treatment then every 4 weeks (177Lu-DOTATATE arm), or 60 mg octreotide LAR every 4 weeks (control arm), stratified by grade (G2 vs G3) and tumor origin (pancreas vs other). The primary endpoint was progression-free survival (PFS), centrally assessed using RECIST 1.1. Objective response rate (ORR), a key secondary endpoint, was tested hierarchically after PFS. Results: Overall, 226 pts were randomized to the 177Lu-DOTATATE (n = 151) or control (n = 75) arms. Most tumors originated in the pancreas (54.4%) or small intestine (29.2%); G3 tumors were reported in 35.0% of pts. Median cumulative dose of 177Lu-DOTATATE was 29.2 GBq, with 87.8% of pts receiving all 4 doses. Median PFS (95% confidence interval [CI]) was significantly prolonged by ~14.3 months from 8.5 months (7.7, 13.8) in the control arm to 22.8 months (19.4, not estimable) in the 177Lu-DOTATATE arm; stratified hazard ratio 0.276 (95% CI: 0.182, 0.418; p < 0.0001). The ORR was significantly higher in the 177Lu-DOTATATE arm (43.0%) vs the control arm (9.3%); stratified odds ratio 7.81 (95% CI: 3.32, 18.4; p < 0.0001). PFS and ORR results were consistent across all pre-specified demographic and prognostic subgroups. Among adverse events of special interest to RLT, G3/4 leukopenia, anemia and thrombocytopenia occurred in ≤3 pts each in the 177Lu-DOTATATE arm. One case of myelodysplastic syndrome was reported (177Lu-DOTATATE arm). Conclusion: 177Lu-DOTATATE significantly prolonged PFS and demonstrated a clinically meaningful ORR, compared with high-dose octreotide LAR, in pts with newly diagnosed advanced G2 and G3 GEP-NETs. Safety was in line with the established profile of 177Lu-DOTATATE. This is the first randomized study to demonstrate efficacy of RLT as 1L treatment in any malignancy and will change clinical practice. Further investigations of RLT as a therapeutic option in other settings is warranted. Clinical trial information: NCT03972488 .

Background Aortic valve calcium score is associated with hemodynamic severity of aortic stenosis. Whether this association is present in calcific mitral stenosis remains unknown. Methods and Results This study was a retrospective analysis of consecutive patients with mitral stenosis secondary to mitral annular calcification (MAC) undergoing transseptal catheterization. All patients underwent invasive mitral valve assessment via direct left atrial and left ventricular pressure measurement. Computed tomography within 1 year of cardiac catheterization and with adequate visualization of the mitral annulus was included. MAC calcium score quantification by Agatston method was obtained offline using dedicated software (Aquarius, TeraRecon, V.4). Median patient age was 66.9±11.2 years, 47% of patients were women, 50% had coronary artery disease, 40% had atrial fibrillation, 47% had prior cardiac surgery, and 33% had prior chest radiation. Median diastolic mitral valve gradient was 9.4±3.4 mm Hg on echocardiography and 8.5±4 mm Hg invasively. Invasive median mitral valve area using the Gorlin formula was 1.87±0.9 cm 2 . Median MAC calcium score for the cohort was 7280±7937 Hounsfield units. MAC calcium score correlated with the presence of atrial fibrillation ( P =0.02) but was not associated with other comorbidities. There was no correlation between MAC calcium score and mitral valve area ( r =0.07; P =0.6) or mitral valve gradient ( r =−0.03; P =0.8). Conclusions MAC calcium score did not correlate with invasively measured mitral valve gradient and mitral valve area in patients with MAC‐related mitral stenosis, suggesting that calcium score should not be used as a surrogate for invasive hemodynamic parameters.

