Tumor Distant Metastasis Research Articles

The association between controlling nutritional status and postoperative pulmonary complications in patients with colorectal cancer

BackgroundPostoperative pulmonary complications (PPCs) significantly impact surgical outcomes, and Controlling Nutritional Status (CONUT) score, a simple and easily available nutritional score, has been demonstrated to be significantly associated with postoperative patient outcomes and complications, including PPCs. However, there are few studies that specifically focus on patients undergoing radical surgery for colorectal cancer (CRC).MethodsWe retrospectively analyzed the clinical data of 2,553 patients who underwent radical surgery for CRC at the Sixth Affiliated Hospital of Sun Yat-sen University. Patients were divided into three groups: normal nutrition group (CONUT≤1), mild malnutrition group (2 ≤ CONUT≤4), and moderate-to-severe malnutrition group (CONUT≥5). Risk factors for PPCs and all-cause mortality were evaluated by multivariate regression. In addition, we assessed surgical outcomes including ICU admission, hospital stay, 1-year mortality and tumor-related mortality.ResultsThe incidence of PPCs was 9.0% (n = 230). Multiple regression showed that the higher the CONUT score, the higher the risk of PPCs (mild malnutrition group vs. normal nutrition group, OR: 1.61, 95% CI: 1.18–2.20, p = 0.003; moderate-to-severe malnutrition group vs. normal nutrition group, OR: 2.41, 95% CI: 1.51–3.84, p < 0.001). All-cause mortality was significantly higher in moderate-to-severe malnutrition group than that in normal nutrition group, HR: 1.88, (95% CI: 1.34–2.62, p < 0.001). Older age, male sex, chronic heart disease, open surgery, blood transfusion during surgery, distant metastasis of tumor and colon tumor were all risk factors for PPCs. Furthermore, the malnutrition groups had poor surgical outcomes including postoperative pneumonia (mild vs. normal nutrition, OR: 1.64, 95% CI: 1.07–2.52, p = 0.024; moderate-to-severe vs. normal nutrition, OR: 2.51, 95% CI: 1.36–4.62, p = 0.00), ICU admission (mild vs. normal nutrition, OR: 2.16, 95% CI: 1.31–3.56, p = 0.002; moderate-to-severe vs. normal nutrition, OR: 3.86, 95% CI: 2.07–7.20, p < 0.001), hospital stay ≥14 days (mild vs. normal nutrition, OR: 1.30, 95% CI: 1.08–1.56, p = 0.006) and 1-year mortality (mild vs. normal nutrition, HR: 1.65, 95% CI: 1.11–2.46, p = 0.014; moderate-to-severe vs. normal nutrition, HR: 2.27, 95% CI: 1.28–4.02, p = 0.005).ConclusionThe preoperative CONUT score is a potential indicator for predicting PPCs and surgical outcomes in CRC patients.

A high number of tumor deposits (≥ 4) is an isolated predictor of local recurrence and distant metastasis in non-metastatic colorectal cancer: a single center study

IntroductionLocal recurrence and distant metastasis after curative surgery and chemotherapy for colorectal cancer (CRC) is a serious complication and is considered a failure of the therapeutic strategy. The aim of this study is to identify the different prognostic factors associated with tumor recurrence and distant metastasis in CRC.DesignAn analytical cross-sectional design was employed, and our hospital clinical and pathology databases were queried for non-metastatic CRC (stage I-III). Patients were included if they underwent surgery and chemotherapy between 01/2016 to 12/2018 and demographic information, tumor characteristics and postoperative outcomes were extracted from each case. The data were entered into a database using SPSS version 21. Univariate analysis was initially performed, followed by a multivariate analysis to develop a prognostic model for tumor recurrence and distant metastasis in CRC.ResultA total of 138 non-metastatic CRC patients were enrolled in this study. The demographic characteristics of all patients are summarized in Table 1. Our study included 65 male and 73 female patients with a Median (IQR) age of 69 (17.7) years. Among the cases, 91 (65.9%) patients had no recurrence, and 47 (34.1%) patients developed a recurrence during follow-up. Univariate analysis revealed that positive lymph nodes (p = 0.03) and tumor deposits ≥ 4 (p = 0.04) were significantly associated with colorectal tumor recurrence and/or metastasis. However, variables such as age, sex, smoking, alcohol consumption, family history of CRC, PNI, LVI, tumor size, and histological features like mucinous or signet ring cell morphology did not show any statistical significance (p > 0.05). Multivariate analysis adjusted for age, lymph node status, and tumor deposits, identified that tumor deposits ≥ 4 was the only predictor of tumor recurrence following colorectal surgery and chemotherapy. Conversely, positive lymph node status did not show statistical significance (p = 0.3). Further analysis revealed that patients who had tumor deposit number ≥ 4 tend to experience local recurrence/distant metastasis more than patients with tumor deposit number < 4.ConclusionIn non-metastatic CRC patients, TD ≥ 4 is a strong predictor of local tumor recurrence and distant metastasis. Based on these findings, patients who have TDs in primary CRC resection should be subjected to enhanced surveillance.

