Late-stage Cancer Research Articles

Single-cell analyzing of tumor microenvironment and cell adhesion between early and late-stage lung cancer

Lung adenocarcinoma (LUAD) is a highly heterogeneous disease that threaten human life with serious incidence and high mortality. High heterogeneity of tumor microenvironment (TME) was reported in multiple studies. However, the factor of controlling the tumor migration progression between eary and late-stage LUAD is still not fully understood. In this study, we conducted a comprehensive analysis of single-cell RNA sequencing (scRNA-seq) data of LUAD obtained from the GEO database. The identification of cell clusters revealed significant expansion of epithelial cells in late-stage patients. Interpretation of the cell-cell communication results between early-stage and late-stage patient samples indicated that early tumor cells may interact with epithelial cells through the TGF-β pathway to promote tumor progression. The cell cycle analysis demonstrated a significant increase in the number of cells in the G2 and M phases in late-stage lung cancer. Further analysis using Non-negative Matrix Factorization (NMF) revealed early-stage cell-specific gene features involved in cell adhesion-related biological processes. Among these, the Tensin (TNS) gene family, particularly TNS1, showed high expression in epithelial cells and fibroblasts of early-stage samples, specifically associated with cell adhesion. Survival analysis using TCGA database for LUAD demonstrated that patients with high expression of TNS1 exhibited significantly higher overall survival rates compared to those with low expression. Immunofluorescence experiments have demonstrated co-expression of TNS1 with fibroblast and tumor cell markers (α-SMA and EPCAM). Immunohistochemistry experiments further validated the significantly higher expression levels of TNS1 in early-stage LUAD tissues compared to late-stage lung cancer tissues (P<0.05). Pathway experiments have shown that early-stage tumor patients with high expression of TNS1 exhibit stronger phosphorylation levels of Akt and mTOR, indicating a more potent activation of the Akt/mTOR signaling pathway. In conclusion, the results of this study demonstrate that TNS1 is an adhesive molecule in the immune microenvironment of early-stage tumor cells, and it may serve as a novel prognostic marker for lug cancer.

Development and therapeutic evaluation of 5D3(CC-MLN8237)3.2 antibody-theranostic conjugates for PSMA-positive prostate cancer therapy.

Prostate cancer (PC) is an aggressive cancer that can progress rapidly and eventually become castrate-resistant prostate cancer (CRPC). Stage IV metastatic castrate-resistant prostate cancer (mCRPC) is an incurable late-stage cancer type with a low 5-year overall survival rate. Targeted therapeutics such as antibody-drug conjugates (ADCs) based on high-affinity monoclonal antibodies and potent drugs conjugated via smart linkers are being developed for PC management. Conjugating further with in vitro or in vivo imaging agents, ADCs can be used as antibody-theranostic conjugates (ATCs) for diagnostic and image-guided drug delivery. In this study, we have developed a novel ATC for PSMA (+) PC therapy utilizing (a) anti-PSMA 5D3 mAb, (b) Aurora A kinase inhibitor, MLN8237, and (c) for the first time using tetrazine (Tz) and trans-cyclooctene (TCO) click chemistry-based conjugation linker (CC linker) in ADC development. The resulting 5D3(CC-MLN8237)3.2 was labeled with suitable fluorophores for in vitro and in vivo imaging. The products were characterized by SDS-PAGE, MALDI-TOF, and DLS and evaluated in vitro by optical imaging, flow cytometry, and WST-8 assay for cytotoxicity in PSMA (+/-) cells. Therapeutic efficacy was determined in human PC xenograft mouse models following a designed treatment schedule. After the treatment study animals were euthanized, and toxicological studies, complete blood count (CBC), blood clinical chemistry analysis, and H&E staining of vital organs were conducted to determine side effects and systemic toxicities. The IC50 values of 5D3(CC-MLN8237)3.2-AF488 in PSMA (+) PC3-PIP and PMSA (-) PC3-Flu cells are 8.17nM and 161.9nM, respectively. Pure MLN8237 shows 736.9nM and 873.4nM IC50 values for PC3-PIP and PC3-Flu cells, respectively. In vivo study in human xenograft mouse models confirmed high therapeutic efficacy of 5D3(CC-MLN8237)3.2-CF750 with significant control of PSMA (+) tumor growth with minimal systemic toxicity in the treated group compared to PSMA (-) treated and untreated groups. Approximately 70% of PSMA (+) PC3-PIP tumors did not exceed the threshold of the tumor size in the surrogate Kaplan-Meyer analysis. The novel ATC successfully controlled the growth of PSMA (+) tumors in preclinical settings with minimal systemic toxicities. The therapeutic efficacy and favorable safety profile of novel 5D3(CC-MLN8237)3.2 ATC demonstrates their potential use as a theranostic against aggressive PC.

