Colorectal cancer (CRC) is a leading cause of cancer-related mortality in the Western world. While brain metastasis (BMs) are relatively uncommon in CRC, they represent the fourth most frequent cause of BMs overall, and their occurrence is increasingly recognized as a complication in advanced CRC, associated with poor prognosis and limited treatment options. The brain microenvironment presents unique metabolic challenges, including low oxygen levels and restricted lipid availability. In order to survive in this hostile environment, CRC cells must acquire metabolic adaptations allowing them to survive and proliferate. To identify key drivers that enable CRC cells to metastasize to and survive within the brain, we conducted a transcriptomic screen of CRC BMs and compared it to liver metastasis (LMs). FOXM1, a transcription factor critical for tumor progression, was identified among the upregulated genes, and these results were validated by immunohistochemistry. To study the role of the brain microenvironment in mediating FOXM1 expression, we examined FOXM1 expression in CRC cell lines grown in either astrocyte-conditioned media (A-CM) or hepatocyte-conditioned media (H-CM). We observed a marked upregulation of FOXM1 following exposure to A-CM. Moreover, using an intracranial CRC BMs mouse model, a significant FOXM1 overexpression was observed. In accordance with the importance of fatty acid metabolism in BMs, our study revealed a significant correlation between FOXM1 and fatty acid synthase (FASN) in the CRC BMs, in agreement with public databases. These findings suggest that FOXM1 plays a key role in CRC BMs progression and may serve as a promising therapeutic target in this challenging disease setting.

BACKGROUND:Diabetes and cancer exhibit a high likelihood of co-occurrence. Diabetes serves as a risk factor for various forms of cancer and is associated with a poorer prognosis. SGLT2 (sodium-glucose cotransporter 2) inhibitors (SGLT2i) are effective antidiabetic therapies associated with reduced all-cause mortality in the general population; however, data among the population with cancer are scarce. We aimed to assess the safety and efficacy of SGLT2i therapy among patients with diabetes and cancer. METHODS:A large retrospective, single-center study including 849 patients diagnosed with diabetes and active cancer. Patients were divided into 2 groups: 169 patients treated with SGLT2i before cancer diagnosis and 680 patients SGLT2i naive. The primary end point was all-cause mortality. The secondary end point was the composite of cardiovascular outcomes, including heart failure, acute coronary syndrome, and arrhythmias. RESULTS:After a median follow-up of 48 months (interquartile range, 27-72), all-cause mortality was significantly lower in the SGLT2i group (67% versus 53%, P=0.001). Multivariable Cox regression identified SGLT2i as an independent predictor of reduced all-cause mortality (hazard ratio, 0.676 [95% CI, 0.532-0.860], P=0.001). Cardiovascular outcomes were higher in the SGLT2i group (28% versus 16%, P=0.001), driven by increased heart failure events (14% versus 7%, P=0.008). After propensity score matching, SGLT2i remained a significant predictor of reduced mortality (P=0.016), with no significant differences in cardiovascular outcome (P=0.067). CONCLUSIONS:SGLT2i was associated with lower all-cause mortality in patients diagnosed with diabetes and cancer. Randomized clinical trials are needed to confirm these findings and explore the underlying mechanism.