Ultrasound-triggered drug-loaded nanobubbles for enhanced T cell recruitment in cancer chemoimmunotherapy.

Chemotherapy combined with immunotherapy is a highly promising approach for treating tumors. However, chemotherapeutic drugs often fail to accumulate effectively at the tumor site after systemic administration and they lack sufficient immunogenicity to activate adaptive immunity, making an effective T-cell immune response within the tumor microenvironmentdifficult to achieve. Here, this work developed drug-loaded nanobubbles (DTX-R837@NBs) that encapsulate the chemotherapy drug docetaxel and the immune adjuvant R837 via a thin-film hydration method. Ultrasound-targeted nanobubble destruction promoted drug accumulation within tumor tissues and damaged tumor cells through the cavitation effect, inducing immunogenic cell death and releasing damage-associated molecular patterns to augment dendritic cell maturation. Notably, DTX-R837@NBs exhibited excellent contrast-enhanced ultrasound imaging capabilities, enabling the seamless integration of diagnosis and treatment. In combination with immune checkpoint blockade targeting programmed cell death protein 1 (PD-1), the generated immunological responses attacked residual tumor cells and ameliorated the immunosuppressive tumor microenvironment, inhibiting distant tumor growth and metastasis. Moreover, this strategy exhibited robust immune memory effects, effectively protecting the host and preventing tumor recurrence upon rechallenge. Overall, ultrasound-mediated DTX-R837@NBs combined with anti-PD-1 immune checkpoint blockade therapy exhibits robust antitumor efficiency, represent a promising strategy for overcoming immunotherapy resistance in cold tumors, and warrant further investigation for clinical translation.

Gene expression profiling for the diagnosis of male breast cancer

BackgroundMale breast cancer (MBC) is a rare malignancy, but its global incidence has shown a notable increase in recent decades. Factors such as limited health literacy, inadequate health education, and reluctance to seek medical attention contribute to the late-stage diagnosis of most MBC patients. Consequently, there is an urgent need for a highly specific and sensitive diagnostic approach to MBC.MethodsThis retrospective study enrolled 20 patients with 30 surgical or biopsy MBC specimens from August 2020 to August 2023. The 90-gene expression assay was performed to determine the tissue of origin. Predicted tumor types were then compared to the reference diagnosis for accuracy calculation. The differentially expressed genes were identified between male and female breast cancer.ResultThe 90-gene expression assay demonstrated an overall accuracy of 96.7% (29/30) when compared with the pathological diagnosis. For primary, lymph node metastatic, and distant metastatic tumors, the accuracies were 100% (15/15), 90.9% (10/11), and 100% (4/4), respectively. Five genes (RPS4Y1, PI15, AZGP1, PRRX1, and AGR2) were up-regulated, and six (XIST, PIGR, SFRP1, PLA2G2A, S100A2, and CHI3L1) were down-regulated in MBC.ConclusionOur findings highlight the promising performance of the 90-gene expression assay in accurately identifying the tumor origin in MBC. Incorporating this assay into pathological diagnoses has the potential to empower oncologists with precision treatment options, ultimately enhancing the care and outcomes for patients with MBC.

Utilization of 3D-Printed Customized Uncemented Stem Prostheses for Revision of Aseptic Loosening in the Distal Femoral Cemented Prostheses: Case Series and Literature Review.

