Improved Survival In Patients Research Articles

Abstract C037: Chemotherapy causes de novo induction of invasive breast cancer cells

Abstract Metastasis is the leading cause of breast cancer (BC) death, and tumor cells must migrate and invade to metastasize. BC cells that express the actin regulatory protein MenaINV have an enhanced ability to migrate and intravasate within the primary tumor, and extravasate at secondary sites. Though chemotherapy improves patient survival, treatment with paclitaxel, a chemotherapy used for BC, leads to upregulation of MenaINV and an increase in metastasis in mice. MenaINV expression can be induced in BC cells through Notch1 signaling with macrophages, which are often recruited to tumors in response to chemotherapy. MenaINV-expressing cells are also resistant to paclitaxel, begging the question of whether paclitaxel increases MenaINV by de novo induction or by selectively killing non-MenaINV-expressing cells. We hypothesized that paclitaxel causes de novo MenaINV induction by increasing macrophage-tumor cell Notch signaling. Understanding this pro-metastatic effect of chemotherapy is crucial to refining treatment strategies. MMTV-PyMT mice bearing spontaneous mammary tumors were used as a model of BC. Mice were treated with paclitaxel or vehicle every 5 days for a total of 3 treatments. To study the role of macrophages in the paclitaxel-mediated MenaINV increase, in addition to paclitaxel, one cohort of mice was co-administered the macrophage-depleting agent clodronate or vehicle. To study the role of Notch signaling, a second cohort of mice was co-administered the Notch inhibitor DAPT or vehicle. Immunofluorescence staining was used to evaluate tumors for: %MenaINV+ area, proportion of apoptotic cells, macrophage density, and macrophage expression of Notch ligands Jag1 and Jag2. Paclitaxel-treated tumors expressed significantly more MenaINV even when tumor cell death did not increase, indicating that chemotherapy increases MenaINV expression by induction. Both macrophages and Notch signaling were needed for this effect to occur. Interestingly, paclitaxel did not increase macrophage infiltration or macrophage expression of Notch ligands, suggesting that paclitaxel may increase MenaINV by acting on tumor cells to promote Notch signaling. Paclitaxel causes de novo MenaINV induction that is macrophage- and Notch-dependent. Studies aiming to further elucidate the mechanism behind paclitaxel-mediated MenaINV induction are ongoing. These results lay the groundwork for novel microenvironment-based therapies to alleviate the pro-metastatic effects of chemotherapy in BC. Citation Format: Madeline Friedman-DeLuca, George S. Karagiannis, Camille L. Duran, Luis Rivera Sanchez, Prachiben P. Patel, Suryansh Shukla, Nicole D. Barth, Ved P. Sharma, Michael Papanicolaou, John S. Condeelis, Maja H. Oktay, David Entenberg. Chemotherapy causes de novo induction of invasive breast cancer cells [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 C037.

Abstract B016: Utilizing gene expression profiles (GEP) to assess tumor microenvironment (TME) and response to immunotherapy

