Stage Of Disease Research Articles

Revealing key proteins in comparison of tumor and para-tumor tissues in stage I esophageal squamous cell carcinoma: A combined gene expression clustering and protein interaction network analysis

Esophageal Squamous Cell Carcinoma (ESCC) which is diagnosed in advanced stages and metastasis to the vital organs, remained the sixth fatal malignancy among other types of cancer-related death. Considering the lack of specific clinical symptoms in the early development of the disease, finding suitable biomarkers and tissue-specific alterations for effective screening of ESCC is targeted in this project. Gene expression profiles of tumor tissue and para-tumors of stage I ESCC patients were retrieved from the Gene Expression Omnibus (GEO) database. The significant tissue-specific differentially expressed genes (DEGs) were identified and studied based on fold change distribution and the functional role of genes in the action map. A total number of 11,483 significant DEGs discriminated the tumor tissue from para-tumor tissue. Clustering analysis of significant DEGs led to identifying 220 DEGs as the final significant genes. Protein interaction network and action map analysis of the final gene list showed matrix metallopeptidase-9 (MMP9) as the critical gene related to the development of ESCC diseases in stage I. Significant expression change of MMP9 in esophageal carcinoma was validated in UALCAN (The University of Alabama at Birmingham Cancer Data Analysis Portal). This study highlighted the pivotal role of MMP9 in combination with SPP1, MMP13, and IL18 as a possible biomarkers panel in studies of tumor invasion and prognosis for stage I ESCC disease.

Somatic mutation of targeted sequencing identifies risk stratification in advanced ovarian clear cell carcinoma

BackgroundOvarian clear cell carcinoma (OCCC) is a unique subtype of epithelial ovarian cancer. Advanced OCCC display a poor prognosis. Therefore, we aimed to make risk stratification for precise medicine. MethodsWe performed a large next generation sequencing (NGS) gene panel on 44 patients with OCCC in FIGO stage II-IV. Then, by machine learning algorithms, including extreme gradient boosting (XGBoost), random survival forest (RSF), and Cox regression, we screened for feature genes associated with prognosis and constructed a 5-gene panel for risk stratification. The prediction efficacy of the 5-gene panel was compared with FIGO stage and residual disease by receiver operating characteristic curve and decision curve analysis. ResultsThe feature mutated genes related to prognosis, selected by machine learning algorithms, include MUC16, ATM, NOTCH3, KMT2A, and CTNNA1. The 5-gene panel can effectively distinguish the prognosis, as well as platinum response, of advanced OCCC in both internal and external cohorts, with the predictive capability superior to FIGO stage and residual disease. ConclusionsMutations in genes, including MUC16, ATM, NOTCH3, KMT2A, and CTNNA1, were associated with the poor prognosis of advanced OCCC. The risk stratification according to these genes demonstrated acceptable prediction power of prognosis and platinum response, suggesting the potential to be a novel target for precision medicine.

Risk of recurrence in early-onset versus late-onset non-metastatic colorectal cancer, 2004–2019: a nationwide cohort study

The incidence of colorectal cancer (CRC) in individuals younger than 50 years of age (early-onset CRC) is increasing. Early-onset CRC often present at advanced stage, suggesting a more aggressive cancer course compared to late-onset CRC (age 50-79). This nationwide cohort study estimates the incidence of recurrence following early-onset CRC and late-onset CRC. The study included all Danish patients <80 years old operated for first-time Union for International Cancer Control (UICC) stage I-III CRC between January 2004 and December 2019. Recurrence status was determined by applying a validated algorithm to individual-level data from nationwide health registries. The 5-year cumulative incidence functions (CIF) of recurrence were reported for early-onset versus late-onset CRC. The difference in time to recurrence was estimated as a time ratio (TR) using an accelerated failure time model. Among 25,729 CRC patients, 1441 (5.6%) had early-onset CRC. Compared to late-onset CRC, early-onset was associated with advanced disease stages and higher treatment intensity. The 5-year CIF of recurrence was 29% (95% CI: 26%-31%) in early-onset versus 21% (95% CI: 21%-22%) in late-onset CRC. The higher CIF of recurrence for early-onset patients persisted in stage-stratified analysis. Time to recurrence was shorter in early-onset versus late-onset patients with TR=0.76 (95% CI: 0.67-0.85). The 5-year CIF of recurrence decreased from 2004 to 2019 for both early- and late-onset patients-most prominent for early-onset patients. Early-onset CRC was associated with higher incidence of recurrence at all disease stages. Indicating that the increased risk is not explained by delayed diagnosis. The excess risk diminished from 2004 to 2019, suggesting that early-onset CRC may achieve a similar recurrence risk as late-onset CRC in a contemporary setting. Aarhus University, Novo Nordisk Foundation, Innovation Fund Denmark, and the Danish Cancer Society.