BackgroundGastric neuroendocrine tumors (gNETs) are rare malignancies with distinct biological behavior compared with gastric adenocarcinoma. Data directly comparing surgical and oncologic outcomes, including lymph node yield, recurrence pattern, and survival, remain limited.MethodsA retrospective review of 285 gastrectomies (2014-2024) identified 20 gNET and 265 adenocarcinoma cases. After excluding palliative procedures and mixed histology, propensity-score matching (1:2.5; age, sex, BMI, and comorbidities) yielded 18 gNET and 45 adenocarcinoma patients. Outcomes included lymph node harvest, nodal metastasis, lymph node ratio (LNR), recurrence pattern, disease-free survival (DFS), and overall survival (OS).ResultsMedian lymph node yield was lower in gNET than in adenocarcinoma (18 vs 28; P = 0.004), and the overall rate of nodal metastasis did not differ between groups (44.4% vs 44.4%; P = 1.00), although the nodal metastatic burden was significantly lower in gNET as reflected by a lower median number of positive nodes and lymph node ratio (LNR 0.05 vs 0.17; P = 0.008), with no gNET patient exhibiting pN3 disease. DFS was comparable (21.4 vs 18.7 months; P = 0.617), whereas OS favored gNET (45.3 vs 27.4 months; P = 0.045). Peritoneal recurrence was markedly less frequent in gNET (16.7% vs 81.3%; P = 0.003), while hepatic relapse predominated. Perioperative morbidity and 90-day mortality were similar.ConclusionCompared with adenocarcinoma, gastric neuroendocrine tumors show reduced nodal metastatic burden, lower peritoneal dissemination, and improved overall survival. These findings support biology-adapted lymphadenectomy and surveillance for gNET, although validation in larger cohorts is required.

Activating mutations in the ligand-binding domain of the estrogen receptor (ER)-encoding (ESR1) gene are present in up to 40% of metastatic breast cancer (BC) patients and are strongly associated with a high risk of liver metastasis (LM) formation. Using the MCF-7 BC model, we investigated whether the increased hepatic tropism of ESR1-mutated BC cells is driven by their metabolic adaptation to the liver microenvironment. Indeed, metabolomic analysis revealed elevated metabolites related to the urea cycle (UC) in LM-forming ESR1-mutated cells compared to wild-type (WT) ER-expressing cells, which failed to generate LM. The subsequent proteomic, western blotting, and qPCR analyses demonstrated a dramatic upregulation of the UC constituent, the mitochondrial ornithine/citrulline transporter SLC25A15, in liver-predilected ESR1-mutated cells relative to their WT counterpart cells. Unlike WT cells, ESR1-mutated cells readily formed spheroids and exhibited enhanced migration in liver mimicking hepatocyte-conditioned media. In addition, we employed a novel ex vivo approach where ESR1 mutated cells were seeded onto colonized fresh liver tissue—which was abolished by SLC25A15 knockout. Moreover, SLC25A15 knockout robustly reduced the ability of ESR1-mutated cells to establish LM in vivo. These findings highlight SLC25A15-mediated dysregulation of the UC as a critical driver of BC hepatic metastasis and identify SLC25A15 as a potential therapeutic target for disrupting metastatic spread of BC to the liver.

Breast cancer is the most diagnosed cancer among women worldwide. Klotho is a protein with well-established anti-aging and tumor-suppressive functions, including a documented role in cancer biology such as breast cancer. However, the role of circulating Klotho levels as a biomarker in breast cancer patients remains unclear. We examined serum Klotho in relation to breast cancer and clinicopathological factors, including estrogen receptor (ER), progesterone receptor (PR), HER2 status, lymph node involvement, and body mass index (BMI). A total of 372 individuals were analysed: breast cancer patients (n=166), ductal carcinoma in situ (DCIS, n=24), and controls (n=182). Serum Klotho was measured by enzyme-linked immunosorbent assay (ELISA); comparisons used nonparametric Kruskal-Wallis and Mann-Whitney U tests with Bonferroni correction. Klotho was higher in breast cancer patients than controls (p < 0.01), similar between invasive and in situ disease, and correlated positively with insulin-like growth factor 1 (IGF-1) (p < 0.01), but not with BMI, ER, PR, HER2, or lymph node invasion. These findings raise the possibility that the Klotho–IGF-1 correlation reflects a negative feedback mechanism, whereby IGF-1 may promote Klotho secretion while Klotho may in turn attenuate downstream IGF-1R signalling, a mechanism that warrants further investigation as a potential regulator of IGF-1-driven tumorigenesis.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment outcomes. However, the response varies across different populations, and their use may lead to life-threatening cardiovascular (CV) events. While pre-treatment reduced left ventricular ejection fraction (LVEF) is considered a marker for high-risk cardiotoxicity and a contraindication for anthracycline and HER2-targeted therapies, there is limited evidence on the safety and efficacy of ICIs therapy in patients presenting with pre-treatment reduced LVEF. The study aims to evaluate the safety and efficacy of ICIs therapy in patients with pre-treatment reduced LVEF. Retrospective single center cohort of patients treated with ICIs therapy, who performed pre-treatment LVEF assessment. The primary endpoint was to evaluate the safety of ICIs among this population, assessed by CV events (composite of myocarditis, acute coronary syndrome, heart failure, and arrhythmias). The secondary endpoint was to evaluate the efficacy of ICIs, assessed by all-cause mortality and progression-free survival (PFS). The cohort included 307 patients, with 30 (10 Safety and Efficacy of ICIs in pre-treatment reduced LVEF. ICIs = Immune checkpoint inhibitors, LVEF=left ventricular ejection fraction, CV=cardiovascular, HF=heart failure, ACS=acute coronary syndrome, HR=hazard ratios.

