Citations

AbstractIntroductionInvasive neuromodulation interventions such as deep brain stimulation (DBS) and vagal nerve stimulation (VNS) are important treatments for movement disorders and epilepsy, but literature focused on young patients treated with DBS and VNS is limited. This retrospective study aimed to examine naturalistic outcomes of VNS and DBS treatment of epilepsy and dystonia in children, adolescents, and young adults.MethodsWe retrospectively assessed patient demographic and outcome data that were obtained from electronic health records. Two researchers used the Clinical Global Impression scale to retrospectively rate the severity of neurologic and psychiatric symptoms before and after patients underwent surgery to implant DBS electrodes or a VNS device. Descriptive and inferential statistics were used to examine clinical effects.ResultsData from 73 patients were evaluated. Neurologic symptoms improved for patients treated with DBS and VNS (p < .001). Patients treated with DBS did not have a change in psychiatric symptoms, whereas psychiatric symptoms worsened for patients treated with VNS (p = .008). The frequency of postoperative complications did not differ between VNS and DBS groups.ConclusionYoung patients may have distinct vulnerabilities for increased psychiatric symptoms during treatment with invasive neuromodulation. Child and adolescent psychiatrists should consider a more proactive approach and greater engagement with DBS and VNS teams that treat younger patients.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second cause of cancer death in the US by 2040. Five-year overall survival is only ~12% despite decades of research. The mainstay of treatment remains chemotherapy in the absence of highly recurrent, therapeutically actionable, genetic targets. For the minority of patients (~15-20%) who are candidates for curative-intent surgical resection, six months of intensive neoadjuvant chemotherapy with/without chemoradiation has become standard-of-care. However, despite evidence of radiographic, metabolic, and biochemical responses, significant viable residual disease on pathologic analysis is almost universally observed with approximately 40-60% risk of disease recurrence. Thus, there is a critical need to better understand why PDAC remains recalcitrant to current therapeutic modalities. Pathologic evaluation of PDAC reveals a complex microenvironment consisting of neoplastic cells dynamically interacting with both “normal” cellular (e.g. mesenchymal, immune) and non-cellular (e.g. collagen) stromal elements. While biologically important, experimental models and small-scale efforts to dissect the PDAC ecosystem are limited by focus on individual tumor compartments and generation of conflicting results. Consequently, there is a need for a more comprehensive understanding of the structure and dynamics of the PDAC TME through the theoretical lens of evolutionary ecology. Current therapies are not focused on the PDAC ecosystem. We hypothesize that cell-cell interactions of PDAC cells with its local niche are important for conferring treatment resistance. Thus, better understanding of said interactions could yield novel ecologically-informed therapies. Consequently, we developed a digital pathology library of approximately 1000 PDAC resection cases (whole-slide H&E images) performed at Mayo Clinic between 2013-2021. Approximately 400 cases are treatment naive while about 600 were treated with neoadjuvant therapy. While some qualitative features of pathologic analysis have prognostic value (e.g., pathologic treatment response, presence of perineural or lymphovascular invasion, extent of desmoplasia), we aim to identify prognostic spatial relationships using tools from landscape ecology. We utilized the HoVer-Net model for nuclei segmentation and classification and spatial statistics methods and landscape fragmentation analysis to understand the spatial organization within the PDAC tumor ecology. With these methodologies, we can assess the spatial context of cell interactions, habitat/niche/microenvironment formation, ecological relationships between cell populations, and the different tissue components. The different spatial statistics/metrics are used to quantify levels of immune cell infiltration, mixing, as well as the complexity and diversity of microenvironment phenotypes leading to high levels of tumor heterogeneity. Such measurements can help predict the likelihood of a PDAC tumor adaptive potential that could lead to fast evolutionary responses to therapy, progression, and poor prognosis. Citation Format: Merih D. Toruner, Luis Cisneros, Zafar Siddiqui, Chady Meroueh, Ritambhara Singh, Carlo Maley, Martin E. Fernandez-Zapico, Ryan M. Carr. Dissecting the pancreatic cancer microenvironment using landscape ecology [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B026.