Determination of positive end-expiratory pressure in COVID-19-related acute respiratory distress syndrome

BACKGROUND The impact of high positive end-expiratory pressure (PEEP) ventilation and the optimization of PEEP titration in COVID-19-induced acute respiratory distress syndrome (ARDS) continues to be a subject of debate. In this systematic review, we investigated the effects of varying PEEP settings on patients with severe ARDS primarily resulting from COVID-19 (C-ARDS). OBJECTIVES Does higher or lower PEEP improve the outcomes in COVID-19 ARDS? Does individually titrated PEEP lead to better outcomes compared with PEEP set by standardised (low and high ARDS network PEEP tables) approaches? Does the individually set PEEP (best PEEP) differ from PEEP set according to the standardised approaches (low and high ARDS network PEEP tables)? DESIGN Systematic review of observational studies without metaanalysis. DATA SOURCES We performed an extensive systematic literature search in Cochrane COVID-19 Study Register (CCSR), PubMed, Embase.com, Web of Science Core Collection, World Health Organization COVID-19 Global literature on coronavirus disease, World Health Organization International Clinical Trials Registry Platform (ICTRP), medRxiv, Cochrane Central Register of Controlled Trials until 24/01/2024. ELIGIBILITY CRITERIA Ventilated adult patients (≧18 years) with C-ARDS. RESULTS We screened 16 026 records, evaluated 119 full texts, and included 12 studies (n = 1431 patients) in our final data synthesis, none of them being a randomised controlled trial. The heterogeneity of study procedures and populations did not allow conduction of a meta-analysis. The results of those studies that compared lower and higher PEEP strategies in C-ARDS were ambiguous pointing out either positive effects on oxygenation with high levels of PEEP, or negative changes in lung mechanics. CONCLUSION The available evidence does not provide sufficient guidance for recommendations on optimal PEEP settings in C-ARDS. In general, well designed platform studies are needed to answer the questions raised in this review and, in particular, to investigate the use of individualised PEEP titration techniques and the inclusion of patients with different ARDS entities, severities and disease stages. TITLE REGISTRATION Our systematic review protocol was registered with the international prospective register of systematic reviews (PROSPERO 2021: CRD42021260303).

Reproducibility of intravoxel incoherent motion quantification in the liver across field strengths and gradient hardware.

To evaluate reproducibility and interlobar agreement of intravoxel incoherent motion (IVIM) quantification in the liver across field strengths and MR scanners with different gradient hardware. Cramer-Rao lower bound optimization was performed to determine optimized monopolar and motion-robust 2D (b-value and first-order motion moment [M1]) IVIM-DWI acquisitions. Eleven healthy volunteers underwent diffusion MRI of the liver, where each optimized acquisition was obtained five times across three MRI scanners. For each data set, IVIM estimates (diffusion coefficient (D), pseudo-diffusion coefficients ( and ), blood velocity SDs (Vb1 and Vb2), and perfusion fractions [f1 and f2]) were obtained in the right and left liver lobes using two signal models (pseudo-diffusion and M1-dependent physical) with and without T2 correction (fc1 and fc2) and three fitting techniques (tri-exponential region of interest-based full and segmented fitting and blood velocity SD distribution fitting). Reproducibility and interlobar agreement were compared across methods using within-subject and pairwise coefficients of variation (CVw and CVp), paired sample t-tests, and Bland-Altman analysis. Using a combination of motion-robust 2D (b-M1) data acquisition, M1-dependent physical signal modeling with T2 correction, and blood velocity SD distribution fitting, multiscanner reproducibility with median CVw = 5.09%, 11.3%, 9.20%, 14.2%, and 12.6% for D, Vb1, Vb2, fc1, and fc2, respectively, and interlobar agreement with CVp = 8.14%, 11.9%, 8.50%, 49.9%, and 42.0%, respectively, was achieved. Recently proposed advanced IVIM acquisition, signal modeling, and fitting techniques may facilitate reproducible IVIM quantification in the liver, as needed for establishment of IVIM-based quantitative biomarkers for detection, staging, and treatment monitoring of diseases.