Aseptic loosening (AL) is a common mechanical complication following reconstruction of the distal femoral cemented prosthesis (DFCP), often resulting in severe bone loss, which complicates prosthesis revision. 3D-printed personalized implants represent an emerging solution for the reconstruction of complex bone defects. This study aimed to investigate the early therapeutic effects of using a 3D-printed, customized, uncemented stem prosthesis for revising aseptic AL in DFCP. From June 2021 to December 2022, a retrospective review was conducted on six consecutive patients who underwent revision surgery due to AL of the DFCP with a 3D-printed customized uncemented stem prosthesis. The study included four male and two female patients, with an average age of 58 ± 11 (range: 46-75) years. All six patients had previously undergone limb salvage surgery using a cemented megaprosthesis after tumor resection. Preoperative imaging evaluation was performed for all patients, and the personalized design of the prostheses was achieved through 3D printing based on CT imaging data. Regular clinical and radiographic follow-up was conducted postoperatively, with the main outcome measures being oncological outcomes, prosthesis survival, osseointegration, complications, and lower limb function. All patients successfully underwent surgery and were followed up for a mean duration of 30.33 ± 6.15 (range: 24-38) months. All patients were alive at the last follow-up, with no tumor recurrence or distant metastasis. No complications such as infection, loosening, or fracture of the prosthesis occurred. Osseointegration was satisfactory, with a mean MSTS score of 26 (range: 20-28) points. 3D-printed, customized, uncemented stem prosthesis exhibit immediate initial stability and reliable biocompatibility. Early clinical outcomes are satisfactory, making them an effective method for revision AL of DFCP.

Susceptibility of Mitophagy-Deficient Tumors to Ferroptosis Induction by Relieving the Suppression of Lipid Peroxidation.

The identification of ferroptosis-sensitive cancers is critical for the application of ferroptosis-inducing therapies in cancer therapy. Here, patient-derived organoid screening models of colorectal cancer are established to identify tumors that are sensitive to ferroptosis-inducing therapy. This study discovers that patient-derived tumors characterized by mitophagy deficiency are hypersensitive to ferroptosis-inducing therapies. Mechanistically, a novel negative feedback regulatory pathway of lipid peroxidation is identified, which is one of the important intrinsic anti-ferroptosis mechanisms of cancer cells. Lipid peroxidation-mediated endoplasmic reticulum stress transcriptionally upregulates Parkin to promote mitophagy through ATF4. Mitophagy limits the generation of lipid peroxidation products and subsequently inhibits ferroptosis by inhibiting the accumulation of mitochondrial ROS. Mitophagy-deficient tumors lack this anti-ferroptotic mechanism, unleashing the generation of lipid peroxidation and potent ferroptotic cell death induced by erastin, RSL3, cysteine deprivation, radiotherapy, and immunotherapy. More importantly, ferroptosis-inducing therapy selectively inhibits the growth and distant metastasis of mitophagy-deficient tumors in vivo. In summary, patient-derived organoids of colorectal cancer patients for screening ferroptosis-sensitive tumors are established, providing a paradigm for identifying that patient-derived tumors are sensitive to ferroptosis-inducing therapies. This study concludes that mitophagy-deficient tumors are vulnerable to ferroptosis induction, which may lead to the development of new therapeutic strategies for tumors deficient in mitophagy.

The value of a nomogram based on 18F-FDG PET/CT metabolic parameters and metabolic heterogeneity in predicting distant metastasis in gastric cancer.

To investigate the value of metabolic parameters and metabolic heterogeneity from pretreatment deoxy-2-[fluorine-18]-fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) in predicting distant metastasis in gastric cancer. Eighty-six patients with pathologically confirmed gastric adenocarcinoma were included in this study. All patients underwent a whole-body 18F-FDG PET/CT scan before treatment. Clinicopathologic and imaging data were collected, including metabolic parameters such as maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary gastric cancer lesions. Heterogeneity index (HI)-1 was expressed as the absolute value of the linear regression slopes between the MTVs at different SUVmax thresholds (40%×SUVmax, 80%×SUVmax), while HI-2 was expressed as the difference between SUVmax and SUVmean. Patients were randomly divided into training and validation cohorts at a 7:3 ratio. The correlation between the above parameters and distant metastasis in gastric cancer was analyzed using the training cohort. A nomogram prediction model was then established and later verified with the validation cohort. Finally, decision curve analysis was used to evaluate the clinical utility of the model. This study included 86 patients with gastric cancer, with 60 (69.8%) in the training cohort and 26 (30.2%) in the validation cohort. There was no significant difference in the balanced comparison between both cohorts (all P>.05). Among all patients, 31 (36.0%) developed distant metastasis, while 55 (64.0%) did not. In patients who developed distant tumor metastasis, carcinoembryonic antigen, carbohydrate antigen (CA)12-5, CA19-9, CA72-4, MTV, TLG, and HI-1 were significantly higher than in patients without distant metastasis (all P<.05). Multivariate logistic regression analysis identified CA72-4 (OR: 1.151, 95% CI: 1.020-1.300, P=.023) and HI-1 (OR: 1.647, 95% CI: 1.063-2.553, P=.026) as independent risk factors for predicting distant metastasis in gastric cancer. The nomogram constructed from this analysis exhibited high predictive efficacy in the training (AUC: 0.874, 95% CI: 0.766-0.983) and validation (AUC: 0.915, 95% CI: 0.790-1.000) cohorts, providing a net clinical benefit for patients. HI-1 is an independent risk factor for predicting distant metastasis in gastric cancer. A comprehensive prediction model combining HI-1 with the tumor marker CA72-4 can increase the net clinical benefit for patients.