Disclosure: E. Osher: None. N. Lubezky: None. R. Geva: None. D. Mirelman: None. Y. Sofer: None. L. Ben-Haim: None. Y. Goykhman: None. I. Wolf: None. Y. Greenman: None. An 86-year-old female presented with mesenteric neuroendocrine tumor (NET) Grade 1 (Ki67 <1%), in May 2021. Due to disease progression the patient underwent palliative small bowel resection, and consequently, somatostatin analog therapy was initiated. Two years later, the patient reported visual disturbances. Full-field electroretinogram revealed retinal dysfunction affecting both rod and cone photoreceptors, with severe vitamin A deficiency (<0.02µg/ml). Symptoms improved 4 days following high dose vitamin A supplementation. Vitamin A deficiency retinopathy is a vision-threatening condition that, while uncommon in developed countries, typically results from malabsorption due to bowel surgery or medication effects rather than poor nutrition. Data on the link between vitamin A deficiency in patients with NETs or endocrine disorders, treated with somatostatin analog is rare. In literature review, a cohort study of 55 patients receiving long-term somatostatin analogue therapy (>18 months), 19 patients were treated for acromegaly and 36 for neuroendocrine tumors (NETs). Of those, vitamin A deficiency was reported in 6%, causing night blindness in 2 NET patients. Risk factors included extended bowel resection and older age. Other fat-soluble vitamin deficiencies were common (K1: 63%, E: 58%, D: 28%), with 78% having at least one deficiency, and 32% showing multiple deficiencies. Conclusions: Fat-soluble vitamin deficiencies are significantly more common than previously thought in long-term somatostatin analogue users including Vitamin A. Regular monitoring and supplementation are recommended, particularly in elderly patients and those with a history of intestinal resection. Presentation: Saturday, July 12, 2025

Supplementary Figure S2 demonstrates the infiltration of mature innate immune cells to the liver during breast carcinogenesis

OBJECTIVE:To examine the role of circulating tumor cell analysis in tailoring therapy for recurrent ovarian cancer by determining the survival outcomes of patients who received circulating tumor cell-guided therapy. METHODS:A retrospective chart review of patients who received circulating tumor cell-guided therapy for recurrent epithelial ovarian cancer at a single center between September 2015 and May 2024. RESULTS:Of 334 records of patients reviewed, 88 patients (26.35%) were referred to circulating tumor cell testing to determine tumor response to therapy and 66 (19.76%) received circulating tumor cell-guided therapy. The median progression-free survival of patients who received circulating tumor cell-guided therapy was significantly longer compared to that of their previous treatment line: 6.70 months (95% confidence interval [CI] 5.30 to 10.80) versus 4.40 months (95% CI 3.77 to 5.83), p = .0042. Twenty-seven patients (55.1%) had a progression-free survival 2/progression-free survival 1 ratio >1.3, suggesting clinical benefit. Patients who received circulating tumor cell-guided therapy had statistically significantly longer median overall survival from circulating tumor cell testing, adjusted for age at diagnosis and stage compared to patients who underwent circulating tumor cell testing but were not treated by circulating tumor cell-guided therapy (13.83 months [95% CI 8.44 to 22.14] versus 2.04 months [95% CI 1.77 to not evaluable], p = .0001). Patients with ≤5 circulating tumor cells expressing epithelial cell adhesion molecule per mL had longer overall survival from circulating tumor cell testing compared to those with >5 epithelial cell adhesion molecule per milliliter. CONCLUSIONS:This retrospective real-world study suggests that circulating tumor cell-guided therapy may enable better disease management, prolonging time on therapy and predicting longer survival after testing. Studies with larger cohorts are necessary to confirm our findings.