Andrographolide prevents renal fibrosis via decelerating lipotoxicity-mediated premature senescence of tubular epithelial cells

Excessive lipid accumulation often occurs in the early stage of chronic kidney disease (CKD) which is prone to induce oxidative stress and mitochondrial damage, promoting the progression of kidney fibrosis. Andrographolide (AP), a multifunctional natural terpenoids derived from Andrographis paniculate, has been suggested to play beneficial roles in metabolic disorders-associated disease. Here, we reported that AP effectively counteracts tubule injury and interstitial fibrosis in mice fed with a long-term high-fat diet (HFD). AP treatment decreased HFD-induced lipid accumulation in kidney parenchyma and attenuated lipotoxicity-mediated oxidative stress and mitochondrial dysfunction, resulting in a marked decrease in of tubular cell senescence. Importantly, AP inhibited senescence-associated secretory phenotype (SASP) secretion by senescent tubular cells, and in turn suppressed proliferation and activation of fibroblasts in a paracrine effect. Furthermore, we revealed that AP functions as an AMP-activated protein kinase (AMPK) activator to ameliorate renal lipid accumulation through coordinately modulating AMP-activated protein kinase AMPK target genes. By stimulation of AMPK activity, AP protects injured kidney against tubular cell senescence and fibroblast activation. These results suggest the potential therapeutic application of AP in the prevention and treatment of CKD, highlighting the promising drug strategy of targeting the lipotoxicity-mediated premature senescence in tubular cells.

More than Skin Deep: Imaging of Dermatologic Disease in the Head and Neck.

Evaluation, staging, and treatment of skin cancers involve a multidisciplinary team, with radiology playing an integral role. Imaging evaluation of dermatologic disease that involves the head and neck is especially important due to the proximity of important structures such as nerves, bone, muscle, and lymph nodes. The authors review the pathophysiology of the most common types of skin cancer, as well as cutaneous lymphoma, and the available treatment modalities and algorithms. Emphasis is placed on pretreatment evaluation and posttreatment surveillance. In the pretreatment setting, a checklist of key radiologic features that are important in the staging of dermatologic disease is discussed, namely superficial and dermal lymphatic spread, perineural tumor invasion and spread, osseous invasion, and metastatic nodal disease. In the setting of high-risk or metastatic disease, a contrast-enhanced CT scan of the neck or a PET/CT scan is typically obtained approximately 12 weeks after treatment; imaging may be used first to detect residual or recurrent disease, metastatic nodal disease, or unexpected complications such as osteoradionecrosis. The authors highlight the radiologist's role in the care of patients with dermatologic disease, which can be more than skin deep. ©RSNA, 2024.

Inhibition of Acute Myeloid Leukaemia Development by Bittersweet Based on miR-let-7a Regulating Vascular Endothelial Growth Factor A Resistance Mechanism

