Citations

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies due to its silent clinical onset, rapid progression, and limited responsiveness to current treatment options. These features underscore the urgent need for early detection strategies and for new molecular targets that can be exploited therapeutically. Epithelial Cell Transforming Sequence 2 (ECT2) is a Rho family guanine nucleotide exchange factor that was originally identified as an oncoprotein and later shown to regulate cytokinesis. In this study, we examined the clinical relevance of ECT2 expression in PDAC and determined its functional contribution to transformed growth and tumorigenicity. Our analyses revealed that ECT2 expression increases at the earliest stages of PDAC development, remains persistently elevated during disease progression, and associates with reduced overall patient survival. Furthermore, a substantial fraction of ECT2 is aberrantly localized to the cytoplasm of PDAC cells. Functional studies demonstrated that depletion of ECT2 suppresses three-dimensional growth, invasive behavior, and tumor formation in vivo, while having little impact on PDAC cell cytokinesis. Mechanistically, we found that ECT2 is required for activation of Rac1 and RhoA and downstream MEK/ERK and ROCK signaling, respectively. Consistent with these results, analyses of PDAC patient datasets revealed a strong positive association between ECT2 expression and Rho GTPase as well as MEK/ERK and ROCK pathway signatures. Together, our data identify ECT2 as an early driver of PDAC transformation and highlight it as a promising therapeutic target. Citation Format: Dania Al-Qasrawi, Nayya N. Murray, Ryan A. Argo, Alicia K. Fleming Martinez, Prita Pandya, Anaya Y. Clarke, Kayla C. Winter, Murli Krishna, Peter Storz, Nicole R. Murray, Verline Justilien, . The Rho-GEF ECT2 links Rho GTPases to MEK/ERK pathway activation in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5993.

Abstract Lung cancer remains the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases. Despite advances in targeted and immuno-therapies, overall survival for NSCLC remains below 25%, due to late-stage detection and therapeutic resistance. Cancer stem cells (CSCs), a highly tumorigenic subpopulation within NSCLC, drive relapse, metastasis, and treatment failure. Understanding the mechanisms by which CSCs promote the aggressiveness of NSCLC may reveal new diagnostic and therapeutic opportunities. CSCs establish an intercellular communication network through the secretion of extracellular vesicles (EVs), membrane-bound nanoparticles that transport proteins, lipids, and nucleic acids that can influence recipient cell behavior. Our previous work demonstrated that CSCs secrete significantly more EVs compared to bulk cancer cells (BCCs) and induce an enhanced tumorigenic phenotype in BCCs. However, the EV protein cargo that mediates these CSC-driven phenotypes and the signaling they promote remain poorly understood. This study aimed to identify and characterize CSC-derived EV protein cargo that contributes to NSCLC growth and metastasis. CSC- and BCC-derived EVs were isolated using tangential flow filtration and characterized according to MISEV guidelines. Mass spectrometry and pathway analysis were performed to compare the proteome of CSC- and BCC-derived EVs, followed by functional characterization in vitro and in vivo. Our results showed that EVs exhibited expected morphological, biochemical, and physical properties. Pathway analyses showed that CSC-derived EVs were enriched in proteins that localize to exosomes and associate with metabolism and cell adhesion. Comparison of BCC and CSC-derived EVs revealed Desmoglein-2 (DSG2) as one of the proteins exclusively detected in CSC-derived EVs. shRNA-mediated knockdown of DSG2 significantly reduced invasion, clonal expansion, and transformed growth in vitro and decreased tumor growth and metastasis in vivo. Furthermore, DSG2-competent EVs partially rescued the effects of DSG2 knockdown on CSC tumor growth in vivo. Together, these findings identify DSG2 as a key CSC-specific EV protein cargo that promotes an enhanced tumorigenic phenotype and NSCLC tumor growth. This work highlights the role of CSC-derived EV proteins as mediators of NSCLC aggressiveness and as candidates for biomarker and therapeutic development. Citation Format: Prita Pandya, Aamena Ahmed, Nayya Murray, Dania S. Al-Qasrawi, Anaya Y. Clarke, Reagan Carris, Verline Justilien. Desmoglein-2 carrying cancer stem cell-derived extracellular vesicles promote lung cancer aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 833.

Abstract Vertebral metastatic disease results from many types of cancer and can have a devastating impact on patient mobility, psychological health, quality of life, and ultimately overall patient survival. However, the development of radiotherapy and surgical techniques has rapidly surged in conjunction with ongoing advances in basic science and translational studies. In this review, we discuss the paradigm shift in our understanding of the epidemiology and treatment algorithms for spinal oncology, ranging from preoperative optimization strategies, radiation and surgical techniques, the utilization of molecular markers and targeted therapeutics in medical oncology, and prognostication tools that underscore a new multidisciplinary approach to spinal oncology care.