Abstract Background: Despite the success of anti-PD-1/PD-L1 immunotherapies, outcomes for lung cancer patients remain suboptimal. There is a critical need to incorporate multi-omics data focused on the tumor microenvironment (TME) to enhance patient selection and treatment individualization. This study aimed to identify predictive and prognostic biomarkers of immunotherapy response by characterizing transcriptional profiles of lung adenocarcinoma patients who underwent genomic profiling at diagnosis. Methods: RNA sequencing data were obtained from 68 lung adenocarcinoma patients who underwent next-generation sequencing with CARIS at our institution. We analyzed gene expression profiles (GEP) comprising 18 inflammatory genes associated with antigen presentation, chemokine expression, cytolytic activity, and adaptive immune resistance, identified as potential biomarkers for immune checkpoint inhibitor (ICI) response (Cristescu et al., 2018). The genes included were CCL5, CD27, CD274 (PD-L1), CD276 (B7-H3), CD8A, CMKLR1, CXCL9, CXCR6, HLA-DQA1, HLA-DRB1, HLA-E, IDO1, LAG3, NKG7, PDCD1LG2 (PD-L2), PSMB10, STAT1, and TIGIT. GEP scores were calculated, and hierarchical clustering identified tumor subsets with similar GEPs. Gene set variation analysis was conducted to assess enrichment of cell-cell interaction activities of specific ligand-receptor pairs of immune checkpoint genes, partially overlapping with the 18 GEP genes. Results: Hierarchical clustering identified four distinct GEP clusters: "T cell-inflamed GEP," "T cell-non-inflamed GEP high," "T cell-non-inflamed GEP medium," and "T cell-non-inflamed low GEP," with average scores of 0.18 (N=9, 13%), 0.11 (N=29, 43%), 0.08 (N=19, 28%), and 0.04 (N=11, 16%), respectively. The gene scores among these clusters showed significant differences (P = 3.3e-09). Additionally, analysis of specific ligand-receptor pairs of immune checkpoint genes (PD1/PD-L1, PD-L2; CTLA4/CD28, CD80, CD86; ICOS/ICOSLG; TIM3/GAL9; SIRP1/CD47) showed consistent positive enrichment in the “T cell-inflamed” cluster, with no or negative enrichment in the “T cell-non-inflamed” clusters. This suggests active immune checkpoint interactions in clusters with high GEP scores. Conclusion: We identified four different clusters among tissues from patients with NSCLC based on GEP scoring highlighting differences in immune activation and TME makeup, which may play a role in predicting response to immunotherapies. Our results suggest that GEP may provide information on identifying optimal immunotherapeutic approaches based on TME. Our findings underscore the importance of using biomarker-guided strategies to improve patient selection for precision immunotherapy approaches in lung cancer. Citation Format: Changde Cheng, Doug Welsch, Kayla F. Goliwas, Jessy Deshane, Sameer Deshmukh, Sanad Ahlushki, Yanis Boumber, Darshan Shimoga Chandrashekar, Alexander C. Mackinnon, Aakash Desai. Utilizing gene expression profiles (GEP) to assess tumor microenvironment (TME) and response to immunotherapy [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 B016.

Atrioventricular Block in the Setting of Immune Myocarditis: A Pragmatic Approach to Diagnosis and Treatment.

Immunotherapy has revolutionized cancer treatment in the last decade and has significantly improved patient survival. However, immunotherapy is associated with serious cardiac adverse events including myocarditis and conduction disturbances. In the literature, the mortality rate in patients with immunotherapy-associated myocarditis and complete AV block is reported to be approximately 60%. Current cardio-oncology guidelines provide a series of recommendations for the management of immune myocarditis (IM). However, there is no recommendation on whether or when pacemaker implantation should be performed in the setting of complete AV block associated with myocarditis. This gap in the literature has led to a trend in cardio-oncology practice to implant permanent pacemakers (PPMs) in a significant proportion of patients without waiting for a response to immunosuppressive therapy. However, in a significant proportion of patients undergoing PPM implantation, complete AV block resolves after immunosuppressive therapy. This suggests that in cases of complete AV block in the setting of IM, more robust clues are needed for PPM implantation. This review aims to present algorithms for the management of myocarditis and complete AV block, one of the most lethal complications of immunotherapy, to help fill this gap in the literature.

Innovations in intraoperative therapies in neurosurgical oncology: a narrative review.

High-grade gliomas (HGG) represent the most aggressive primary brain tumors in adults, characterized by high recurrence rates due to incomplete resection. This review explores the effectiveness of emerging intraoperative therapies that may extend survival by targeting residual tumor cells. The main research question addressed is: What recent intraoperative techniques show promise for complementing surgical resection in HGG treatment? A comprehensive literature review was conducted, examining recent studies on intraoperative therapeutic modalities that support surgical resection of HGG. Techniques reviewed include laser interstitial thermal therapy (LITT), intraoperative brachytherapy, photodynamic therapy (PDT), sonodynamic therapy (SDT), and focused ultrasound (FUS). Each modality was evaluated based on clinical application, evidence of effectiveness, and potential for integration into standard HGG treatment protocols. Findings indicate that these therapies offer distinct mechanisms to target residual tumor cells: LITT provides localized thermal ablation; intraoperative brachytherapy delivers sustained radiation; PDT and SDT activate cytotoxic agents in tumor cells; and FUS enables precise energy delivery. Each method has shown varying levels of clinical success, with PDT and LITT currently more widely implemented, while SDT and FUS are promising but under investigation. Intraoperative therapies hold potential to improve surgical outcomes for HGG by reducing residual tumor burden. While further clinical studies are needed to optimize these techniques, early evidence supports their potential to enhance the effectiveness of surgical resection and improve patient survival in HGG management.