Acute myeloid leukaemia (AML) is closely related to regulation of miR-let-7a and vascular endothelial growth factor A (VEGFA). Picrasidine is a traditional Chinese medicine extract with antitumour effects, but its mechanism of action in AML is unclear. This study investigated picloram’s effect on AML and its relationship with miR-let-7a regulation of VEGFA resistance mechanism. Bone marrow samples from leukaemia patients in the Department of Haematology of our hospital were collected, and RT-PCR detected miR-let-7a and VEGFA expression in the bone marrow of healthy individuals and leukaemia patients. At the same time, cell culture of AML-resistant cell line K562/ADM was performed, which was divided into NC group, Picrasidine L group, Picrasidine M group, Picrasidine H group, si-NC group, Picrasidine H+miR-let-7a inhibitor group, Picrasidine H+miR-let-7a mimic group, miR-let-7a mimic+hVEGF-IN-1 group, miR-let-7a inhibitor+hVEGF-IN-1 group, and Picrasidine H+miR-let-7a mimic+hVEGF-IN-1 group. Cell proliferation and apoptosis was detected and correlation between miR-let-7a and VEGFA was analyzed by clinical samples. Picrasidine had a significant ameliorative effect on acute myeloid leukaemia in a dose-dependent manner. miR-let-7a was lowly expressed and VEGFA was highly expressed in AML patients. miR-let-7a and VEGFA showed significant correlation in human AML disease staging, and there was a statistically significant difference (p &lt;0.05). That is to say, picloram promotes miR-let-7a expression, thus achieving inhibition of VEGFA, which in turn promotes apoptosis of AML drug-resistant cell line K562/ADM and inhibits its proliferation. The ameliorative effect of Picrasidine on acute myeloid leukaemia was achieved by upregulating miR-let-7a and downregulating VEGFA.

Individualizing Care for Patients with Gallbladder Cancer

NCDB cohort study of with resected Stage Groups IB-IVA gallbladder adenocarcinoma between 2004 and 2018. Patients were included. 8484 patients were included, median survival was 29.8 (CI 28.6-31.2); Stage IB: 67.0, Stage II: 36.6, and Stage III/IVA 18.4 months. A survival benefit was noted for surgery beyond cholecystectomy (Stage IB 105 vs. 36 months, HR 0.56, p<0.001; Stage II 56 vs. 20 months, HR 0.72, p<0.001; and Stage III/IVA 23.8 vs. 9.9 months, HR 0.67, p<0.001) and chemoradiotherapy (Stage IB 102 vs. 64.8, HR 0.87, CI 0.62-1.23, p=0.4; ' Stage II 49 vs. 33.5 months, HR 0.78, CI 0.68-0.91, p=0.002; and Stage III/IVA 31 vs. 12.2 HR 0.60, CI 0.52-0.70, p<0.001). Adjuvant chemotherapy improved survival in Stage III/IVA (20 vs. 12.2 months, HR 0.74, p<0.001) but not Stage II and trend toward harm in Stage IB. A nomogram with created with these data. Surgery beyond cholecystectomy provides a benefit to all. Adjuvant chemotherapy (Stage III and IVA) benefits and chemoradiotherapy (II, III, and IVA) only patients with higher stage disease.

The Effect of Denosumab on Risk for Emergently Treated Hypocalcemia by Stage of Chronic Kidney Disease

The Effect of Denosumab on Risk for Emergently Treated Hypocalcemia by Stage of Chronic Kidney Disease

Artificial intelligence in assessing progression of age-related macular degeneration

AbstractThe human population is steadily growing with increased life expectancy, impacting the prevalence of age-dependent diseases, including age-related macular degeneration (AMD). Health care systems are confronted with an increasing burden with rising patient numbers accompanied by ongoing developments of therapeutic approaches. Concurrent advances in imaging modalities provide eye care professionals with a large amount of data for each patient. Furthermore, with continuous progress in therapeutics, there is an unmet need for reliable structural and functional biomarkers in clinical trials and practice to optimize personalized patient care and evaluate individual responses to treatment. A fast and objective solution is Artificial intelligence (AI), which has revolutionized assessment of AMD in all disease stages. Reliable and validated AI-algorithms can aid to overcome the growing number of patients, visits and necessary treatments as well as maximize the benefits of multimodal imaging in clinical trials. Therefore, there are ongoing efforts to develop and validate automated algorithms to unlock more information from datasets allowing automated assessment of disease activity and disease progression. This review aims to present selected AI algorithms, their development, applications and challenges regarding assessment and prediction of AMD progression.