Inhibition of δ-catenin palmitoylation slows the progression of prostate cancer

Prostate cancer (PCa) is the second leading cause of death in males. It has been reported that δ-catenin expression is upregulated during the late stage of prostate cancer. Palmitoylation promotes protein transport to the cytomembrane and regulates protein localization and function. However, the effect of δ-catenin palmitoylation on the regulation of cancer remains unknown. In this study, we utilized prostate cancer cells overexpressing mutant δ-catenin (J6A cells) to induce a depalmitoylation phenotype and investigate its effect on prostate cancer. Our results indicated that depalmitoylation of δ-catenin not only reduced its membrane expression but also promoted its degradation in the cytoplasm, resulting in a decrease in the effect of EGFR and E-cadherin signaling. Consequently, depalmitoylation of δ-catenin reduced the proliferation and metastasis of prostate cancer cells. Our findings provide novel insights into potential therapeutic strategies for controlling the progression of prostate cancer through palmitoylation-based targeting of δ-catenin.

Advancing Evidence Generation for Circulating Tumor DNA: Lessons Learned from A Multi-Assay Study of Baseline Circulating Tumor DNA Levels across Cancer Types and Stages.

Circulating tumor DNA (ctDNA) holds promise as a biomarker for predicting clinical responses to therapy in solid tumors, and multiple ctDNA assays are in development. However, the heterogeneity in ctDNA levels prior to treatment (baseline) across different cancer types and stages and across ctDNA assays has not been widely studied. Friends of Cancer Research formed a collaboration across multiple commercial ctDNA assay developers to assess baseline ctDNA levels across five cancer types in early- and late-stage disease. This retrospective study included eight commercial ctDNA assay developers providing summary-level de-identified data for patients with non-small cell lung cancer (NSCLC), bladder, breast, prostate, and head and neck squamous cell carcinoma following a common analysis protocol. Baseline ctDNA levels across late-stage cancer types were similarly detected, highlighting the potential use of ctDNA as a biomarker in these cancer types. Variability was observed in ctDNA levels across assays in early-stage NSCLC, indicative of the contribution of assay analytical performance and methodology on variability. We identified key data elements, including assay characteristics and clinicopathological metadata, that need to be standardized for future meta-analyses across multiple assays. This work facilitates evidence generation opportunities to support the use of ctDNA as a biomarker for clinical response.

Demographic and clinical characteristics associated with advanced stage colorectal cancer: a registry-based cohort study in Saudi Arabia

BackgroundIn Saudi Arabia, approximately one-third of colorectal cancer (CRC) patients are diagnosed at an advanced stage. Late diagnosis is often associated with a worse prognosis. Understanding the risk factors for late-stage presentation of CRC is crucial for developing targeted interventions enabling earlier detection and improved patient outcomes.MethodsWe conducted a retrospective cohort study on 17,541 CRC patients from the Saudi Cancer Registry (1997–2017). We defined distant CRCs as late-stage and localized and regional CRCs as early-stage. To assess risk factors for late-stage CRC, we first used multivariable logistic regression, then developed a decision tree to segment regions by late-stage CRC risk, and finally used stratified logistic regression models to examine geographical and sex variations in risk factors.ResultsOf all cases, 29% had a late-stage diagnosis, and 71% had early-stage CRC. Young (< 50 years) and unmarried women had an increased risk of late-stage CRC, overall and in some regions. Regional risk variations by sex were observed. Sex-related differences in late-stage rectosigmoid cancer risk were observed in specific regions but not in the overall population. Patients diagnosed after 2001 had increased risks of late-stage presentation.ConclusionOur study identified risk factors for late-stage CRC that can guide targeted early detection efforts. Further research is warranted to fully understand these relationships and develop and evaluate effective prevention strategies.

Intracellular delivery of oncolytic viruses with engineered Salmonella causes viral replication and cell death

Intracellular delivery of oncolytic viruses with engineered Salmonella causes viral replication and cell death

CDK9 inhibition activates innate immune response through viral mimicry.

