Citations

ZUMA-12 is a multicenter phase 2 study evaluating axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy as part of first-line treatment for high-risk large B-cell lymphoma (LBCL). In the primary efficacy analysis (n = 37; median follow-up, 15.9 months), axi-cel demonstrated a high rate of complete responses (CR; 78%) and a safety profile consistent with prior experience. Here, we assessed updated outcomes from ZUMA-12 in 40 treated patients after ≥3 years of follow-up. Eligible adults underwent leukapheresis, lymphodepleting chemotherapy, and axi-cel infusion (2 × 106 CAR T cells/kg). Investigator-assessed CR, objective response, survival, safety, and CAR T-cell expansion were assessed. The CR rate among response-evaluable patients (n = 37) increased after the primary analysis to 86% (95% confidence interval [CI], 71%-95%), with a 92% objective response rate. After a median follow-up of 47.0 months (range, 37.1-57.8 months), 36-month estimates (95% CI) of duration of response and event-free, progression-free, and overall survival were 81.8% (63.9%-91.4%), 73.0% (55.6%-84.4%), 75.1% (57.5%-86.2%), and 81.1% (64.4%-90.5%), respectively. In total, 4 patients had new malignancies, 2 occurring after the data cutoff of the primary analysis; none were axi-cel–related. Eight patients died on study, 2 of whom died from nonrelapse mortality causes. After long-term follow-up, axi-cel demonstrated a high durable response rate, with no new safety signals after the primary analysis, suggestive of an effective first-line therapy with curative intent in high-risk LBCL. Further assessments are needed to determine its benefit vs standard of care. This trial was registered at clinicaltrials.gov, as NCT03761056.

Abstract: Breast cancer1-associated protein 1 (BAP-1)-inactivated melanocytic tumors are a group of familial or sporadic lesions with distinctive histology and molecular features. Inherited germline inactivating mutations in BAP1 have been associated with the development of multiple epithelioid melanocytic neoplasms resembling Spitz nevi and increased susceptibility for developing several malignancies, including uveal melanoma, cutaneous melanoma, renal cell carcinoma, mesothelioma, and other tumors. Cutaneous melanoma with loss of BAP1 expression is rare. We present a unique case of BAP1 -inactivated melanoma with anaplastic lymphoma kinase ( ALK ) fusion arising in a pre-existing BAP1 -inactivated nevus in a 47-year-old female patient who presented with a dome-shaped red papule on the superior crus of the right antihelix. Histology revealed intradermal melanocytic proliferation with biphenotypic morphology. There was a proliferation of atypical melanocytes showing epithelioid features in the background of nevus. Mitotic figures were identified in the cytologically atypical component of the lesion. Mart-1/Ki67 dual stain demonstrated a higher proliferation index in the larger epithelioid atypical cells, supporting the diagnosis of melanoma. Nuclear BAP-1 expression was lost in the larger atypical cells and associated nevoid cells. Preferentially expressed antigen in melanoma stain demonstrated focal positive staining in 20%–30% of the melanocytes. Immunostaining for B-Raf proto-oncogene, serine/threonine kinase V600E was diffusely positive and ALK demonstrated patchy immunoreactivity in the melanocytic proliferation. Interphase fluorescence in situ hybridization studies showed gains at chromosome 6p25 (Ras responsive element binding protein 1) in the tumor cells. The comprehensive next-generation sequencing revealed B-Raf proto-oncogene, serine/threonine kinase V600E mutation, TP53 mutation, ALK fusion, BAP1 loss (copy number variation = 0.0, potentially germline), and loss of MAP2K7, Von Hippel-Lindau tumor suppressor , FGFR3, CDKN2A , 19q, and telomerase reverse transcriptase . The tumor was microsatellite stable with a low tumor mutational burden (5.76 mutations/Mb). The tumor was completely excised with negative margins. The patient is doing well at 17 months follow-up with no signs of recurrence.