Artificial Intelligence and Image Analysis-Assisted Diagnosis for Fibrosis Stage of Metabolic Dysfunction-Associated Steatotic Liver Disease Using Ultrasonography: A Pilot Study

Purpose: Elastography increased the diagnostic accuracy of liver fibrosis. However, several challenges persist, including the widespread utilization of equipment, difficulties in measuring certain cases, and the influence of viscosity factors. A rough surface and a blunted hepatic margin have long been acknowledged as valuable characteristics indicative of hepatic fibrosis. The objective of this study was to conduct an image analysis and quantitative assessment of the contour of the sagittal section of the left lobe of the liver. Methods: Between February and October 2020, 486 consecutive outpatients underwent ultrasound examinations at our hospital. A total of 214 images were manually annotated by delineating the liver contour to create annotation images. U-Net was employed for liver segmentation, with the dataset divided into training (n = 128), testing (n = 42), and validation (n = 44) subsets. Additionally, 43 Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) cases with pathology data from between 2015 and 2020 were included. Segmentation was performed using the program developed in the first step. Subsequently, shape analysis was conducted using ImageJ. Results: Liver segmentation exhibited high accuracy, as indicated by Dice loss of 0.044, Intersection over Union of 0.935, and an F score of 0.966. The accuracy of the classification of the liver surface as smooth or rough via ResNet 50 was 84.6%. Image analysis showed MinFeret and Minor correlated with liver fibrosis stage (p = 0.046, 0.036, respectively). Sensitivity, specificity, and AUROC of Minor for ≥F3 were 0.571, 0.862, and 0.722, respectively, and F4 were 1, 0.600, and 0.825, respectively. Conclusion: Deep learning segmentation of the sagittal cross-sectional contour of the left lobe of the liver demonstrated commendable accuracy. The roughness of the liver surface was correctly judged by artificial intelligence. Image analysis showed the thickness of the left lobe inversely correlated with liver fibrosis stage.

Precision Medicine Proof-of-Concept Study of a TNF Inhibitor in FSGS and Treatment-Resistant Minimal Change Disease

Background: Focal segmental glomerulosclerosis (FSGS) and treatment-resistant minimal change disease (TR-MCD) are heterogeneous disorders with subgroups defined by distinct underlying mechanisms of glomerular and tubulointerstitial injury. A non-invasive urinary biomarker profile has been generated to identify patients with intra-kidney tumor necrosis factor (TNF)-activation and to predict response to anti-TNF treatment. We conducted this proof-of-concept, multi-center, open-label clinical trial to test the hypothesis that in patients with FSGS or TR-MCD and evidence of intra-renal TNF activation based on their biomarker profile, short-term treatment with adalimumab would reverse the elevated urinary excretion of MCP-1 and TIMP-1. Methods: Patients with FSGS or TR-MCD, eGFR&gt;30 ml/min/1.73 m2, urine protein:creatinine ratio (UPCR) ≥1.5 g/g, and age 6-80 year were eligible for this trial. Adalimumab, 20-40 mg, was administered via subcutaneous injection, every 2 weeks for 5 doses. Participants were evaluated at weeks 0 (Baseline), 2, 8, and 10. Excretion of urinary (u) uMCP-1, uTIMP-1, uEGF, and plasma MCP-1 were measured at each visit. Results: Seven participants were enrolled, with median baseline UPCR 12.1 mg/mg (IQR: 2.2, 18.6), serum albumin 2.4 g/dL (IQR: 2.0, 2.8), and eGFR 57 mL/min/1.73 m2 (IQR: 44, 96). Based on self-report, they received all prescribed doses of adalimumab. The patients with the most favorable response based on the changes in urinary biomarkers had the best preserved kidney parenchyma based on uEGF excretion. Conclusions: Precision medicine trials are feasible in rare glomerular disorders. In this pilot study, adalimumab resulted in a heterogenous response of the candidate mechanistic-predictive biomarkers of TNF-mediated inflammation in patients with FSGS or TR-MCD. A reduction was seen in a subgroup of patients with preserved kidney parenchyma. The findings may reflect the challenge to reverse chronic injury at advanced stages of kidney disease or insufficient intra-renal target engagement with the intervention drug dose.