Cancer cells frequently exhibit hyperactivation of transcription, which can lead to increased sensitivity to compounds targeting the transcriptional kinases, in particular CDK9. However, mechanistic details of CDK9 inhibition-induced cancer cell-selective anti-proliferative effects remain largely unknown. Here, we discover that CDK9 inhibition activates the innate immune response through viral mimicry in cancer cells. In MYC over-expressing prostate cancer cells, CDK9 inhibition leads to the gross accumulation of mis-spliced RNA. Double-stranded RNA (dsRNA)-activated kinase can recognize these mis-spliced RNAs, and we show that the activity of this kinase is required for the CDK9 inhibitor-induced anti-proliferative effects. Using time-resolved transcriptional profiling (SLAM-seq), targeted proteomics, and ChIP-seq, we show that, similar to viral infection, CDK9 inhibition significantly suppresses transcription of most genes but allows selective transcription and translation of cytokines related to the innate immune response. In particular, CDK9 inhibition activates NFκB-driven cytokine signaling at the transcriptional and secretome levels. The transcriptional signature induced by CDK9 inhibition identifies prostate cancers with a high level of genome instability. We propose that it is possible to induce similar effects in patients using CDK9 inhibition, which, we show, causes DNA damage invitro. In the future, it is important to establish whether CDK9 inhibitors can potentiate the effects of immunotherapy against late-stage prostate cancer, a currently lethal disease.

Microbiome signatures associated with clinical stages of gastric Cancer: whole metagenome shotgun sequencing study

BackgroundGastric cancer is one of the global health concerns. A series of studies on the stomach have confirmed the role of the microbiome in shaping gastrointestinal diseases. Delineation of microbiome signatures to distinguish chronic gastritis from gastric cancer will provide a non-invasive preventative and treatment strategy. In this study, we performed whole metagenome shotgun sequencing of fecal samples to enhance the detection of rare bacterial species and increase genome sequence coverage. Additionally, we employed multiple bioinformatics approaches to investigate the potential targets of the microbiome as an indicator of differentiating gastric cancer from chronic gastritis.ResultsA total of 65 patients were enrolled, comprising 33 individuals with chronic gastritis and 32 with gastric cancer. Within each group, the chronic gastritis group was sub-grouped into intestinal metaplasia (n = 15) and non-intestinal metaplasia (n = 18); the gastric cancer group, early stage (stages 1 and 2, n = 13) and late stage (stages 3 and 4, n = 19) cancer. No significant differences in alpha and beta diversities were detected among the patient groups. However, in a two-group univariate comparison, higher Fusobacteria abundance was identified in phylum; Fusobacteria presented higher abundance in gastric cancer (LDA scored 4.27, q = 0.041 in LEfSe). Age and sex-adjusted MaAsLin and Random Forest variable of importance (VIMP) analysis in species provided meaningful features; Bacteria_caccae was the most contributing species toward gastric cancer and late-stage cancer (beta:2.43, se:0.891, p:0.008, VIMP score:2.543). In contrast, Bifidobacterium_longum significantly contributed to chronic gastritis (beta:-1.8, se:0.699, p:0.009, VIMP score:1.988). Age, sex, and BMI-adjusted MasAsLin on metabolic pathway analysis showed that GLCMANNANAUT-PWY degradation was higher in gastric cancer and one of the contributing species was Fusobacterium_varium.ConclusionMicrobiomes belonging to the pathogenic phylum Fusobacteria and species Bacteroides_caccae and Streptococcus_anginosus can be significant targets for monitoring the progression of gastric cancer. Whereas Bifidobacterium_longum and Lachnospiraceae_bacterium_5_1_63FAA might be protection biomarkers against gastric cancer.

Real-Life Prognosis of Sinonasal Tumors.