Background: Prior studies indicate a relationship between migraine and MACE. Here we assess whether brain white matter hyperintensities (WMH), which are a common imaging finding in patient with migraine, contribute to the risk of MACE above demographics and common risk factors for MACE. Methods: 60,454 patients, ages 18-89, with a ICD-9 or ICD-10 migraine diagnosis code in 2010 or later were identified from the Mayo Clinic electronic health record. Only patients who were seen for migraine in the Neurology Department were included. Patients with a migraine diagnosis who did not have MACE were included only if they had at least two visits at Mayo Clinic during five years. Only patients with sex and race information were included. The final cohort included 577 migraine patients with and 598 migraine patients without MACE. Presence of WMH was determined from radiology notes. Individuals without a brain MRI were assumed not to have WMH. A logistic regression model that included sex, race, known lifetime MACE risk factors (atrial fibrillation, diabetes, hypertension, hyperlipidemia, tobacco use) and WMH as independent variables to predict MACE outcome was fit. Results: Significant factors that increased the risk of MACE in individuals with migraine included being Black or African American (adjusted OR: 2.9, 95% CI: 1.24-6.82, p = 0.014), presence of atrial fibrillation (adj. OR: 1.63, 95% CI: 1.23-2.17, p < 0.001), diabetes (adj. OR: 1.34, 95% CI: 1.02-1.75, p = 0.036), hypertension (adj. OR: 1.9, 95% CI: 1.39-2.6, p < 0.001), tobacco use (adj. OR: 1.66, 95% CI: 1.29-2.14, p < 0.001), and the presence of WMH (adj. OR: 1.43, 95% CI: 1.1-1.87, p = 0.008). Hyperlipidemia showed a marginal association (adj. OR: 1.34, 95% CI: 0.99-1.81, p = 0.061), while other variables such as sex and other racial/ethnic groups did not significantly alter the risk of MACE outcome. Discussion: Results indicate that African American race and presence of WMH in addition to common comorbidities independently increase the risk of MACE outcome.

Introduction: Prior data suggest that migraine increases the risk of stroke. However, there is a lack of understanding whether specific migraine features like white matter hyperintensities (WMH) commonly found on brain magnetic resonance (MR) imaging in migraine patients and migraine medications might contribute to Major Adverse Cardiovascular Event (MACE) outcomes including ischemic and hemorrhagic stroke. We assess MACE risk estimation model stratified by event types using Mayo Clinic Electronic Health Record (EHR) data. Methods: Case and control sets, based on MACE occurrence among migraine patients at Mayo Clinic Neurology Department, were propensity matched on age, sex, and MACE risk-factors (atrial fibrillation, diabetes, hyperlipidemia, hypertension, tobacco use) to capture migraine-specific predictors ( Figure 1) . Migraine medications were categorized into 9 classes; Triptans, Ditans, Gepants, Ergots, calcitonin gen-related peptide targeting medications (CGRPs), Beta-blockers, Topiramate, Tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs). Demographics (age and sex), migraine characteristics (chronic migraine, migraine with aura), and presence of WMH on MR imaging were curated. To model non-linear relationship between predictors, two comparative Random Forest (RF) models were evaluated for MACE prediction; i) Model-1: using demographics, migraine characteristics and WMH, ii) Model-2: medications, demographics, migraine characteristics and WMH ( Table 1) . Results: Model-2 outperformed Model-1 indicating combined interaction between medications, WMH, and migraine characteristics for estimating MACE risk. Model-2 achieved AUC of 0.68 for overall MACE, but showed higher performance for ischemic stroke (AUC 0.76). We visualized the effects of input features on ischemic stroke risk for four individual patients using SHAP force plots ( Figure 2 ). The model often considered use of betablockers, chronic migraine, and presence of WMH as factors for increasing ischemic stroke risk. Discussion: Our experiments show that medications, migraine features, WMH and demographics are more effective estimators for ischemic risk stroke risk compared to overall MACE risk, indicating stronger predictive correlation between ischemic stroke and migraine related clinical features. Interestingly, the model inferred the clinical practice pattern of not prescribing Triptans (TRIPTAN=0) to the patients with high risk of stroke from the data itself.