Neurofilament heavy phosphorylated epitopes as biomarkers in ageing and neurodegenerative disease

AbstractFrom the day we are born, the nervous system is subject to insult, disease and degeneration. Aberrant phosphorylation states in neurofilaments, the major intermediate filaments of the neuronal cytoskeleton, accompany and mediate many pathological processes in degenerative disease. Neuronal damage, degeneration and death can release these internal components to the extracellular space and eventually the cerebrospinal fluid and blood. Sophisticated assay techniques are increasingly able to detect their presence and phosphorylation states at very low levels, increasing their utility as biomarkers and providing insights and differential diagnosis for the earliest stages of disease. Although a variety of studies focus on single or small clusters of neurofilament phosphorylated epitopes, this review offers a wider perspective of the phosphorylation landscape of the neurofilament heavy subunit, a major intermediate filament component in both ageing and disease.image

Cutaneous T cell lymphoma atlas reveals malignant TH2 cells supported by a B cell-rich tumor microenvironment

AbstractCutaneous T cell lymphoma (CTCL) is a potentially fatal clonal malignancy of T cells primarily affecting the skin. The most common form of CTCL, mycosis fungoides, can be difficult to diagnose, resulting in treatment delay. We performed single-cell and spatial transcriptomics analysis of skin from patients with mycosis fungoides-type CTCL and an integrated comparative analysis with human skin cell atlas datasets from healthy and inflamed skin. We revealed the co-optation of T helper 2 (TH2) cell-immune gene programs by malignant CTCL cells and modeling of the tumor microenvironment to support their survival. We identified MHC-II+ fibroblasts and dendritic cells that can maintain TH2 cell-like tumor cells. CTCL tumor cells are spatially associated with B cells, forming tertiary lymphoid structure-like aggregates. Finally, we validated the enrichment of B cells in CTCL and its association with disease progression across three independent patient cohorts. Our findings provide diagnostic aids, potential biomarkers for disease staging and therapeutic strategies for CTCL.

Abstract IA020: Deciphering the mechanisms of neutrophil immune response in bone metastatic prostate cancer

Abstract Metastatic disease of prostate cancer (PCa) is currently incurable. Bone is the most common tissue site for prostate cancer metastasis and progression in bone is largely dictated by tumor-stromal interactions in the bone microenvironment. We showed previously that bone marrow neutrophils inhibit bone metastatic PCa growth, however metastatic PCa becomes resistant to neutrophil response and progresses within the bone compartment. It is unclear how these findings translate to a clinical setting. Further, the mechanisms associated with tumor resistance to neutrophil immune response remain unknown and presents a new avenue for therapeutic intervention. Thus, the goals of this study were: 1) to define the impact of metastatic PCa on neutrophil function throughout prostate cancer progression and 2) to determine the potential of neutrophils as predictive biomarkers of PCa disease progression. To do this, peripheral blood polymorphonuclear neutrophils (PMNs) were collected from 4 patient cohorts (localized PCa, metastatic hormone-sensitive PCa (mHSPC), metastatic castration-resistant (mCRPC) and healthy men) and PMN molecular and functional properties assessed, including: cancer cell cytotoxicity and cell surface markers. There was a significant decrease with disease progression in PMN expression of CD10, a marker for differentiation, while in tandem, there was an increase in pro-inflammatory marker, CD88 (complement receptor) in mCRPC men compared to mHSPC. PMNs from all disease stages were equally cytotoxic to human PCa cell lines (LNCaP, C42B, and PC3). However, second generation androgen deprivation therapy (ADT) suppressed patient PMN cytotoxicity against mCRPC cells (C42B, PC3). This suppression was due to androgen receptor (AR)-mediated regulation of the pleotropic and immune suppressant cytokine, transforming growth factor beta receptor I (TβRI). PMNs from mCRPC patients who received 2nd generation ADT, expressed significantly more TβRI than patients who only received 1st line ADT. Further, we found that PMNs in CRPC patient bone metastases express more TβRI than PMNs in matched liver metastases, which express little to no TβRI. Treatment of mouse bone marrow neutrophils with enzalutamide, increased neutrophil TβRI expression in a dose dependent manner and blocked cytotoxicity against PCa cells. Exogenous testosterone treatment in vivo, pharmacologic inhibition (using Repsox, a small molecule kinase inhibitor of TβRI) or genetic deletion (using conditional TβRI knockout mice) rescued enzalutamide-mediated neutrophil suppression and restored neutrophil cytotoxicity. These data collectively suggest that AR inhibition suppresses anti-tumor neutrophil responses via TβRI however, this study highlights the ability to leverage standard-care ADT to generate neutrophil anti-tumor responses against bone metastatic PCa. Citation Format: Leah M Cook. Deciphering the mechanisms of neutrophil immune response in bone metastatic prostate cancer [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 IA020.