Clinical applications of circulating tumor cell detection: challenges and strategies.

Circulating tumor cells (CTCs) are pivotal in the distant metastasis of tumors, serving as one of the primary materials for liquid biopsy. They hold significant clinical importance in assessing prognosis, predicting efficacy, evaluating therapeutic outcomes, and studying recurrence, metastasis, and resistance mechanisms in cancer patients. Nevertheless, the rareness and heterogeneity of CTC and the complexity of metastasis make the clinical application of CTC detection confront many challenges, which may need to be settled by some practical strategies. This article will review the content mentioned above.

Tumor-derived exosomes: unravelling the pathogenesis of pancreatic cancer with liver metastases and exploring the potential for clinical translation.

Pancreatic cancer (PC) is one of the most malignant solid cancers, and PC metastasis, particularly liver metastasis, is a major cause of cancer mortality. A key event in tumor metastasis is the formation of pre-metastatic niche (PMN), which provides a microenvironment conducive to tumor cells colonization and progression. Various molecules loaded in tumor-derived exosomes (TDEs) contribute to PMN formation and distant tumor metastasis, by regulating immune and stromal cell function, inducing angiogenesis, and promoting metabolic reprogramming. Therefore, therapies targeting PMN may offer novel advantages to prevent tumor metastasis at an earlier stage. In this review, we summarize multifaceted mechanisms underlying hepatic PMN formation, with a focus on how PC TDEs participate in angiogenesis and vascular permeability, create immune suppressive microenvironment, remodel the extracellular matrix, and regulate metabolic reprogramming. In addition, we highlight the promise of TDEs for early diagnosis and effective therapy of PC liver metastases.

Dissection of RET p.M918T-driven progression of hereditary vs. sporadic medullary thyroid cancer.

Whether inherited in the context of multiple endocrine neoplasia 2B at germline level or acquired in a lifetime, all RET p.M918T (RET c.2753T>C) mutations should activate the RET tyrosine kinase receptor alike, with similar degrees of medullary thyroid cancer (MTC) progression when disparities in disease onset and multifocal growth are accounted for. This cross-sectional analysis of RET p.M918T-driven progression of hereditary MTC (33 patients) vs. sporadic MTC (36 patients) sought to explore this hypothesis. Patients with hereditary disease were significantly younger at thyroidectomy (medians of 10 vs. 57 yrs.) and featured significantly more often multifocal growth (69 vs. 14%) with more thyroid tumor foci (medians of 2 foci vs. 1 focus) than patients with sporadic disease. Although the former had 3.6-fold smaller primary thyroid tumor diameters (medians of 5 vs. 18mm) and twice as many neck nodes dissected (medians of 66.5 vs. 32 nodes) than the latter, extrathyroid tumor extension (42 vs. 36%), node metastasis (64 vs. 77%), distant metastasis (33 vs. 17%), and biochemical cure rates (45 vs. 35%) were fairly comparable, as was the number of dissected node metastases (medians of 7 vs. 8 involved nodes). Sensitivity analyses, with breakdown of patients by tumor multifocality and nodal status, corroborated these findings. RET p.M918T-driven progression of MTC is similar in hereditary and sporadic disease, barring earlier development and more frequent multifocal growth of hereditary MTC. This makes a compelling case for referral of patients with RET p.M918T-driven MTCs to specialist surgical centers.

18F]FDG PET/CT beyond staging: Prognostic significance of sarcopenia and adipose tissue metabolism in esophageal carcinomas.