Recounting the untold stories of breast cancer patient experiences: lessons learned from a patient-public involvement and engagement storytelling event.

Breast cancer remains a prevalent disease in women worldwide. Though advancements in breast cancer care have improved patient survival, a breast cancer diagnosis, and subsequent interventions have a lasting impact on patients' lived experiences during the pandemic. We present the collaborative learning process from this patient engagement workshop series as a community-academic partnership. Narrative medicine tools were used to recount patients' lived experiences following diagnosis, where both patients and researchers shared their cancer research activities in each workshop, and the role of the multidisciplinary healthcare team was discussed. We used an iterative approach to cohort building, narrative development, and the use of multiple media formats to capture stories. Over 20 patients with breast cancer shared their stories for the first time since their diagnosis with a wider audience. Here, we present the learning process and considerations from this event. Understanding patients' lived experiences can support researchers and healthcare professionals in developing an empathetic approach to shared healthcare decision making. Moreover, understanding the lived experiences of patients is critical to addressing disparities in healthcare.

Abstract B043: Molecular profiling of serially collected cerebrospinal fluid uncovers therapy-resistant subclones in recurrent leptomeningeal metastatic disease

Abstract Leptomeningeal metastatic disease (LMD) is the spread of cancer cells to the cerebrospinal fluid (CSF)-filled spaces surrounding the central nervous system. After symptom onset, LMD patients survive for only weeks to months while enduring devastating neurologic symptoms. Current clinical tools to diagnose LMD, such as CSF cytology and magnetic resonance imaging, do not detect mutations susceptible to treatment, quantitatively monitor response to therapy, or identify mutation-based resistance mechanisms. Here, we sought to profile LMD using next-generation sequencing by studying CSF-derived cell-free DNA (CSF-cfDNA) from 9 breast cancer and 5 lung cancer patients with LMD and 4 LMD-negative controls. To conduct an unbiased search for somatic mutations, we used a custom-designed gene panel and our validated True2 sequencing workflow with a specificity of <1 false positive per 100kb panel positions and a 97.6% sensitivity for detecting single nucleotide variants (SNVs) with a variant allele frequency (VAF) ≥0.1%. Although CSF-cfDNA quantity ranged widely (<1 to 91 ng), genomic alterations were observed in 100% of LMD patients vs. none in the controls. In 13 patients with a SNV, an average of 4.5±3.3 variants were detected with a VAF ranging from 0.051% (HER2 p.S1151L associated with a 12-fold amplification and read depth of 25,542X) to 98.7% (PTEN p.Q733X associated with a loss of heterozygosity). Importantly, subclones in cancer driver genes were detected in 10 of 13 (76.9%) samples consistent with a high prevalence in LMD. Somatic mutations in genes common to both cancers were discovered (e.g., TP53, KMT2D, and EGFR), while other affected genes segregated based on cancer type (e.g., PIK3CA, ATM, and CDH1 in breast cancer; PTEN, MTOR and PDGFRA in lung cancer). An amplification or deletion was detected in 10 of 14 patients (71.4%), a subset of which segregated by cancer type (e.g., HER2 and ESR1 amplifications in breast cancer; CDKN2A and TP53 codeletions in lung cancer). Using serially collected CSF samples, we observed: (1) loss of subclones in response to therapy followed by resurgence at clinical recurrence showing suppression of disease but not eradication; (2) multiple subclones in the same gene supporting evidence of convergent evolution; and (3) emergence of new subclones at clinical recurrence consistent with mutation evolution in response to therapy. For example, in a breast cancer patient with a known HER2 amplification receiving intrathecal Trastuzumab, a previously absent HER2 p.V777L mutation was present at the end of therapy with a VAF of 18.6% which increased at clinical recurrence to 94.8% in association with a 2.4-fold HER2 amplification indicating the mutated HER2 subclone was already therapy-resistant. Our findings support a panel-based approach to detect and monitor LMD-derived somatic mutations using CSF-cfDNA. Moreover, the untargeted search for somatic mutations via True2 has the potential to guide personalized, adaptive therapeutics for LMD patients which may prove essential in improving patient survival. Citation Format: Yingqi Zhang, Rachna Malani, Charlie S Dean, Laura A Boatz, Brion E Harrison, Mei Wei, Wallace Akerley, Mary P Bronner, Hunter R Underhill. Molecular profiling of serially collected cerebrospinal fluid uncovers therapy-resistant subclones in recurrent leptomeningeal metastatic disease [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B043.