Abstract A031: ECM architecture drives distinct evolutionary patterns of tumor immune escape and elimination in breast cancer

Abstract Cancer progression poses a clinical hurdle due to tumor heterogeneity that contributes to treatment resistance and immune evasion. While the adaptive immune system can effectively eliminate cancer in certain instances, tumor escape remains challenging. The immune microenvironment plays an important role in this process. One unanswered question is the role of ECM geometry, also known as Tumor Associated Collagen Signatures (TACS), and its effects on tumor immune recognition. In solid malignancies, ECM geometry has been associated with disease stage and T cell infiltration. Specifically, empirically observed ECM topologies are frequently categorized based on fiber arrangement: random fibers (TACS1), circumferentially aligned fibers (TACS2), and radially arranged fibers (TACS3). Even though a clear negative correlation between TACS and patient survival has been established, the specific roles and extent of TACS in T cell-driven cancer evolution remain uncharacterized. The precise mechanisms underlying how TACS influences cell movement are still not fully elucidated, with divergent opinions on whether and how the ECM mediates immune cell infiltration. At present, we currently lack a physical model relating the impact of TACS on the spatial co-evolution between an adaptive immune repertoire and a heterogeneous population of evading cancer cells. Here, we developed the EVO-ACT (EVOlutionary Agent-based Cancer T cell interaction) model, which is based on the Gillespie algorithm, to study the effects of TACS on tumor evolution and dynamical tumor-T cell interactions. Our analysis of tumor-T cell interactions across three TACS types reveals distinct migration patterns, with TACS3 showing the highest efficiency, TACS1 intermediate, and TACS2 the lowest. TACS impacts T cells more than tumors, with stronger chemokine gradients aiding T cell infiltration. Our model suggests that despite TACS2's limited efficiency, it cannot fully impede T cell infiltration. Varied migration efficiencies lead to diverse T cell infiltration patterns and immunoediting levels. TACS3 shows a benefit to immune recognition and higher survival, contrary to lower survival in TACS3 patients observed clinically in breast cancer. Our results indicate that only after introducing phenotypic changes, such as Epithelial-Mesenchymal Transition (EMT), and noting that EMT occurs exclusively after the TACS2-TACS3 progression, can our findings successfully explain the clinically observed trends. Considering mesenchymal tumor cells' ability to upregulate PD-1/PD-L1, we explore TACS-specific tumor evolution's impact on PD-1/PD-L1 inhibitor responses and patient survival. We observe higher tumor escape rates and lower survival in TACS3 compared to TACS2. Thus, TACS3 alone does not account for lower survival in breast cancer; TACS3-associated late-stage cancer byproducts like EMT and elevated checkpoint expression significantly decrease survival. Citation Format: Yijia Fan, Jason Tomas George. ECM architecture drives distinct evolutionary patterns of tumor immune escape and elimination in breast cancer [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 A031.

Induced pluripotent stem-cell-derived corneal epithelium for transplant surgery: a single-arm, open-label, first-in-human interventional study in Japan