Abstract Recent advances in the field of immuno‐oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high‐throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi‐marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Abstract Background: KRAS is a significant driver gene for pancreatic ductal adenocarcinoma (PDAC) and is present in up to 90% of PDAC cases. KRAS mutant (mt) PDAC tends to have worse prognosis compared to KRAS wild-type (wt) PDAC. However, the clinical and biological impact of the KRAS mutation subtypes (e.g. G12D, G12R, G12V, G12C and Q61) remains unclear. We sought to explore the clinical and molecular characteristics of the KRAS mt subtypes. Methods: We performed a retrospective review of patients with KRAS mt PDAC who underwent next generation sequencing at our institution from December 1, 2018 to December 1, 2021. We collected patient demographics, disease characteristics, clinical outcomes, DNA and RNA sequencing results via chart review. Bulk RNA-seq was performed via Tempus and The Cancer Genome Atlas. Count data were processed and separated by KRAS mutation subtype using a custom python script. Differential gene expression was performed using the DifSeq2 R package. Results: A total of 158 KRAS mt patients (at diagnosis, average age 63.8 years, 57% male, 88 (56%) Stage IV) were included. 10% of patients had KRAS Q61 mutation, 14% G12R, 30% G12V and 46% G12D; only 1.1% had the potentially actionable G12C mutation. G12R had a longer overall survival (OS) compared to the others (median 24.8 vs 17.5 months (m), p=0.05). Among patients with de novo metastatic disease, G12V had the lowest OS (median 9.8 vs 12.4 m, p=0.02). Between the KRAS mt subtypes, there were no statistically significant differences in tumor mutation burden, location of PDAC or subsequent metastasis, lines of treatment (average 2.3), age at diagnosis, gender, or stage at diagnosis. One hundred thirty-seven (87%) patients had at least one pathogenic somatic variant, 14 of which had statistically significant differences between KRAS mt subtypes. 82 (52%) patients had at least one RNA expression variant and bulk RNA-seq showed that each KRAS G12 mutation subtype had unique gene expression patterns, including several oncogenes and tumor suppressor genes. Conclusions: Our data suggest that KRAS mt subtypes may confer different clinically significant phenotypes of PDAC. We found G12R to be associated with improved prognosis compared to other KRAS mt subtypes and that among patients with de novo metastatic disease, G12V had the worst prognostic implication. As there were no statistically significant differences in patient demographics between the KRAS mt subtypes, we hypothesize survival differences are driven by biological phenotype. This is supported by our RNA-seq findings, which demonstrated unique gene expression patterns for each KRAS mt subtype. Citation Format: Alexander Xiao, Jack Korleski, Ryan Carr. KRAS mutation subtypes are associated with clinical and phenotypic differences in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C095.

Background We aimed to identify patients with subphenotypes of postacute coronary syndrome (ACS) using repeated measurements of high‐sensitivity cardiac troponin T, N‐terminal pro‐B‐type natriuretic peptide, high‐sensitivity C‐reactive protein, and growth differentiation factor 15 in the year after the index admission, and to investigate their association with long‐term mortality risk. Methods and Results BIOMArCS (BIOMarker Study to Identify the Acute Risk of a Coronary Syndrome) was an observational study of patients with ACS, who underwent high‐frequency blood sampling for 1 year. Biomarkers were measured in a median of 16 repeated samples per individual. Cluster analysis was performed to identify biomarker‐based subphenotypes in 723 patients without a repeat ACS in the first year. Patients with a repeat ACS (N=36) were considered a separate cluster. Differences in all‐cause death were evaluated using accelerated failure time models (median follow‐up, 9.1 years; 141 deaths). Three biomarker‐based clusters were identified: cluster 1 showed low and stable biomarker concentrations, cluster 2 had elevated concentrations that subsequently decreased, and cluster 3 showed persistently elevated concentrations. The temporal biomarker patterns of patients in cluster 3 were similar to those with a repeat ACS during the first year. Clusters 1 and 2 had a similar and favorable long‐term mortality risk. Cluster 3 had the highest mortality risk. The adjusted survival time ratio was 0.64 (95% CI, 0.44–0.93; P =0.018) compared with cluster 1, and 0.71 (95% CI, 0.39–1.32; P =0.281) compared with patients with a repeat ACS. Conclusions Patients with subphenotypes of post‐ACS with different all‐cause mortality risks during long‐term follow‐up can be identified on the basis of repeatedly measured cardiovascular biomarkers. Patients with persistently elevated biomarkers have the worst outcomes, regardless of whether they experienced a repeat ACS in the first year.