Sinonasal cancer represents a challenging disease because of its difficult diagnosis and different histology. Despite a multidisciplinary evaluation and treatments, a poor prognosis is still present. We retrospectively analyzed patients with sinonasal cancer treated in our institution, paying attention to histology and real-life prognosis. A total of 51 consecutive patients were included in the study. Clinical features were described. Overall, disease-free, and disease-specific survival (OS, DFS, DSS) according to histology were calculated. Kaplan-Meyer estimator curves were reported. The most prevalent primary tumor was squamous cell carcinoma, followed by adenocarcinoma. Global 2- and 5-year OS was 68.80% and 54.58%, respectively. Global 2- and 5-year DFS was 48.53% and 29.56%, while global 2- and 5-year DSS was 82.86% and 74.57%, respectively. The median OS was 74 and 43 months for early- and late-stage cancer, respectively. The Cox multivariate regression analysis did not reveal any statistically significant effects of age, stage, or histology on survival outcomes. The diagnosis is often late and the prognosis poor. An appropriate treatment, which is always quite multimodal, allows us to achieve a global 5-year OS slightly higher than 50%. An adequate diagnosis to increase the percentage of early-stage tumors is mandatory to improve prognosis.

TGFβ-Responsive Stromal Activation Occurs Early in Serrated Colorectal Carcinogenesis.

Activated TGFβ signaling in the tumor microenvironment, which occurs independently of epithelial cancer cells, has emerged as a key driver of tumor progression in late-stage colorectal cancer (CRC). This study aimed to elucidate the contribution of TGFβ-activated stroma to serrated carcinogenesis, representing approximately 25% of CRCs and often characterized by oncogenic BRAF mutations. We used a transcriptional signature developed based on TGFβ-responsive, stroma-specific genes to infer TGFβ-dependent stromal activation and conducted in silico analyses in 3 single-cell RNA-seq datasets from a total of 39 CRC samples and 12 bulk transcriptomic datasets consisting of 2014 CRC and 416 precursor samples, of which 33 were serrated lesions. Single-cell analyses validated that the signature was expressed specifically by stromal cells, effectively excluding transcriptional signals derived from epithelial cells. We found that the signature was upregulated during malignant transformation and cancer progression, and it was particularly enriched in CRCs with mutant BRAF compared to wild-type counterparts. Furthermore, across four independent precursor datasets, serrated lesions exhibited significantly higher levels of TGFβ-responsive stromal activation compared to conventional adenomas. This large-scale analysis suggests that TGFβ-dependent stromal activation occurs early in serrated carcinogenesis. Our study provides novel insights into the molecular mechanisms underlying CRC development via the serrated pathway.

Monitoring ROS Responsive Fe3O4-based Nanoparticle Mediated Ferroptosis and Immunotherapy via 129Xe MRI.

The immune checkpoint blockade strategy has improved the survival rate of late-stage lung cancer patients. However, the low immune response rate limits the immunotherapy efficiency. Here, we report a ROS-responsive Fe3O4-based nanoparticle that undergoes charge reversal and disassembly in the tumor microenvironment, enhancing the uptake of Fe3O4 by tumor cells and triggering a more severe ferroptosis. In the tumor microenvironment, the nanoparticle rapidly disassembles and releases the loaded GOx and the immune-activating peptide Tuftsin under overexpressed H2O2. GOx can consume the glucose of tumor cells and generate more H2O2, promoting the disassembly of the nanoparticle and drug release, thereby enhancing the therapeutic effect of ferroptosis. Combined with Tuftsin, it can more effectively reverse the immune-suppressive microenvironment and promote the recruitment of effector T cells in tumor tissues. Ultimately, in combination with α-PD-L1, there is significant inhibition of the growth of lung metastases. Additionally, the hyperpolarized 129Xe method has been used to evaluate the Fe3O4 nanoparticle-mediated immunotherapy, where the ventilation defects in lung metastases have been significantly improved with complete lung structure and function recovered. The ferroptosis-enhanced immunotherapy combined with non-radiation evaluation methodology paves a new way for designing novel theranostic agents for cancer therapy.

Dielectrophoretic Characterization and Computational Analysis of Peripheral Blood Mononuclear Cells from MMTV-PyMT Mammary Carcinoma Models for Late Carcinoma Detection