ABSTRACT Recent advances in the diagnosis and management of reflux disease were the central focus of the inaugural Gatherings in Esophagology (GiE), which convened experts across gastroenterology, surgery, otolaryngology, pulmonology, and basic research. The sessions highlighted innovations in reflux monitoring—including high‐resolution manometry, wireless pH monitoring, and novel salivary biomarkers—while critically evaluating their diagnostic accuracy and clinical utility. Presentations explored the limitations of traditional proton‐pump inhibitor therapy, the emergence of potassium‐competitive acid blockers as a new class of acid suppressants, and the evolving role of adjunctive treatments such as mucosal protectants, reflux reducers, and neuromodulators for refractory symptoms. The discourse extended to advanced interventional procedures, including transoral incisionless fundoplication, magnetic sphincter augmentation, and the RefluxStop device, with discussion of patient selection, efficacy, and complication management. Discussants emphasized the pathophysiology and management of extraesophageal manifestations of reflux, the interplay between reflux and pulmonary disease, and the diagnostic challenges in pediatric populations. The meeting also addressed the integration of behavioral therapies, the role of the microbiome, and the application of artificial intelligence in reflux diagnostics. Collectively, these insights underscore a shift toward precision medicine in reflux disease, emphasizing individualized diagnostic strategies and tailored therapeutic approaches to improve patient outcomes.

INTRODUCTION: Chronic gastroduodenal disorders are highly prevalent and encompass heterogeneous pathophysiology. Autonomic dysfunction may contribute, but its relative contribution to disease pathophysiology and symptoms is unclear. This study aimed to clarify the contributions of autonomic dysfunction in gastroduodenal disorders and symptom associations using multimodal testing, hypothesizing that distinct disorder subgroups would be revealed. METHODS: This prospective observational cohort study included 80 patients with chronic gastroduodenal symptoms. Participants underwent expert clinician-led autonomic evaluation, body surface gastric mapping (BSGM; Gastric Alimetry, New Zealand), and gastric emptying scintigraphy testing. BSGM phenotyping, gastric emptying cutoffs, and autonomic criteria followed standard criteria. RESULTS: Gastroparesis was diagnosed in 27 (33.8%) patients. Autonomic dysfunction was present in 21 (26.3%) patients, and abnormal BSGM in 20 (25%). Autonomic dysfunction and abnormal BSGM were both more prevalent in gastroparesis (51.9% vs 13.2%, P = 0.001; and 44.4% vs 15.1%, P = 0.005, respectively). However, these diagnoses tended not to overlap, with patients having autonomic dysfunction generally exhibiting normal BSGM tests. Autonomic dysfunction independently predicted delayed gastric emptying (OR 13.8, P < 0.001) and was associated with earlier meal responses (higher meal response ratio, P = 0.04) and worse postprandial distress symptoms ( P < 0.05). DISCUSSION: Autonomic dysfunction independently predicted delayed gastric emptying and revealed a gastroparesis mechanism distinct from gastric myoelectrical impairment. Autonomic dysfunction altered the postprandial gastric motor response and was associated with a greater symptom burden. Multimodal physiological testing including autonomic profiling reveals distinct mechanistic subgroups in patients with chronic gastroduodenal symptoms.