AbstractBackgroundInter‐cellular communication within the gliovascular unit (GVU) is critical for cerebral blood flow regulation, and maintenance of the blood‐brain‐barrier (BBB) properties. The breakdown of BBB in Alzheimer’s disease (AD) is well‐established, but precise underlying molecular changes remain unclear. Additionally, whether GVU molecular alterations observed in AD brains are also detected in blood from living patients is unknown. Further, these GVU molecular perturbations require further investigation in different model systems to identify both human brain‐specific and cross‐species conserved alterations. In this study, we investigated prioritized GVU molecules altered in AD brains for their conservation in blood and cross‐species model systems.MethodsWe performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue in AD and control brains. We analyzed this data to detect cell‐specific GVU molecular perturbations and their interactions. We investigated molecular interactions between vascular and astrocyte clusters, the major cell types of the GVU of the BBB. To determine whether GVU transcriptional alterations detected in the brain are preserved in the blood, existing blood expression, genetic, and neuroimaging data from two longitudinal antemortem cohorts were analyzed. Using model systems, including mouse, drosophila, and zebrafish, we evaluated the cross‐species conservation of the top GVU alterations detected in AD brains.ResultsBrain snRNAseq revealed transcriptional profiles of 6,541 astrocytes and 2,210 vascular cells. The latter formed three distinct vascular clusters characterized as pericytes, endothelia and perivascular fibroblasts. We identified differentially expressed genes and their enriched pathways within these clusters and observed the highest levels of transcriptional changes within pericytes. Vascular targets that interact with astrocytic ligands have biological functions in cell signaling, angiogenesis, amyloid ß metabolism, and cytoskeletal architecture. We discovered that genetic variants influencing blood expression levels of some of the prioritized GVU genes were associated with neuroimaging burden of cerebrovascular disease in living human cohorts. Our ongoing studies in model systems revealed conservation of some of the top prioritized molecular perturbations across species.ConclusionOur findings prioritized by multiscale, cross‐tissue human data revealed GVU perturbations within interacting pericyte and astrocyte molecules, which are conserved across multiple cross‐species models. These results nominate new molecular targets and mechanistic insights for BBB disruptions in AD.

Abstract Calmodulin‐binding transcriptional activator 1 (CAMTA1) is highly expressed in the brain and plays a role in cell cycle regulation, cell differentiation, regulation of long‐term memory, and initial development, maturation, and survival of cerebellar neurons. The existence of human neurological phenotypes, including cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA), associated with CAMTA1 variants, has further supported its role in brain functions. In this study, we phenotypically and molecularly characterize the largest cohort of individuals ( n = 26) with 23 novel CAMTA1 variants (frameshift‐7, nonsense‐6, splicing‐1, initiation codon‐1, missense‐5, and intragenic deletions‐3) and compare the findings with all previously reported cases (total = 53). We show that the most notable phenotypic findings are developmental delay/intellectual disability, unsteady or uncoordinated gait, hypotonia, behavioral problems, and eye abnormalities. In addition, there is a high incidence of dysarthria, dysgraphia, microcephaly, gastrointestinal abnormalities, sleep difficulties, and nonspecific brain MRI findings; a few of which have been under‐reported. More than one third of the variants in this cohort were inherited from an asymptomatic or mildly affected parent suggesting reduced penetrance and variable expressivity. Our cohort provides a comprehensive characterization of the spectrum of phenotypes and genotypes among individuals with CECBA and the large data will facilitate counseling and formulating management plans and surveillance recommendations for these individuals.