This study aimed to investigate the relationship between PET and CT parameters and sarcopenia, adipose tissue, and tumor metabolism in esophageal carcinoma (EC) and its impact on survival in EC. Our study included 122 EC patients who underwent PET/CT for staging. Muscle and adipose tissue characteristics were evaluated, including lumbar (L3) and cervical (C3) muscle areas, psoas major (PM) and sternocleidomastoid muscle (SCM) parameters, and PET parameters for visceral and subcutaneous adipose tissue (SAT). Sarcopenia was determined using CT images, with a threshold for muscle tissue at the L3 vertebral level, and its impact on overall survival (OS) was investigated. Sarcopenia was detected in 48 patients. SULmax in the primary tumor (PT) was significantly higher in sarcopenic patients (SP). The frequency of distant metastasis was higher in SP and OS was significantly lower. In the locally advanced stage, sarcopenia status decreased survival. L3, PM, C3, and SCM muscle areas were highly correlated. Subcutaneous adipose tissue SUVmax was significantly increased in SP and those with distant metastasis. Univariate analysis identified PT SULmax, PT SUVmean, PT TLG, lymph node and distant metastasis, SAT SUVmax, and sarcopenia as poor prognostic factors, while multivariate analysis confirmed BMI, distant metastasis, PT SUVmean, PT TLG as independent predictors of OS. This study demonstrated that sarcopenia, linked to reduced survival, correlates with primary tumor SULmax, distant metastasis, and subcutaneous tissue PET parameters, exerting a notable impact on survival, particularly in locally advanced stages. Attenuation-corrected CT can be used instead of diagnostic CT, and sarcopenia can be diagnosed using not only L3 but also C3 slices.

ASPH dysregulates cell death and induces chemoresistance in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is resistant to multiple conventional drugs including sorafenib, leading to poor prognosis. Inducing cell death has been inextricably pursued in therapeutics, although targeted therapy and immunotherapy have made very limited progress. ASPH (Aspartate β-hydroxylase) can be breakthrough in meeting this unmet clinical need. In HCC, high expression of ASPH enhanced proliferation, migration and invasion. High levels of ASPH predicted worse clinical outcomes of sorafenib-treated HCC patients. Mechanistically, ASPH upregulated SQSTM1/P62 and SLC7A11-GPX4 axis, thereby promoting tumor cell autophagy but blocking ferroptosis. Sorafenib-induced enhancement of autophagy was attenuated by knockout (KO) of ASPH, resulting in sensitization of tumor cells to sorafenib. By silencing ASPH combined with sorafenib, senescence, apoptosis and ferroptosis were mediated, whereas proliferation, migration, invasion, tube formation and stemness were inhibited. As validated by in vivo murine models of HCC, ASPH promoted tumor growth, distant metastasis, and resistance to sorafenib. By contrast, KO ASPH combined with sorafenib effectively inhibited tumor development and progression, including intrahepatic, pulmonary, and splenic metastases. Targeting ASPH generated antitumor efficacy will pave the way for HCC therapy.

The clinical significance of signal regulatory protein alpha expression in the immune environment of gastric cancer.

Signal regulatory protein alpha (SIRPα) inhibits phagocytosis by macrophages by interacting with CD47. Despite its known role in various cancers, the clinical significance of SIRPα in gastric cancer (GC) remains unclear. This study aimed to elucidate the clinical implications of SIRPα in GC, exploring its relevance to immunotherapy efficacy and the tumor microenvironment. Two cohorts were studied: a gastrectomy cohort (137 patients) and an immune checkpoint inhibitor (ICI)-treated cohort (19 patients with unresectable advanced GC who received nivolumab). Immunohistochemistry was used to assess SIRPα, CD80, CD163, CD8, and PD-L1 expressions. Kaplan-Meier curves and Cox models were used to analyze the clinical outcomes. In vitro experiments used peripheral blood mononuclear cells and THP-1 macrophage cell lines to examine SIRPα responses to interferon-γ (IFN-γ). In the gastrectomy cohort, high SIRPα expression correlated with advanced tumor invasion, distant metastasis, and poor recurrence-free and overall survival. SIRPα expression was also significantly associated with macrophage and CD8 + T cells infiltration and PD-L1 expression. In the ICI-treated cohort, high SIRPα expression was associated with better overall survival after nivolumab induced. Moreover, in vitro IFN-γ stimulation upregulated SIRPα expression on monocytes in peripheral blood mononuclear cells and THP-1 cells, suggesting high SIRPα expression may reflect an active immune microenvironment. SIRPα expression is not only a poor prognostic factor for GC, possibly through inhibition of the CD47-SIRP⍺ pathway, but may also be involved in the efficacy of ICI therapy in GC.