Breast cancer is the leading cancer in women, with 284,200 new cases and an estimated 43,600 deaths in 2021. Early detection and proper treatment can enhance outcomes. This study probes the dielectric properties of peripheral blood mononuclear cells (PBMCs) from MMTV-PyMT mice at 14+ weeks (stage IV) using a microfluidic platform for early breast cancer detection. The central hypothesis is that changes in subcellular components like the cytoskeleton, membrane, cytoplasm, and extracellular matrix at carcinoma onset regulate dielectric properties (conductivity, permittivity), affecting bioelectric signals that aid cancer detection. This is based on preliminary data showing unique PBMC dielectric properties from WT and PyMT tumor-bearing mice, identifying bioelectric signals regulating human adenocarcinoma cells. We hypothesize isolated PBMCs are altered in cancer compared to healthy bodies, evident in the MMTV-PyMT mouse model for analyzing human breast cancer mechanisms. Although specific PBMC change mechanisms are not investigated, we hypothesize these alterations can be detected using dielectrophoresis, a dielectric characterization technique utilizing non-uniform electric fields to manipulate and separate normal and cancer cells based on differing electrophysiological plasma membrane properties. Our results present dielectric properties of murine PyMT and WT PBMCs exhibiting unique cellular behavior, with numerical simulations validating these results. These unique characteristics can discriminate between cancer and non-cancer cells. This novel, label-free, rapid (~2 min), low-cost cell sorting technology detects and separates early and late breast cancer stages, leading to preclinical development and future clinical trials. The long-term goal is a non-invasive tool to determine breast cancer at earliest stages without false positives/negatives of standard mammography screening

Knowledge of cancer symptoms and risk factors: A cross-sectional study from a developing country.

The delayed presentation of cancer patients to healthcare facilities for diagnosis is a pressing issue, as late-stage cancer cases are often more challenging to treat effectively. In low-resource settings, such as those with limited access to healthcare facilities, the impact of inadequate awareness of cancer signs and symptoms can be particularly severe. Therefore, this study aimed to evaluate public knowledge of cancer signs and symptoms and risk factors in the context of Jordan. This cross-sectional study was conducted among participants from all settings. Data was obtained from an Arabic version of the cancer awareness measure (CAM), which was answered online. It described demographic data and knowledge of cancer prevalence, age-related risk, signs, symptoms, and risk factors in recall and recognition-type questions. Participants (n = 1998) completed the questionnaire with a Median age of 35 and an interquartile range of 24. About half (n = 1070) thought that cancer is unrelated to age. Most participants identified breast cancer as the most common cancer among women (81%). Awareness of cancer signs/symptoms significantly differed in the level of knowledge in favor of females. The symptom "unexplained weight loss" was most commonly recognized (66.3%) and "persistent difficulty swallowing" the least (42.6%). As for risk factors, "smoking" was the most identified (76.9%) and "eating less than 5 portions of fruits and vegetables a day" was the least (19%), and "doing <30 minutes of moderate physical activity 5 times a week" as a close second least (19.95%). Females identified "smoking," "passive smoking," "HPV infection," and "having a close relative with cancer" as risk factors significantly more than males. Those with good economic status were more aware that smoking is a cancer risk factor by 1.51 times compared to those with poor economic status. To enhance early diagnosis and presentation in Jordan, there is a need for increased public awareness of the signs, symptoms, and risk factors of cancer. One effective strategy to achieve this goal is to conduct targeted public campaigns that cater to different population groups, such as the youth, to improve their understanding and ensure that the message resonates.

Late-Stage Cancer End Points to Speed Cancer Screening Clinical Trials—Not So Fast

Late-Stage Cancer End Points to Speed Cancer Screening Clinical Trials—Not So Fast

Cancer Stage Compared With Mortality as End Points in Randomized Clinical Trials of Cancer Screening

Randomized clinical trials of cancer screening typically use cancer-specific mortality as the primary end point. The incidence of stage III-IV cancer is a potential alternative end point that may accelerate completion of randomized clinical trials of cancer screening. To compare cancer-specific mortality with stage III-IV cancer as end points in randomized clinical trials of cancer screening. This meta-analysis included 41 randomized clinical trials of cancer screening conducted in Europe, North America, and Asia published through February 19, 2024. Data extracted included numbers of participants, cancer diagnoses, and cancer deaths in the intervention and comparison groups. For each clinical trial, the effect of screening was calculated as the percentage reduction between the intervention and comparison groups in the incidence of participants with cancer-specific mortality and stage III-IV cancer. Randomization to a cancer screening test or to a comparison group in a clinical trial of cancer screening. End points of cancer-specific mortality and incidence of stage III-IV cancer were compared using Pearson correlation coefficients with 95% CIs, linear regression, and fixed-effects meta-analysis. The included randomized clinical trials tested benefits of screening for breast (n = 6), colorectal (n = 11), lung (n = 12), ovarian (n = 4), prostate (n = 4), and other cancers (n = 4). Correlation between reductions in cancer-specific mortality and stage III-IV cancer varied by cancer type (I2 = 65%; P = .02). Correlation was highest for trials that screened for ovarian (Pearson ρ = 0.99 [95% CI, 0.51-1.00]) and lung (Pearson ρ = 0.92 [95% CI, 0.72-0.98]) cancers, moderate for breast cancer (Pearson ρ = 0.70 [95% CI, -0.26 to 0.96]), and weak for colorectal (Pearson ρ = 0.39 [95% CI, -0.27 to 0.80]) and prostate (Pearson ρ = -0.69 [95% CI, -0.99 to 0.81]) cancers. Slopes from linear regression were estimated as 1.15 for ovarian cancer, 0.75 for lung cancer, 0.40 for colorectal cancer, 0.28 for breast cancer, and -3.58 for prostate cancer, suggesting that a given magnitude of reduction in incidence of stage III-IV cancer produced different magnitudes of change in incidence of cancer-specific mortality (P for heterogeneity = .004). In randomized clinical trials of cancer screening, incidence of late-stage cancer may be a suitable alternative end point to cancer-specific mortality for some cancer types, but is not suitable for others. These results have implications for clinical trials of multicancer screening tests.