OBJECTIVE:Advanced epithelial ovarian cancer (EOC) poses a significant clinical challenge due to its typically late diagnosis and poor prognosis. However, a subset of patients exhibit remarkably prolonged survival. Identifying prognostic factors and developing tools for estimating outcomes may provide tailored strategies for treatment escalation or de-escalation. This study aimed to identify prognostic factors associated with patient survival and develop a prognostic model estimating EOC patients' overall survival and risk of recurrence (ROR). METHODS:We conducted a retrospective analysis of 1049 women diagnosed with EOC from January 2002 until June 2024. Clinical, pathological, and molecular data, including germline BRCA pathogenic variants (PVs), and homologous recombination repair analysis were performed. Long-term survivors (LTS), defined as those surviving over 7 or 10 years, and short-term survivors (STS), defined as those surviving less than 2 years were compared. A prognostic model was developed using multivariable logistic regression to estimate survival probabilities and recurrence risk. RESULTS:Among the study cohort with advanced disease (FIGO stage III-IV), 20.3% survived beyond 7 years and 9.8% beyond 10 years. Factors significantly associated with LTS included younger age, lower disease stage, complete tumor resection, BRCA PV, and treatment with poly (ADP-ribose) polymerase inhibitors. The prognostic model, integrating age, stage, BRCA status, and tumor resection, provided survival estimates and ROR for 2, 5, 7, and 10 years from diagnosis. This tool is based on retrospective logistic regression analysis of long-term and STS across all stages (I-IV). CONCLUSIONS:This study reaffirms established prognostic factors of LTS with advanced EOC and introduces a novel prognostic calculator integrating clinical variables. The tool may assist in personalizing treatment plans and guiding clinical decisions. Validation in multi-institutional cohorts is necessary to confirm its universal utility and applicability.

INTRODUCTION:Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment. While generally well-tolerated, some immune-related adverse events (ir-AEs) can impact patient care, highlighting the need for accurate diagnosis. Immunotherapy-related gastritis and duodenitis (ir-GD) is a rare ir-AE. Due to its low incidence and nonspecific symptoms, standardized diagnostic criteria and evidence-based treatment guidelines are lacking. METHODS:We conducted a retrospective analysis of patients undergoing esophagogastroduodenoscopy (EGD) while receiving ICI. Our diagnostic criteria for ir-GD required at least two of three gastritis or duodenitis (GD) criteria (symptoms, EGD findings, or microscopic findings) along with at least one ICI-related criterion. Patients with ir-GD were compared to those without ir-GD. RESULTS:Of 2553 patients treated with ICI between 2017 and 2023, 62 (2.4%) underwent EGD, of whom nine (0.4%) met the ir-GD diagnostic criteria. Nine other patients (0.4%) had GD unrelated to ICI. Notably, three of the nine patients (33%) with ir-GD had preexisting inflammatory gastrointestinal conditions, compared to two of 53 patients (4%) in the non-ir-GD cohort (P = .019). Patients with ir-GD were significantly more symptomatic (100% vs 58%, P = .009). However, no single symptom was specific to ir-GD. While eight of nine (89%) patients with ir-GD were treated with proton pump inhibitors, only three (33%) required corticosteroids. Symptom resolution occurred in all patients, and three patients successfully underwent rechallenge. CONCLUSION:ir-GD is a rare ir-AE that can be challenging to distinguish from GD caused by other etiologies. Once diagnosed, clinicians may consider nonsteroidal treatment approaches in mild cases and, in selected cases, even ICI rechallenge.