Liver resection in patients with a history of local ablation for hepatocellular carcinoma has the risk of poor survival and serosal invasion

AbstractAimThe aim was to evaluate the impact of previous local ablation (LA) on long‐term prognoses and tumor histopathological findings following hepatectomy for hepatocellular carcinoma (HCC).MethodsThis retrospective study used data from patients who underwent initial hepatectomy for HCC at Ehime University Hospital between October 2003 and July 2021. Using data from a total of 234 patients, after excluding patients with distant metastasis or macroscopic residual tumors and patients with mixed HCC, a group of 39 patients who underwent post‐ablation liver resection (PALR) was compared with a group of 195 non‐PALR patients with respect to patient characteristics, perioperative data, pathological findings, and outcomes.ResultsNumber of tumors was significantly greater and diameter of tumor was smaller in PALR group than those of non‐PALR group. Both overall survival (OS) and recurrence‐free survival (RFS) were significantly poor in PALR group than those of non‐PALR (5‐year OS 54.1% vs. 66.9%, p = 0.024; 5‐year RFS 24.7% vs. 37.0%, p = 0.019). However, PALR was not selected as independent prognosticator in multivariate analyses. In PALR group, tumor size ≥3 cm was sole independent prognosticator in multivariate analyses. Multivariate analysis showed that PALR [odds ratio (OR), 8.989; 95% confidence interval (CI), 2.807–28.787], alpha‐fetoprotein level &gt;40 ng/mL (OR, 2.923; 95% CI, 1.063–8.035), and des‐γ‐carboxyprothrombin level &gt;170 mAU/mL (OR, 5.164; 95% CI, 1.622–16.438) were independent predictors of pathological serosal invasion.ConclusionsHepatectomy for patients with history of LA for HCC had a risk of serosal invasion and poor survival.

Abstract C010: Tumor MK2 drives tumor progression and an immunosuppressive microenvironment in head and neck squamous cell carcinoma

Abstract Background: Head and neck squamous carcinoma (HNSCC) results in poor patient outcomes driven primarily by locoregional and distant metastatic tumor spread. We have demonstrated that highly phosphorylated/active MAPKAPK-2 (MK2) is a poor prognostic factor in HNSCC patients. MK2 is associated with the expression of pro-inflammatory cytokines that are linked with creating a pro-tumorigenic microenvironment. Nevertheless, how MK2 contributes to HNSCC development has not been established. In this study, we aimed to identify the effect of MK2 on cancer progression, immune infiltration, and cytokine secretion. Method: To assess the effect of tumor MK2 in vivo, we used CRISPR-Cas9 to knock out (KO) MK2 in a metastatic murine HNSCC cell line, Ly2, and orthotopically implanted wildtype (WT) or MK2 KO cells into the floor-of-mouth of Balb/c mice. At the endpoint of the experiment, the tumors were excised, and myeloid and lymphocyte immune profiling was done via flow cytometry. Mouse lungs and cervical lymph nodes were dissected, paraffin-fixed, sectioned, and H&amp;E stained, and the presence/quantity of metastatic foci was evaluated by a blinded board-certified pathologist. We broadly evaluated the tumor secretome via a 105-cytokine dot blot array using 8 mg of the same resected tumor sample and performed densitometric analysis comparing WT and KO tumors. Results: Loss of MK2 significantly reduced primary tumor growth, as well as lymph node and lung metastasis, compared to WT tumors. Tumor immunophenotyping by flow cytometry revealed that MK2 KO tumors had increased overall immune cell (CD45+) infiltration, but decreased quantities of immunosuppressive neutrophils (CD11b+Ly6G+Arg1+Ly6C-) and a shift in macrophage polarity favoring M1 (anti-tumor) macrophages (CD11b+Ly6G-F4-80+CD80+). In addition, there were increased quantities of anti-tumor immune cells including natural killer (NK)-T, CD4+, and CD8+ T cells in the MK2-KO tumors, while the proportion of CD4+CD25+ Tregs and exhausted CD8 T cells (CD8+PD1+) was decreased compared to WT tumors. Furthermore, cytokine array analysis revealed that secreted levels of several cytokines, including CXCL1, CXCL2, GM-CSF, G-CSF, IL-1alpha, and IL-6, were significantly lower in MK2 KO tumors compared to WT tumors. Conclusion: These results show that tumoral MK2 signaling promotes tumor growth, metastasis, immunosuppressive inflammation, and pro-tumorigenic cytokine release which substantiates future therapeutic targeting of this pathway. Citation Format: Dakota D.D. Okwuone, Deri Morgan, Alyssa Schmidt, Devin Shrock, Yuting Lin, Hao Gao, Sufi M. Thomas, Gregory N. Gan. Tumor MK2 drives tumor progression and an immunosuppressive microenvironment in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C010.