Abstract SY38-02: Clinical investigations of obesity in cancer: BMI and other confounders

Abstract SY38-02: Clinical investigations of obesity in cancer: BMI and other confounders

Abstract LB075: Small molecule procaspase activating compound 1 (PAC-1) enhances CAR-T immunotherapy for solid tumors in syngeneic murine models

Abstract Chimeric antigen receptor (CAR)-T cell therapy has been shown to effectively treat solid tumors in syngeneic murine models, but antigen loss and T cell trafficking into the tumors pose major obstacles to its long-term efficacy. Here we explored a combination therapy against advanced stages of colorectal and ovarian syngeneic murine tumor models using a tumor-specific small molecule (PAC-1) that triggers the engagement of the host immune system and synergizes with a Tn-specific adoptively transferred 237 CAR-T immunotherapy. PAC-1 has been shown to induce apoptosis in tumor cells with high expression of procaspase 3, via chelation of inhibitory zinc and release of active executioner caspase 3. PAC-1 also recently completed a phase I trial (NCT02355535) and was shown to be well-tolerated in late-stage cancer patients. RNA sequencing of CT26 colorectal cells stimulated with PAC-1 for 24 hours revealed that PAC-1 induced global changes at the transcriptome level, up-regulating genes involved in immune activation and apoptosis, and down-regulating genes involved in DNA repair, cell cycle regulation, and myc-driven proliferation. Validation of RNAseq data was performed using a combination of RT-qPCR, Western blot, flow cytometry, and co-culture studies. A combination of transcriptome and exome sequencing analyses in murine colorectal cell line CT26 revealed that the PAC-1-mediated down-regulation of DNA repair machinery led to somatic alterations in the genome and a higher mutational load in tumor cells, subsequently presented as neo-antigens by antigen-presenting cells. As a result, host CD8+ cytotoxic T cells were able to infiltrate tumors and reduce the tumor burden. Tn-dependent CARs have been used recently to demonstrate the proof of concept in the targeting of cancer-specific Tn-antigens such as the Tn-MUC1 antigen in humans, and an analogous Tn-OTS8 target in mice. In our murine ID8 ovarian tumor model, untreated mice with disseminated tumors have a median survival of 71 days. As a single agent administered intraperitoneally, PAC-1 extended the median survival to 90 days (p&amp;lt;0.0001), while 237 CAR-T treated mice have a median survival of 103 days (p&amp;lt;0.0001). A combination of the two treatment modalities (PAC-1 administered before 237 CAR-T) further extended the median survival to 145 days (p=0.048). Administering PAC-1 after 237 CAR-T also modestly extended the median survival to 132 days (p=0.06). Taken altogether, our results demonstrate that PAC-1 engages the immune system to treat cancer by inducing expression of pro-inflammatory cytokines in tumor cells allowing the recruitment of CD8+ effector T cells to the tumor microenvironment. Combination strategies that boost T cell trafficking shows great promise to enhance the anti-tumor efficacy and feasibility of adoptive CAR-T therapy against solid tumors. Citation Format: Diana R. Ranoa, Yifei Kang, Jenny Drnevich, Gloria Rendon, Christopher J. Fields, Keith Bailey, Edward J. Roy, Timothy M. Fan, David M. Kranz, Paul J. Hergenrother. Small molecule procaspase activating compound 1 (PAC-1) enhances CAR-T immunotherapy for solid tumors in syngeneic murine models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB075.