BN SO26 - Predicting successful and safe day-case laparoscopic cholecystectomy: Validation of the Cholecystectomy as a Day Case (CAAD) score

Abstract Background Day case surgery is a major target for the NHS as it improves patient satisfaction and reduces financial costs. The CAAD score, using pre-operative variables from clinic letters and electronic sources, aids in selecting patients for day-case lists. This study assessed the validity of the CAAD score in predicting successful and safe day-case laparoscopic cholecystectomy (LC) at an isolated day unit. Method A retrospective analysis was performed on patients scheduled for elective LC between January 2020 and March 2022. Outcomes (same day discharge rate, length of stay, conversion to open, bile leak, mortality) were stratified by CAAD score (≤5, >5). Statistical analyses included Chi square and independent t-tests using SPSS 28.0. Results 58 patients were analysed.18/38 patients with CAAD ≤5 achieved same day discharge compared to 4/20 with CAAD >5 (p<0.05). 36 patients stayed for ≥1 day. The mean length of hospitalization was 1.38 days (range 1-2) for the 13 patients with CAAD ≤5. 15 patients with CAAD >5 stayed significantly longer i.e. 2.53 days (range 1-10) (p <0.05). Longer stay for scores >5 was due to difficult dissection (13%), conversion to open (13%) and drain insertion (7%). For scores ≤5, reasons were drain insertion, postoperative pain, nausea, and difficult dissection, each at 8%. No major complications were noted in either group. Conclusion The CAAD score is a predictive tool for successful and safe day-case LC, correlating lower scores with higher success rates and shorter hospital stays. Implementing the CAAD score can improve patient selection, potentially reduce unnecessary overnight stays, and support operational efficiency in isolated day units.

Abstract A003: CD45 positive circulating tumor cells as a prognostic marker in prostate cancer

Abstract Prostate cancer is one of the most common types of cancer among male patients worldwide, making early diagnosis and effective treatment crucial for improving patient survival rates. In this regard, circulating tumor cells (CTCs) have garnered attention as an important biomarker for cancer staging and monitoring treatment response. In prostate cancer, CTCs are typically identified as keratin+/CD45- cells, with additional markers such as PSA or PSMA also being used. The conventional CTC identification way have dismissed CD45+/keratin+ double-positive cells as artifacts by nonspecific binding during the staining process. However, recent studies have reported the presence of CD45+/keratin+ CTCs in various types of cancers, highlighting metastatic potential and their ability to evade the immune system. These findings require re- examination of the role for the double positive CTCs. Therefore, this study aimed to identify the presence of CD45+ CTCs in prostate cancer and to assess their clinical significance. Blood samples were collected from 80 prostate cancer patients, followed by unbiased isolation of CTCs, which were stained using PSA, keratin, and CD45. The detected CTCs were categorized based on CD45 expression, and the clinical relevance of each group was validated using patient information. Through this study, we aimed to confirm whether the CD45+ CTCs can be a clinical indicator in prostate cancer. The results revealed that CD45+ CTCs accounted for 90% of all detected CTCs, likely due to their high immune evasion capabilities. Additionally, in 17% of the patients, only CD45+ CTCs were detected, indicating the potential to expand CTC detection even in patients where CTCs were previously undetected using conventional criteria. The number of CD45+ CTCs was significantly higher in patients with progressive disease compared to those with complete or partial response, showing greater statistical significance than analyses using CD45- CTCs. Furthermore, the number of PSA+ CTCs was closely linked to changes in plasma PSA levels, suggesting they could be used as a supporting marker to enhance the accuracy of current plasma PSA tests. These findings indicate that CD45+ CTCs in prostate cancer are not merely artifacts of nonspecific binding but are indeed meaningful cells closely related to cancer progression. This study suggests that CD45+ CTCs have the potential to be utilized as a prognostic biomarker in prostate cancer. By including CD45+ CTCs, which were previously overlooked in conventional CTC analysis methods, more sensitive and accurate cancer monitoring could be achieved. In-depth future studies on the clinical applicability of CD45+ CTCs could significantly contribute to predicting prognosis and developing personalized treatment strategies for prostate cancer patients. Citation Format: Hyeongjung Woo, Woon-Hae Kim, Hyun Young Shin, Hyerin Jung, Hyung Ho Lee, Minseok S. Kim, Jae Young Joung. CD45 positive circulating tumor cells as a prognostic marker in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A003.