Abstract A003: Snord67 promotes breast cancer metastasis through U6-mediated alternative splicing

Abstract Small nucleolar RNAs (snoRNAs) a class of ncRNAs that canonically guide post-transcriptional modifications, including 2'-O-methylation, on ribosomal RNA (rRNA) and small nuclear RNA (snRNA). While traditionally considered housekeeping genes, snoRNAs have increasingly been found to function in diverse physiologic and pathologic processes, including cancer. In an immune-competent murine model of triple negative breast cancer (TNBC) lymphatic metastasis, we identified the snoRNA Snord67 as one of the most upregulated noncoding RNAs in axillary LN (AxLN) tumors relative to mammary fat pad (MFP) tumors and lung metastases. Loss of Snord67 resulted in decreased colony formation and spheroid size in murine and human TNBC cell lines, and led to decreased lymph node tumor growth and decreased distant metastases in two immune-competent murine models of TNBC lymphatic dissemination. To determine the mechanism by which Snord67 promotes tumor growth and metastasis, we examined the impact of Snord67 on 2'-O-methylation, gene expression, and alternative splicing. Loss of Snord67 in TNBC cell lines led to decreased 2'-O-methylation at the C60 nucleotide (Cm60) in the core spliceosome component U6 snRNA. Re-introduction of wild-type Snord67 rescued Cm60 in U6 snRNA and rescued the colony formation and spheroid phenotypes of the Snord67 knockout cell lines. However, a mutant Snord67 incapable of guiding U6 Cm60 only partially rescued these in vitro phenotypes, suggesting that Snord67 promotes in vitro tumor cell growth at least in part by guiding Cm60 in U6 snRNA. We then performed RNA sequencing of Snord67 knockout and wild-type murine and human TNBC cell lines. We found that loss of Snord67 led to widespread changes in alternative splicing, consistent with its role in guiding 2'-O-methylation of the core spliceosome component U6. We further demonstrated that the inclusion of alternatively spliced cassette exons in MYO18A and NFYA was not only downregulated upon Snord67 knockout in a human TNBC cell line, but also positively correlated with Snord67 expression levels in primary breast tumors and lymph node metastases from breast cancer patients. Based on these results, we propose a model in which Snord67 guides U6 Cm60, which leads to a pro-metastatic alternative splicing program and thereby promotes lymph node tumor growth and distant metastasis. Citation Format: Katherine I Zhou, Yvonne Chao, Kwame K Forbes, Alessandro Porrello, Gabrielle M Gentile, Aaron C Chack, Dixcy J.S. John Mary, Haizhou Liu, Yinzhou Zhu, Eric Cockman, Lincy Edatt, Grant A Goda, Justin Zhao, Hala Abou Assi, Hannah J Wiedner, Yi-Hsuan Tsai, Lily Wilkinson, Amanda E Van Swearingen, Lisa A Carey, Jimena Giudice, Daniel Dominguez, Christopher L Holley, Chad V Pecot. Snord67 promotes breast cancer metastasis through U6-mediated alternative splicing [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A003.

The Impact of Synchrotron Microbeam Radiation Therapy Combined With Broad Beam in a Preclinical Breast Cancer Model

PURPOSEBoth local tumor control and distant metastasis are important indicators of the efficacy of radiotherapy treatment. Synchrotron Microbeam Radiotherapy (MRT), spatially fractionated radiation delivered at ultra-high dose-rates, shows remarkable normal tissue sparing with excellent local control in some models. Some MRT regimens trigger an antitumor immune response that contributes not only to the local, but also to systemic treatment efficacy. Despite recent advances for treatment of primary breast cancer, metastatic disease is still the major cause of treatment failure in the clinic. Here, in an aggressive preclinical triple-negative breast cancer model, we compared local tumor response and metastasis following different MRT treatment programs. EXPERIMENTAL DESIGN4T1.2 mouse mammary tumors were treated with 300-Gy peak-/7-Gy valley-dose MRT and/or 8-Gy broad-beam (BB) radiation, all delivered as daily fractionated programs (three consecutive daily sessions of either MRT or BB, or one MRT combined with two BB sessions, the first or last of the three fractions). The mice were euthanized on day 9 post-last irradiation, when unirradiated control animals reached ethical endpoint. Primary tumors were collected to evaluate immune cell prevalence, while lungs, spinal cords, and locoregional lymph nodes were collected to measure metastatic burden. In parallel, local tumor growth and survival were monitored. RESULTSThe combined MRT/BB treatment shifted the balance between pro- and anti-tumorigenic macrophages towards accumulation of anti-tumorigenic macrophages in the tumor. Monitoring of the tumor volume and animal health indicated the benefit of the combined MRT/BB treatment for local control and treatment tolerance, while animal survival was only marginally longer for one combined schedule. The metastatic burden was similar for all four treatment schedules. CONCLUSIONAddition of single MRT to BB treatment improved the primary tumor response. This provides a basis for future experiments incorporating adjuvant immunotherapy or chemotherapy, to improve local and systemic treatment outcomes.