Abstract The dismal outcome of acute leukemia undergoing immunophenotype-switch, compounded by the increased incidence in the era of immunotherapy, highlights the need for in-depth systemic studies. We investigated the clinicopathological, cytogenetic, and molecular features of 33 patients experiencing switch between acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The median duration from the primary diagnosis to lineage switch was 7.8 months, with the subsequent median survival being < 3 months. The majority experienced a transition from B-ALL to AML. The AML cases demonstrated a spectrum of differentiation, ranging from minimal to erythroid, with monocytic being the most common. Cytogenetic analysis revealed 11q23/KMT2A fusions as the most recurrent abnormalities (n = 18); also observed were complex karyotype, 7/7q-, 9p-/CDKN2A deletion, t(5;14)/TCLX3::BCL11b, t(8;9)/PCM1::JAK2, t(9;22)/BCR::ABL1, and t(12;19)/TCF3::ZNF384. Remarkably, in 60% of patients lacking KMT2A fusions, a chronic myeloid neoplasm was observed preceding the first leukemia. In contrast, no prior hematological malignancies were observed in KMT2A cases. Deep mutational profiling reinforced the inherent clonal relationship between the initial and subsequent leukemias, evident from the overlapping mutational signatures. The presence of distinct additional mutations across the two phases supports the long-standing theory of lineage switch emerging via divergent evolution of a multipotential progenitor.

AbstractBackgroundCytology is extremely important for diagnosis of lung carcinoma and the Papanicolaou Society of Cytopathology (PSC) had proposed a new classification system for respiratory cytology for better communication between physicians and better patient management. The objective of this study is to analyze our samples in accordance with this classification and to evaluate the diagnostic accuracy of various cytologic techniques and to assess the risk of malignancy.MethodsEight hundred and twenty respiratory cytology specimens (FNA, BAL, washing, brushing, sputum) collected between 2019 and 2022 were classified according to the PSC system and the risk of malignancy was assessed for each category using follow‐up surgical samples. Sensitivity, specificity, and accuracy rates were determined based on a categorial approach, according to a similar study.ResultsThe data of 820 respiratory cytology specimens from 576 patients were analyzed. 2.6% of these were non‐diagnostic, 64.1% were NM, 5% were AC, 0.4% were N‐B‐LG, 4% were SM and 23.9% were ML. The risk of malignancy for each diagnostic category were: 42.8% for non‐diagnostic, 31.2% for NM, 43.9% for AC, 87.9% for SM, 94.3% for ML. Sensitivity and specificity was calculated using only the malignant cases considered as positive tests and was 45.57% and 97.34% respectively.ConclusionOur results correlated with the PSC system, and it was considered useful in clinical practice. However, more studies should be performed to evaluate the usefulness of this system. The ROMs of each category and the impact of different techniques should be further studied.

ImportanceLip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning.ObjectiveTo analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates.Evidence ReviewThe incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019.FindingsIn 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia.Conclusions and RelevanceIn this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts.

Objectives: Herein, we present the PancreaSeq® results of 28 patients and emphasize the usefulness of molecular testing in evaluation of pancreatic cysts. Material and Methods: A total of 10 (35.7%) non-diagnostic, 6 (21.4%) negative, 5 (17.8%) atypical, and 7 (25%) were positive for mucinous cystic neoplasm (MCN) pancreatic cyst aspirates were analyzed with PancreaSeq® at Mayo Clinic, Jacksonville between September 2021 and February 2023. Results: Three non-diagnostic, two negative, three atypical, and two positive for MCN cysts were positive for KRAS and GNAS mutations. They were interpreted as intraductal papillary mucinous neoplasm (IPMN) with low risk for progression to high-grade dysplasia/adenocarcinoma. One negative case was positive for KRAS and GNAS mutation and RNF43 copy number alteration. It was interpreted as IPMN with a low risk of progression. Two non-diagnostic, one negative, and two positive for MCN cysts were positive for KRAS mutation. All were interpreted as IPMN/MCNs with low risk of progression. One positive for MCN case was positive for GNAS mutation and ALK fusion and one positive for MCN case was positive for GNAS mutation, ALK fusion, and RNF43 copy number alteration. Both were interpreted as IPMN and their risk of progression was interpreted as not well understood. One atypical case was positive for KRAS and TP53 mutation and was interpreted as IPMN/ MCNs with a high risk of progression. VHL mutation was present in one non-diagnostic case. It was interpreted as serous cystadenoma and the risk for progression was low. Conclusion: Molecular analysis of pancreatic cysts with PancreaSeq® is useful in accurate diagnosis, especially when cytologic material is non-diagnostic and helps improve patient management.