OBJECTIVE Chordomas are rare, locally aggressive primary neoplasms. Resection with negative margins is the primary recommended therapeutic approach, while adjuvant radiotherapy and chemotherapy can also play a role in their treatment in certain situations, including lesions with positive margins or those that are poorly differentiated or dedifferentiated. Cervical spine chordomas pose significant surgical challenges given their proximity to critical anatomical structures and the mechanical constraints of the cervical spine. In the current case series, authors aimed to explore the clinical and patient-reported outcomes (PROs) of the surgical treatment of cervical chordomas in a large multicenter cohort. METHODS This multicenter case series analysis utilized data from the prospectively collected Primary Tumor Research and Outcomes Network (PTRON) registry, from its inception (May 16, 2016) to data extraction (February 29, 2024). The study population was restricted to patients with histologically confirmed cervical chordomas involving levels C0–7, who underwent surgical treatment at one of the participating centers, and for whom both the initially planned and postoperatively pathologically confirmed surgical margins were documented. Patient demographics, tumor characteristics, surgical and adjuvant treatments, local recurrence–free survival (LRFS), overall survival (OS), and perioperative adverse events were retrieved. PROs included the Spine Oncology Study Group Outcomes Questionnaire version 2.0 (SOSGOQ2.0), EQ-5D, and SF-36 version 2.0 (SF-36v2). RESULTS Thirty-eight patients were identified, 12 of whom underwent true en bloc resection (EBR), 18 of whom underwent deliberate intralesional resection, and 8 of whom underwent EBR after intralesional surgery or in whom EBR failed. True EBR led to better LRFS (92% vs 83% vs 63%, respectively) and OS (83% vs 39% vs 50%, respectively). Surgical adverse events within 1 year were more frequent with true EBR (100% vs 39% vs 75%, respectively). EQ-5D, SOSGOQ2.0, and SF-36v2 showed improvement with true EBR, whereas the trends for PROs from the other groups were more variable. CONCLUSIONS This multicenter case series analysis provides critical insights into the clinical outcomes and PROs in the largest cohort of surgically treated cervical spine chordomas described to date. It underscores the importance and challenges of wide resection for oncological control. It establishes the associated morbidity and provides an overview of PROs following surgery. These findings contribute valuable evidence to inform shared decision-making and optimize patient care.

Abstract Hypoparathyroidism is an endocrine disease caused by insufficient levels of PTH, which acts directly on bone and kidney and indirectly on the intestine to regulate calcium and phosphate balance. In clinical trials, palopegteriparatide (TransCon PTH) treatment enabled independence from conventional therapy (no active vitamin D, ≤600 mg/d calcium) and maintained serum biochemistries within normal ranges. The current analyses describe patterns of change in BMD, serum bone turnover markers, and serum and urine calcium in adults with chronic hypoparathyroidism treated with palopegteriparatide through 3 years of the PaTH Forward trial. Baseline BMD Z-scores for the LS, TH, FN, and 1/3 distal radius were above zero, indicating bone mass exceeding age-adjusted normative values. BMD decreased from these elevated baseline levels with palopegteriparatide treatment, with larger reductions during the first 26 weeks and modest declines thereafter. Mean BMD Z-scores at week 162 remained above zero for all 4 sites. Participants with lower baseline BMD (Z-scores below −1 and T-scores below −2.5) generally exhibited lesser declines in BMD versus those with higher baseline BMD. Palopegteriparatide treatment was associated with early increases in bone resorption (serum C-terminal telopeptide of type I collagen, CTx) and bone formation (serum procollagen type 1 N-terminal propeptide, P1NP) that peaked at weeks 12 and 26, respectively, followed by declines to levels moderately higher than baseline at week 162. Mean CTx and P1NP in the overall population and the subgroup of postmenopausal women were below their upper limits of normal from weeks 58-162. At week 162, mean serum and median urine calcium remained within normal ranges and 91% of participants were independent from conventional therapy. These results suggest that long-term palopegteriparatide therapy in adults with chronic hypoparathyroidism gradually returns the skeleton toward its natural state thereby enhancing the skeleton’s contribution to calcium homeostasis.

Study Design Narrative Review. Objectives To summarize the scientific contributions generated from the AO Spine Knowledge Forum Tumor (AOSKFT) databases, focusing on primary spine tumors, and highlight key findings, research trends, and future directions. Methods Data from the Primary Tumor Retrospective (PT-Retro) and Primary Tumor Research Outcome Network (PTRON) registries were analyzed. The nineteen studies included were peer-reviewed manuscripts focused on primary spine tumors, excluding abstracts, book chapters, systematic reviews, and metastatic studies. Results The PT-Retro registry compiled data from 1495 patients across 18 primary tumor histologies, offering insights into recurrence, survival, and treatment paradigms. Key findings emphasize the importance of Enneking-appropriate (EA) resection in improving survival and reducing recurrence in tumors such as chordoma, chondrosarcoma, and osteosarcoma. Genetic markers, including hTERT promoter mutations and rs2305089 SNP, were linked to prognosis in specific histologies. Benign tumors, such as giant cell tumors and aneurysmal bone cysts, demonstrated variable outcomes with different surgical approaches and selective arterial embolization. Conclusions The AOSKFT registries have significantly advanced knowledge in primary spine tumor management, emphasizing preoperative staging, surgical margins, and multidisciplinary approaches. International, multicentric registries are essential for studying rare diseases like primary spine tumors, enabling robust data collection, improved statistical power, and broader applicability of findings across diverse clinical settings. Ongoing prospective data collection through PTRON will further refine evidence-based care for these rare and challenging conditions.