Bioorthogonal Janus microparticles for photothermal and chemo-therapy.

Bioorthogonal chemistry, recognized as a highly efficient tool in chemical biology, has shown significant value in cancer treatment. The primary objective is to develop efficient delivery strategies to achieve enhanced bioorthogonal drug treatment for tumors. Here, Janus microparticles (JMs) loaded with cyclooctene-modified doxorubicin prodrug (TCO-DOX) and tetrazine-modified indocyanine green (Tz-ICG) triggers are reported. Besides activating TCO-DOX, Tz-ICG is also a photothermal agent used in photothermal therapy (PTT), enabling the simultaneous use of biorthogonal chemotherapy and PTT. Additionally, the DOX could be significantly reduced in systemic toxicity with the modification of cyclooctene. Thus, the developed drug-carrying JMs system exhibits effective tumor cell killing in vitro and effectively inhibits tumor local progress and distant lung metastasis after postoperative treatment with good safety. These results demonstrate that the prepared JMs provide a paradigm for bioorthogonal prodrug activation and localized delivery, and hold great promise for cancer therapy as well as other related applications.

Rare carcinoma of the ampulla of Vater with mixed histologies: A case report

The current case is about a 62-year-old female presented with persistent fever for 10 days and yellowing of the skin for 5 days at our outpatient clinic. Laboratory tests revealed elevated levels of total bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and &amp;gamma;-glutamyl transpeptidase. Abdominal computed tomography, magnetic resonance imaging, and magnetic resonance cholangiopancreatography revealed a mass in the ampulla of Vater, as well as dilatation of the intra- and extra-hepatic bile and pancreatic ducts. The patient underwent pancreaticoduodenectomy under general anesthesia. Post-operative pathological and immunohistochemical results confirmed a tumor located in the ampulla, measuring 1.5 &amp;times; 1 &amp;times; 1 cm. The main component of the tumor was a moderately differentiated pancreaticobiliary adenocarcinoma (ADC), combined with squamous cell carcinoma (SCC) as well as small cell neuroendocrine carcinoma (SCNEC). The cancer tissue infiltrated the entire intestinal wall, with no invasion of microvessels, lymphatic vessels, or nerves observed. Until 46 months later, there was no tumor recurrence or distant metastasis. We present an uncommon case of ADC of the ampulla of Vater combined with SCC and SCNEC. Carcinoma of the ampulla of Vater may have mixed histological components; therefore, in cases of ampullary carcinoma, appropriate specimen collection is necessary, and further studies with more focus on histological origins are required.

EPID-26. STEREOTACTIC RADIOSURGERY FOR CRANIAL NERVE METASTASES: A SINGLE INSTITUTION EXPERIENCE

Abstract Cranial nerve metastases (CNM) can be primary via leptomeningeal metastasis or secondary by spread due to head and neck cancers or due to distant tumor metastasis to the skull base. In addition, they may cause cranial nerve-related symptoms that can impact patient quality of life. We performed a single-center retrospective cohort study of all patients with CNM treated with SRS at our institution between April 2003 and February 2021. Demographic and clinical information were retrieved from the electronic medical record. Median follow-up was 12.9 months. Our study cohort consisted of 9 patients with primary CNM and 8 with secondary CNM – for a total of 17 patients, with a total of 33 lesions (23 primary, 10 secondary). Eleven patients (64.7%) had symptoms caused by cranial nerve metastases. Symptoms were resolved in 5 of 11 patients (45.5%) after SRS. Patients with secondary CNM were more likely to have cranial nerve symptoms and more likely to have resolution of symptoms following SRS. The median time between SRS and symptom improvement was 3 months. Local tumor control was achieved in 30 of 33 lesions (90.9%). Local tumor control at 6 months and at 1 year were 100%. Our study suggests that SRS may be a safe and effective treatment for cranial nerve metastasis providing 90.9% local tumor control at final follow-up, and symptomatic stability or improvement in 90.9% of symptomatic cases. Patients with secondary CNM may stand to benefit more from a symptom management standpoint.