Introduction: We assess the risk of stroke in individuals with and without a migraine diagnosis, adjusting for demographic variables and stroke risk factors using participant information from the All of Us database. Method: Diagnoses of migraine, stroke and comorbidities were identified using ICD9 and ICD10 codes. A multivariable logistic regression analysis was performed to assess the association between migraine and risk of stroke adjusting for comorbidities including hypertension, atrial fibrillation, hyperlipidemia, diabetes, tobacco use, depression and demographics (age, sex at birth, race and ethnicity). To compare the prevalence of stroke between individuals with and without migraine, odds ratios using a 95% confidence interval (CI) were calculated. Results: Within the All of Us database, 31,444 individuals received a migraine diagnosis (female=25,374/81%, male=5,391/17%, other=679/2%; mean (std) age=54.9 (15.6)) and 379,283 did not have a migraine diagnosis (female=222,104/59%, male=149,182/39%, other=7,997/2%; mean (SD) age=55.9 (17.2)), see Figure 1 for detailed demographics. The migraine cohort had a greater proportion of women (81% vs 59%, p<0.001), a higher proportion of white individuals (61% vs. 55%, p<0.001) fewer African American individuals (15% vs. 19%, p<0.001) and a lower proportion of individuals who were 61 or older (39% vs 45%, p<0.001) compared to the non-migraine cohort. Compared to the non-migraine cohort, individuals with migraine had significantly higher rates of comorbidities, including depression (13% vs. 4%, p<0.001), diabetes (16% vs. 7%), tobacco use (23% vs. 9%, p<0.001), hyperlipidemia (48% vs. 22%, p<0.001), hypertension (57% vs. 27%, p<0.001), and atrial fibrillation (7% vs. 4%, p<0.001). A multivariate regression model adjusted for differences between cohort demographics and comorbidities found that individuals with migraine had 2.14 higher odds of overall stroke compared to the non-migraine cohort (OR 2.14, 95% CI [ 2.04, 2.24]. Discussion: After adjusting for cohort imbalances in demographics and comorbidities, individuals with migraine had a 2.14 times higher risk of stroke compared to those without a migraine diagnosis. Our analysis, using data from the All of Us database, confirms previous findings and suggests that while comorbidities are more prevalent in those with migraine, they do not fully account for the increased stroke risk.

ABSTRACTBackgroundThe carbon‐13 spirulina gastric emptying breath test (GEBT) is approved to identify delayed, but not accelerated, gastric emptying (GE). We compared the utility of the GEBT to scintigraphy for diagnosing abnormal GE in patients with diabetes mellitus.MethodsTwenty‐eight patients with diabetes ate a 230‐kcal test meal labeled with technetium 99 m and 13C‐spirulina, after which 10 scintigraphic images and breath samples (baseline, 15, 30, 45, 60, 90, 120, 150, 180, 210, and 240 min) were collected on 2 occasions 1 week apart. We assessed the accuracy of 13C‐spirulina GEBT excretion rate (percent dose multiplied by 1000 [kPCD] min−1) values to predict scintigraphic half‐life and distinguish between normal, delayed, and accelerated GE and the intraindividual reproducibility of the GEBT.Key ResultsScintigraphy revealed normal, delayed, and accelerated GE, respectively, in 17 (30%), 29 (52%), and 10 (18%) test results. GE T½ values measured with scintigraphy and GEBT were highly concordant within individuals; the intraindividual reproducibility was 34% (scintigraphy) and 15% (GEBT). Compared to current criteria, the kPCD150 (150 min) and kPCD180 values provided equally sensitive (90%) and more specific (81% vs. 67%) approach for distinguishing between delayed versus normal/accelerated GE. A new metric (kPCD60–kPCD15 min) was 90% sensitive and 83% specific for distinguishing between accelerated versus normal/delayed GE. These findings were used to create nomograms and an algorithm for interpreting GEBT results.Conclusions and InferencesAmong patients with poorly controlled diabetes, the 13C‐spirulina GEBT can accurately and precisely assess GE and effectively distinguish between normal, delayed, and accelerated GE.

ABSTRACTObjectiveTo assess how patient and caregiver factors influence caregiver readiness for hospital discharge in palliative care patients.Study Setting and DesignThis transitional care study uses cross‐sectional data from a randomized controlled trial conducted from 2018 to 2023 testing an intervention for caregivers of hospitalized adult patients with a serious or life‐limiting illness who received a palliative care consult prior to transitioning out of the hospital.Data Sources and Analytical SampleCaregiver readiness was measured with the Family Readiness for Hospital Discharge Scale (n = 231). Caregiver demographic, intra‐ and interpersonal factors were self‐reported. Patient demographic, comorbidity score, and risk score for complicated discharge planning were extracted from electronic health records. Stepwise regression models estimated variance explained (r2) in caregiver readiness for patient hospital discharge.Principal FindingsPatient demographics and complexity were not statistically associated with caregiver readiness for discharge. Caregiver depressive symptoms, poor caregiver‐patient relationship quality, and fewer hours spent caregiving prior to hospitalization explained 29% of the variance in caregiver readiness.ConclusionsReliance on patient data may not be sufficient for explaining caregiver readiness for discharge. Assessing caregiver factors may be a better alternative for identifying caregivers at risk for low discharge readiness and those in need of additional support.Trial Registration: ClinicalTrials.gov on November 13, 2017, (No. NCT03339271)

