Citations

AbstractBackgroundWith modern treatment paradigms, olfactory neuroblastoma (ONB) has favorable overall survival (OS); however, the incidence of recurrence remains high. The primary aims of this study were to delineate the prognosis of recurrence of ONB and explore how recurrence subsites are associated with OS, disease‐specific survival (DSS), and further recurrence.MethodsA retrospective chart review of ONB cases from nine academic centers between 2005 and 2021 was completed. Tumor characteristics, recurrence subsites, timelines to recurrence, additional recurrences, and survival estimates were determined using descriptive and time‐to‐event analyses.ResultsA final cohort of 233 patients was identified, with 70 (30.0%) patients recurring within 50.4 (standard deviation ±40.9) months of diagnosis on average, consisting of local (50%), neck (36%), intracranial (9%), and distant (6%) recurrence. Compared with subjects without recurrence, patients with recurrence had significantly different primary American Joint Committee on Cancer T stage (p < 0.001), overall stage (p < 0.001), and modified Kadish scores (p < 0.001). Histopathology identified that dural involvement and positive margins were significantly greater in recurrent cases. First recurrence was significantly associated with worse 5‐year DSS (hazard ratio = 5.62; p = 0.003), and subjects with neck or local recurrence had a significantly better DSS compared to intracranial or distant recurrence.ConclusionsRecurrent cases of ONB have significantly different stages and preoperative imaging factors. Patients with local or neck recurrence, however, have better DSS than those with intracranial or distant recurrence, independent of initial tumor stage or Hyams grade. Identifying specific factors that confer an increased risk of recurrence and DSS is important for patient counseling in addition to surveillance planning.

Abstract DNA damage response (DDR) mechanisms are critical to maintenance of overall genomic stability, and their dysfunction can contribute to oncogenesis. Significant advances in our understanding of DDR pathways have raised the possibility of developing therapies that exploit these processes. In this expert-driven consensus review, we examine mechanisms of response to DNA damage, progress in development of DDR inhibitors in IDH-wild-type glioblastoma and IDH-mutant gliomas, and other important considerations such as biomarker development, preclinical models, combination therapies, mechanisms of resistance and clinical trial design considerations.

ImportanceFrontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD.ObjectiveTo evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations.Design, Setting, and ParticipantsIn this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)–based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes.ExposureParticipants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests.Main Outcomes and MeasuresInternal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy.ResultsIn the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized β range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, −2.49 [95% CI, −0.19 to −0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back β = −0.49 [95% CI, −0.72 to −0.25]; P &amp;lt; .001) but not a composite of traditional neuropsychological measures (β = −0.14 [95% CI, −0.42 to 0.14]; P = .32).Conclusions and RelevanceThe findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.

AbstractIntroductionAdvanced diagnostic bronchoscopy includes endobronchial ultrasound (EBUS) guided transbronchial lung and lymph node biopsies, CT navigation and robotic bronchoscopy. Interventional bronchoscopy refers to procedures performed for therapeutic purposes such as balloon dilation of the airway, tissue debulking, cryotherapy, removal of foreign bodies and insertion of endobronchial valves [1]. For adult patients, these procedures are standard of care [2, 3]. Despite a lack of formalized training, there are numerous case reports and case series describing the use of advanced diagnostic and interventional bronchoscopy techniques in children. The safety and feasibility of EBUS‐TBNA, cryotherapy techniques, endobronchial valves among other techniques have been demonstrated in these publications [1, 4‐9].MethodsWe sought to better understand the current practices and perspectives on interventional and advanced bronchoscopy among pediatric pulmonologists through surveys sent to pediatric teaching hospitals across the United States.ResultsWe received 43 responses representing 28 programs from 25 states. The highest bronchoscopy procedure volume occurred in the 0‐5 years age group. Among our respondents, 31% self‐identified as a pediatric interventional/advanced bronchoscopist. 79% believe that advanced and interventional training is feasible in pediatric pulmonology and 77% believe it should be offered to pediatric pulmonary fellows.DiscussionThis is the first study to characterize current practices and perspectives regarding advanced diagnostic and interventional bronchoscopy procedures among pediatric pulmonologists in the United States. Pediatric interventional pulmonology (IP) is in its infancy and its beginnings echo those of the adult IP where only certain centers were performing these procedures.