Supplementary Table S4 lists the antibodies used for FACS

Supplementary Extended Data 1 describes the FACS gating startegy

Background/Objective: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting adverse effect of various chemotherapeutic agents. Previous work demonstrated that cannabis alleviates symptoms of oxaliplatin-induced CIPN. To evaluate the effects of cannabis components, cannabidiol (CBD) and tetrahydrocannabinol (THC), on CIPN-related symptoms. Methods: We reviewed a patient-reported outcomes dataset from “Tikun Olam,” a major medical cannabis provider. Of 1493 patients, 802 reported at least one CIPN symptom at baseline, including a burning sensation, cold sensation, paresthesia (prickling) and numbness, and 751 of them met the study inclusion criteria. Patients were categorized into THC-high/CBD-low and CBD-high/THC-low groups. Symptom changes after six months of cannabis use were analyzed using K-means clustering and logistic regression, incorporating interactions between baseline symptoms and THC and CBD doses. Linear regression assessed changes in activities of daily living (ADL) and quality of life (QOL). Results: Both groups reported symptom improvement. The THC-high group showed significantly greater improvement in burning sensation and cold sensation (p = 0.024 and p = 0.008). Improvements in ADL and QOL were also significantly higher in the THC group (p = 0.029 and p = 0.006). A significant interaction between THC and CBD was observed for symptom improvement (p < 0.0001). Conclusions: Cannabis effectively reduces CIPN symptoms and improves QOL and ADL. Higher THC doses were more effective than lower doses, with combined CBD and THC doses yielding greater symptom relief.

e24118 Background: Cancer immunotherapy has emerged as a cornerstone of modern cancer treatment. While generally considered well-tolerated, some immune-related adverse events (irAEs) can impact patient care, making accurate diagnosis essential. Immune-related gastritis and duodenitis (irGD) are two rare side effects of immunotherapy. Since these conditions affect only a small number of patients, standardized diagnostic criteria and evidence-based treatment guidelines are lacking. Methods: We conducted a retrospective analysis of patients undergoing esophagogastroduodenoscopy (EGD) while receiving immune checkpoint inhibitors (ICIs). For this study, a diagnosis of irGD required meeting at least two of three criteria to qualify as GD (suggestive symptoms, EGD findings, or pathology findings) and at least one criterion supporting a causal link to ICI treatment. Patients with irGD were compared to those without irGD. Results: Of 2,553 patients treated with ICI, 62 (2.4%) underwent EGD and were eligible for our study, of whom nine (0.4%) met the diagnostic criteria for irGD. An additional, nine patients (0.4%) had gastritis or duodenitis unrelated to ICI treatment. Notably, three of the nine patients (33%) with irGD had pre-existing inflammatory gastrointestinal conditions including inflammatory bowel disease or celiac disease, compared to two of 53 patients (4%) in the non-irGD cohort (P = 0.019). Patients with irGD were significantly more symptomatic (100% vs 58%, P = 0.009). However, no single symptom was specific for irGD, including epigastric pain (33% vs. 19%, P = 0.38), nausea (44% vs. 15%, P = 0.062) and gastrointestinal bleeding (33% vs. 17%, P = 0.357). While all patients with irGD were treated with proton pump inhibitors, only three (33%) required steroid treatment. Treatment discontinuation was more common in patients with irGD (44% vs. 6%, P = 0.001). Symptom resolution was recorded in all patients, and three patients successfully underwent rechallenge, including one with grade 3 irGD, after completing a course of steroid treatment. Conclusions: irGD is a rare irAE that is challenging to distinguish from GD caused by other etiologies. Upon diagnosis, clinicians may consider non-steroid treatment regimen and, in selected patients, even ICI rechallenge.

Supplementary Figure S1 demonstrates global metabolic changes in liver metabolism during early BC carcinogenesis