PURPOSE There is limited cancer clinical research in sub-Saharan African countries despite the significant burden of cancers. The primary objective of this strengths, weaknesses, opportunities, and threats (SWOT) analysis was to understand and document factors affecting the successful implementation of prostate cancer (CaP) clinical research in Nigeria. METHODS The research team used a qualitative design involving International Registry of Men with Advanced Prostate Cancer (IRONMAN) study team members as participants from four regional sites in Nigeria. One-hour listening sessions were conducted via Zoom at each site, focusing on SWOT related to the IRONMAN study. All sessions were recorded, transcribed, and analyzed. Themes were inductively coded and then synthesized across all four sites. RESULTS The study teams identified several strengths and weaknesses in conducting the IRONMAN study at their respective sites. Key strengths included access to robust patient population for recruitment and the availability of essential resources, such as lab space, clinical knowledge, and adequate staffing. Weaknesses centered on the social determinants of health that hinder patient participation, such as transportation challenges, distance to clinics, limited access to care, and insufficient biorepository space for sample storage. A prominent opportunity identified was the potential for Nigerian institutions to engage in more clinical research, particularly multisite global trials. Threats included difficulties in retaining research staff and political instability. CONCLUSION This study highlights the promising research opportunities in Nigeria. The lessons learned from the IRONMAN study provide valuable insights into the feasibility of conducting CaP clinical research and trials tailored to the needs of Black men in sub-Saharan Africa. These findings offer a roadmap for future research efforts, with the potential to expand clinical trials and improve health outcomes across the region.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Lung Cancer Screening provide criteria for selecting individuals for screening and offer recommendations for evaluating and managing lung nodules detected during initial and subsequent annual screening. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Lung Cancer Screening.

AbstractBackgroundTwo main risk factors of Alzheimer’s disease (AD) are aging and APOE‐ε4. However, some individuals remain cognitively normal despite having these risk factors. They are considered “cognitively resilient”. This study aimed to identify molecular factors that confer cognitive resilience in APOE‐ε4 carriers ≥ 80 years of age and may serve as biomarkers.MethodWe applied weighted gene co‐expression network analysis (WGCNA) to generate consensus co‐expression networks from blood of participants in two antemortem cohorts, the Mayo Clinic Study of Aging (MCSA, n=105), and the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n=91), using RNA‐sequencing and microarray data, respectively. We associated these networks with resilience (resilient vs non‐resilient), cognitive endophenotypes and hippocampal volume. Preservation between consensus networks from blood and those derived from postmortem brain tissues of AD and control donors from AMP‐AD (n=1174) was evaluated. We validated the human findings in four AD mouse models. Finally, machine learning models were utilized to discriminate cases (AD+mild cognitive impairment (MCI)) from controls in MCSA, ADNI and ANMerge antemortem cohorts.ResultFour consensus networks were significantly correlated with a memory phenotype (logical memory delayed recall=LMDR) and hippocampal volume in both MCSA and ADNI. Among these, blood expression module M3 was most preserved with the brain transcriptome. M3 was enriched with NDUF hub genes that are involved in the mitochondrial respiratory chain. Expression levels of M3 and many blood NDUFs had significant associations with better LMDR and hippocampal volume. In brain, NDUFs were upregulated in controls compared to AD, and their expression levels were associated with better global cognition and decreased AD neuropathology. Many NDUFs were significantly downregulated in the hippocampus or cortex of AD mice compared to wild‐types. Lastly, models that included blood NDUFs improved diagnostic accuracy of AD+MCI compared to models that only included demographic and risk variables (age, sex, APOE‐ε4) in MCSA, ADNI and ANMerge. In MCSA and ADNI, adding NDUFs’ expression to models that included established blood biomarkers (Aβ42/40, ptau181, NFL) further improved diagnostic accuracy.ConclusionOur results suggest that mitochondrial NDUFs are centrally‐linked peripheral molecular signatures that may be resilience factors against AD and serve as both therapeutic targets and novel diagnostic biomarkers.