Abstract Meningiomas are the most common intracranial neoplasms in adults. While most meningiomas are cured by resection, further treatment by radiotherapy may be needed, particularly in WHO grades 2 and 3 tumors which have an increased risk of recurrence, even after conventional therapies. Still, there is an urgent need for novel therapeutic strategies after the exhaustion of local treatment approaches. Radionuclide therapies combine the specificity of tumor-specific antibodies or ligands with the cytotoxic activity of radioactive emitters. Alongside this, integrated molecular imaging allows for a noninvasive assessment of predictive biomarkers as treatment targets. Whereas the concept of “theranostics” has initially evolved in extracranial tumors such as thyroid diseases, neuroendocrine tumors, and prostate cancer, data from retrospective case series and early phase trials underscore the potential of this strategy in meningioma. This review aims to explore the available evidence of radionuclide treatments and ongoing clinical trial initiatives in meningioma. Moreover, we discuss optimal clinical trial design and future perspectives in the field, including compound- and host-specific determinants of the efficacy of “theranostic” treatment approaches.

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.

Abstract The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. We leveraged aptamer-based proteomics (> 4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations (C9orf72, GRN, MAPT) compared to 39 noncarrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in C9orf72 and GRN) and extracellular matrix (particularly in MAPT) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic signatures was tested and confirmed in independent cohorts of 1) sporadic progressive supranuclear palsy-Richardson syndrome and 2) frontotemporal dementia spectrum syndromes. Network-based proteomics hold promise for identifying replicable molecular pathways in adults living with FTLD. ‘Hub’ proteins driving co-expression of affected modules warrant further attention as candidate biomarkers and therapeutic targets.

Abstract Pancreatic cancer is a significant public health concern, with increasing incidence rates and limited treatment options. Recent studies have highlighted the role of the human microbiome, particularly the gut microbiota, in the development and progression of this disease. Microbial dysbiosis, characterized by alterations in the composition and function of the gut microbiota, has been implicated in pancreatic carcinogenesis through mechanisms involving chronic inflammation, immune dysregulation, and metabolic disturbances. Researchers have identified specific microbial signatures associated with pancreatic cancer, offering potential biomarkers for early detection and prognostication. By leveraging advanced sequencing and bioinformatics tools, scientists have delineated differences in the gut microbiota between pancreatic cancer patients and healthy individuals, providing insights into disease pathogenesis and potential diagnostic strategies. Moreover, the microbiome holds promise as a therapeutic target in pancreatic cancer treatment. Interventions aimed at modulating the microbiome, such as probiotics, prebiotics, and fecal microbiota transplantation, have demonstrated potential in enhancing the efficacy of existing cancer therapies, including chemotherapy and immunotherapy. These approaches can influence immune responses, alter tumor microenvironments, and sensitize tumors to treatment, offering new avenues for improving patient outcomes and overcoming therapeutic resistance. Overall, understanding the complex interplay between the microbiome and pancreatic cancer is crucial for advancing our knowledge of disease mechanisms and identifying innovative therapeutic strategies. Here we report phylogenetic analysis of the 16S microbial sequences of the pancreatic cancer mice microbiome and corresponding age matched healthy mice microbiome. We successfully identified differentially abundance of microbiota in the pancreatic cancer.

Abstract Background: Cholangiocarcinoma (CCA) is a lethal and heterogenous malignancy of the biliary tree characterized by perineural invasion. About 85% of CCA show activation of YAP signaling, which promotes proliferation, anti-apoptosis, and therapeutic resistance. YAP signaling is mediated by Src family kinases (SFK) by phosphorylation of YAP (pYAPy357). NXP900 is a first-in-class, highly selective, SFK inhibitor with a novel mechanism of action which locks SFK in its closed and inhibited conformation, in contrast to other Src inhibitors such as dasatinib. A phase 1a study of NXP900 in patients with advanced solid tumors was recently initiated. Here, we examined treatment responses of CCA to NXP900 in vitro and in vivo. Methods: Cell viability was determined in seven CCA cell lines by CellTiter-Glo. Cell death and apoptosis were assayed by PI/Hoechst and Caspase-Glo 3/7 assay. CalcuSyn software was used to determine synergistic drug effects. Immunoblot analysis, RT-PCR, and IF staining of YAP localization were used to evaluate YAP knockdown. Clones of human CCA cell lines resistant to NXP900 were generated through escalating exposure to NXP900 over 6 months. Five patient-derived xenograft (PDX) tumors were expanded into flanks of NOD/SCID mice. Tumor bearing mice were randomized 1:1 with 5 mice per arm and treated with vehicle or NXP900 (40 mg/kg) once daily for up to 4 weeks. To determine drivers of sensitivity and resistance, predicted sensitivity scores based on tumor growth were linked to multi-omics (RNA seq and [phospho-]proteomics) of our PDX models. Results: All cell lines were sensitive to NXP900 with IC50 values between 7nM-15µM; IC50’s of resistant clones were 1000 times higher. NXP900 induced more cell death compared to vehicle, which appeared to be through apoptosis. NXP900 inhibited pSrc, decreased pYAPy357, and upregulated inactive pYAPs127. Correspondingly, decreased YAP target gene (Cyr61, NUAK, and CTGF) levels and a nuclear-to-cytoplasmic translocation were observed. NXP900/GemCis combination therapy increased cell death demonstrated a synergistic effect (Combination Indices &lt;1) at all concentrations. In our PDX models, treatment was associated with a significant decrease in tumor growth in 3 models (mean fold change 3.1 vs. 14.2; 1.0 vs. 7.6; 1.4 vs. 2.6). The major resistant signature was the TRK signaling network, involved in nerve growth factor binding activity, while drivers of sensitivity included the SRC network. Conclusion: NXP900 demonstrated therapeutic activity in vitro and in human PDX models. We are currently performing multi-omic approaches in NXP900 sensitive and resistant cell lines to unravel determinants of activity and resistance. Additional in vivo studies will be performed to determine effects of NXP900/GemCis and NXP900/anti-PDL-1 combination therapy. Citation Format: Hendrien Kuipers, Jennifer L. Tomlinson, Danielle M. Carlson, Amro M. Abdelrahman, Erik Jessen, Jack W. Sample, Nathan W. Werneburg, Hannah E. Stumpf, Mark J. Truty, Sumera I. Ilyas, Gregory J. Gores, Rory L. Smoot. Src family kinase inhibition demonstrates antitumor activity in vitro and in patient-derived xenograft models of human cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 614.