Demographic differences in early vs. late-stage laryngeal squamous cell carcinoma

PurposeThis study aims to evaluate how various demographic factors impact the stage at diagnosis and, therefore, prognosis of laryngeal cancer. Materials and methodsUsing the National Cancer Database, 96,409 patients were diagnosed with laryngeal squamous cell carcinoma between 2004 and 2020. Early (stage 0 or I) vs. late-stage (stage IV) cancers were compared based on demographic variables utilizing Chi-square and multivariate analysis with a significance of p < 0.05. ResultsFemale, Black, and generally older patients were more likely to have late-stage cancer than their counterparts. When compared with a community cancer program, patients treated at other facility types were more likely to be diagnosed late. Patients with private insurance, Medicare, or other government insurance were all less likely to have late-stage cancer compared to patients without insurance. Compared to patients in the lowest median household income quartile, patients in the third quartile and fourth quartile were diagnosed earlier. Patients living in an area with the lowest level of high school degree attainment were most likely to be diagnosed late. Living in a more populous area was associated with a lower chance of being diagnosed late. Increasing Charlson-Deyo Score was associated with a stronger likelihood of being diagnosed at a later stage. ConclusionPatients who are female, Black, uninsured, have a low household income, live in less populated and less educated areas, are treated at non-community cancer programs, and have more comorbid conditions have later stage diagnoses. This data contributes to understanding inequities in healthcare.

Recent Advances in Minimally Invasive Management of Osteolytic Periacetabular Skeletal Metastases.

Painful skeletal osteolytic metastases, impending pathological fractures, and nondisplaced fractures present as a devastating clinical problem in advanced stage cancer patients. Open surgical approaches provide excellent mechanical stabilization but are often associated with high complication rates and slow recovery times. Percutaneous minimally invasive interventions have arisen as a pragmatic and logical treatment option for patients with late-stage cancer in whom open surgery may be contraindicated. These percutaneous interventions minimize soft tissue dissection, allow for the immediate initiation or resumption of chemotherapies, and present with fewer complications. This review provides the most up-to-date technical and conceptual framework for the minimally invasive management of osseous metastases with particular focus on periacetabular lesions. Fundamental topics discussed are as follows: (1) pathogenesis of cancer-induced bone loss and the importance of local cytoreduction to restore bone quality, (2) anatomy and biomechanics of the acetabulum as a weight-bearing zone, (3) overview of ablation options and cement/screw techniques, and (4) combinatorial approaches. Future studies should include additional studies with more long-term follow-up to better assess mechanical durability of minimally invasive interventions. An acetabulum-specific functional and pain scoring framework should be adopted to allow for better cross-study comparison.

Effect of 2-methoxyestradiol on mammary tumor initiation and progression.

The anti-cancer agent 2-methoxyestradiol (2-ME) has been shown to have anti-proliferative and anti-angiogenic properties. Previously, the effect of 2-ME on early- and late-stage breast cancer (BC) was investigated in vivo using a transgenic mouse model (FVB/N-Tg(MMTV-PyVT)) of spontaneous mammary carcinoma. Anti-tumor effects were observed in late-stage BC with no effect on early-stage BC. Given the contrasting results obtained from the different BC stages, we have now investigated the effect of 2-ME when administered before the appearance of palpable tumors. Each mouse received 100 mg/kg 2-ME on day 30 after birth, twice per week for 28 days, while control mice received vehicle only. Animals were terminated on day 59. Lung and mammary tissue were obtained for immunohistochemical analysis of CD163 and CD3 expression, and histological examination was performed to analyze tumor necrosis. Additionally, blood samples were collected to measure plasma cytokine levels. 2-ME increased tumor mass when compared to the untreated animals (p = .0139). The pro-tumorigenic activity of 2-ME was accompanied by lower CD3+ T-cell numbers in the tumor microenvironment (TME) and high levels of the pro-inflammatory cytokine interleukin (IL)-1β. Conversely, 2-ME-treatment resulted in fewer CD163+ cells detectable in the TME, increased levels of tumor necrosis, increased IL-10 plasma levels, and low IL-6 and IL-27 plasma levels. Taken together, these findings suggest that 2-ME promotes early-stage BC development.