The loss of corneal epithelial stem cells from the limbus at the edge of the cornea has severe consequences for vision, with the pathological manifestations of a limbal stem-cell deficiency (LSCD) difficult to treat. Here, to the best of our knowledge, we report the world's first use of corneal epithelial cell sheets derived from human induced pluripotent stem cells (iPSCs) to treat LSCD. This non-randomised, single-arm, clinical study involved four eyes of four patients with LSCD at the Department of Ophthalmology, Osaka University Hospital. They comprised a woman aged 44 years with idiopathic LSCD (patient 1), a man aged 66 years with ocular mucous membrane pemphigoid (patient 2), a man aged 72 years with idiopathic LSCD (patient 3), and a woman aged 39 years with toxic epidermal necrosis (patient 4). Allogeneic human iPSC-derived corneal epithelial cell sheets (iCEPSs) were transplanted onto affected eyes. This was done sequentially in two sets of HLA-mismatched surgeries, with patients 1 and 2 receiving low-dose cyclosporin and patients 3 and 4 not. The primary outcome measure was safety, ascertained by adverse events. These were monitored continuously throughout the 52-week follow-up period, and during an additional 1-year safety monitoring period. Secondary outcomes, reflective of efficacy, were also recorded. This study is registered with UMIN, UMIN000036539 and is complete. Patients were enrolled between June 17, 2019 and Nov 16, 2020. We had 26 adverse events during the 52-week follow-up period (consisting of 18 mild and one moderate event in treated eyes, and seven mild non-ocular events), with nine recorded in the additional 1-year safety monitoring period. No serious adverse events, such as tumourigenesis or clinical rejection, occurred during the whole 2-year observational period. At 52 weeks, secondary measures of efficacy showed that the disease stage had improved, corrected distance visual acuity was enhanced, and corneal opacification had diminished in all treated eyes. Corneal epithelial defects, subjective symptoms, quality-of-life questionnaire scores and corneal neovascularisation mostly improved or were unchanged. Overall, the beneficial efficacy outcomes achieved for patients 1 and 2 were better than those achieved for patients 3 and 4. iCEPS transplantation for LSCD was found to be safe throughout the study period. A larger clinical trial is planned to further investigate the efficacy of the procedure. The Japan Agency for Medical Research and Development, the Ministry of Education, Culture, Sports, Science, and Technology-Japan, and the UK Biotechnology and Biological Sciences Research Council.

The impact of diet on the inflammatory bowel disease course – a literature review

Introduction and Objective. Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic gastrointestinal disorder marked by relapsing symptoms. Current treatments mainly involve immunosuppressive therapies, which are effective but may have significant side effects. Diet as an adjunctive treatment is appealing due to its accessibility, low cost, and minimal adverse effects. This review explores the role of diet in managing IBD, focusing on dietary strategies during both active disease and remission. Methods. A literature review was conducted using PubMed and Google Scholar with search terms like "inflammatory bowel disease", "Crohn’s disease", "ulcerative colitis", "diet", "IBD treatment", "anti-inflammatory food" and related variations. Articles published within the last five years were prioritized. Brief description of the state of Knowledge. Ulcerative colitis and Crohn’s disease cause gastrointestinal inflammation. Crohn’s disease symptoms include abdominal pain, fistulas and rectal lesions, while UC is characterized by diarrhea, severe discomfort, and blood in the stool. Certain foods often exacerbate IBD symptoms. Proper nutrition during disease stages can improve patients’ quality of life. Diets high in processed foods, sugar, and red meat may increase IBD risk, while fiber and vitamin D3 are associated with fewer flare-ups. Regular malnutrition screening is essential for all IBD patients. Conclusions. Understanding the dietary components that influence inflammation in IBD could lead to better treatment outcomes and longer-lasting symptom relief. Integrating nutrition into personalized treatment strategies should become standard practice for managing IBD.

ACE and chitotriosidase as possible predictive biomarkers for activity of sarcoidosis in correlation with PET/CT findings

Sarcoidosis is a granulomatous disease which can afflict virtually any tissue in human body, most commonly the mediastinal lymph nodes and lungs. Pathohistological confirmation is the gold standard in establishing a diagnosis; however, determining the activity of the disease requires multiple clinical, radiographic and laboratory procedures. PET/CT scan is considered the gold standard for determining the presence of active granuloma, but has several significant limitations (radioactive material, cost, overall access to device). ACE and chitotriosidase are biomarkers used for diagnosis of sarcoidosis, and could have a place in determining the activity of the disease, when compared with the results of PET/CT scan. We have compared the levels of ACE and chitotriosidase with the levels of SUVmax values in patients with sarcoidosis. SUVmax and chitotriosidase level were significantly correlated both at the baseline and after the follow-up period, regardless of gender, age, duration of disease and radiography stage, while SUVmax and ACE level were not. Chitotriosidase had also shown a significant predictive ability of the decrease of the activity of sarcoidosis represented as the decrease of SUVmax as the effect of therapy in comparison with ACE. In the absence of ideal biomarker for sarcoidosis (high sensitivity, specificity and stability), chitotriosidase can be used in determining the activity of disease, as it had shown a significant correlation to the gold standard- PET/CT scan.