Abstract Introduction Cholangiocarcinoma (CCA) is a highly lethal, heterogenous biliary malignancy. Despite the development of targeted therapies, treatment success has been hindered by primary or acquired resistance. New therapeutic strategies are necessary to improve outcomes in these patients. NXP800 is a GCN2 small-molecule activator that phosphorylates eIF2a inducing selective ATF4 transcription which stimulates stress-induced genes leading to apoptosis. NXP800 has been previously validated in ovarian cancers with ARID1A mutations, well-known players in cholangiocarcinoma. We sought to determine the treatment efficacy of novel NXP800 in CCA utilizing patient derived xenograft (PDX) preclinical models. Methods In our preliminary studies, four human and two murine CCA cell lines were tested for cell viability using CellTiter-Glo to determine the maximal inhibitory concentration (IC50). Immunoblot analysis of HuCCT-1 cells incubated with 1 mM of NXP800 for 6 hours vs. vehicle was performed. We also evaluated response to GCN2 activation in multiple RNA sequenced PDX models. Xenografts were expanded into the flank of NOD/SCID mice and treatment begun when tumors averaged 120mm3. Tumor bearing mice were treated with NXP800 (35 mg/kg) or vehicle via oral gavage five days on, two days off, for 28 days. Tumor volume and animal weight were collected twice weekly. Predicted sensitive signatures were determined using multi-omics. Results IC50 dose response curves showed nanomolar activity in all six cell lines, ranging from 5-170 nM. Immunoblotting demonstrated an upregulation of phosphorylated eIF2a and in turn upregulation of ATF4 with treatment of NXP800 compared to vehicle. Five PDX tumors from patients with intrahepatic or distal CCA was established and validated by histologic analysis. Molecular characterization of the tumor identified tumor mutation and a total tumor mutational burden. RNA sequencing was completed and identified 21-gene signatures related to YAP activity, which were cross-referenced against our existing PDX model tumor bank. Treatment with NXP800 was associated with a statistically significant decrease in tumor size in three of five PDX models tested, which included an ARID1A, FGFR1, and ATM mutants. Preliminary multi-omics on the PDX models revealed that sensitivity mechanisms were centered around EGFR signaling. Conclusion The novel GCN2 kinase activator, NXP800, has nanomolar efficacy in both human and murine CCA cell lines in vitro. Additionally, NXP800 demonstrated therapeutic activity in multiple cholangiocarcinoma PDX models in vivo. We are opening a Phase 1b clinical trial investigating the effects of NXP800 use in patients with advanced CCA. Future studies determining the cellular effect of GCN2 activation utilizing NXP800 are being conducted. Citation Format: Danielle Marie Carlson, Hendrien Kuipers, Amro Abdelrahman, Erik Jessen, Joshua Roldan Kalil, Jack Sample, Jennifer Tomlinson, Mark Truty, Rory Smoot. A novel GCN2 kinase activator demonstrates therapeutic efficacy in preclinical PDX models of human cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2098.