Total Gastrectomy for Gastric Malignancy: Trends Over 15 Years in Major Morbidity, Mortality, and Patient Selection From The National Surgical Quality Improvement Program.

We examined trends in major morbidity and mortality following total gastrectomy for malignancy in a national cohort. The National Surgical Quality Improvement Program was used to identify patients who underwent total gastrectomy for malignancy from 2007 to 2021. Joinpoint regression was used to determine annual percent changes (APCs) in thirty-day postoperative major morbidity, mortality, and length of stay (LOS). Major morbidity included deep and organ space surgical site infection, venous thromboembolism, cardiac event, pneumonia, acute renal failure, sepsis, and respiratory failure. Of 3515 patients, the median age was 65 years (IQR = 55-73), 59% were male, and 57.9% were White. Major morbidity was 23%, which did not change over time (APC = -1.4, 95% CI = -3.4 to 0.58), nor were there changes in individual morbidities with time. The most common morbidities were organ space surgical site infection (9.2%) and pneumonia (8.5%). Mortality rate in the study cohort was 2.7% and did not change (APC = -6.2, 95% CI = -13.0 to 1.1). LOS (median 9 days) also did not vary with time (APC = -2.3, 95% CI = -7.8 to 3.9). There was an increase in patients with diabetes (21.6% vs. 11.2%, p < 0.05), BMI ≥ 30 (31.1% vs. 18.2%, p < 0.05), and ASA IV-V status (11.6% vs. 3.5%, p < 0.05). Morbidity and mortality following total gastrectomy for malignancy have not significantly changed over the last fifteen years. While this may in part be explained by increased patient comorbidity, efforts should be made to improve patient selection and mitigate postoperative complications to allow for timely adjuvant therapies.

BIOM-23. DEUTERIUM METABOLIC IMAGING OF RESPONSE TO PRECISION THERAPY IN BRAF-V600E MUTANT GLIOMAS

Abstract Oncogenic BRAF-V600E mutations are frequently observed in low- and high-grade gliomas in adults and children. BRAF transduces signals from receptor tyrosine kinases to downstream effectors such as MEK1/2 and ERK, which regulate both metabolism and proliferation. The combination of the BRAF-V600E inhibitor dabrafenib and the MEK1/2 inhibitor trametinib (Dab/Tra) improves patient survival. However, there is considerable variation in the durability of response, underscoring the need for early biomarkers of treatment response. Magnetic resonance imaging (MRI), which is the gold standard for patient management, does not reliably assess response to therapy. Since the BRAF/MEK pathway regulates metabolism, the goal of this study was to determine whether Dab/Tra induces alterations in glucose metabolism that can be leveraged for non-invasive imaging. Using gene expression profiling, in vivo metabolomics, and stable isotope tracing, we show that Dab/Tra downregulates glucose metabolism to lactate in human and murine BRAF-V600E mutant models (AM38, 2341). In vivo infusion with [U-13C]-glucose in mice bearing intracranial AM38 tumors confirmed that Dab/Tra downregulates glucose metabolism to lactate in the tumor in vivo. Mechanistically, Dab/Tra destabilizes hypoxia inducible factor-1a and downregulates glycolytic genes, including SLC2A1, HK2, PFKFB3, and LDHA. Deuterium metabolic imaging (DMI) is a novel, clinical stage method of tracing glucose metabolism in vivo. Our studies show that lactate production from [6,6-2H]-glucose is reduced in AM38 and 2341 cells treated with Dab/Tra. Importantly, lactate production is reduced within 48 h of treatment with Dab/Tra in mice bearing intracranial AM38 tumors at the clinical magnetic field strength of 3T. Furthermore, this drop in 2H-lactate production is observed in the absence of MRI-detectable volumetric alterations and is predictive of extended survival. Collectively, our studies mechanistically link BRAF/MEK inhibition with downregulation of glycolysis and identify [6,6’-2H]-glucose as a novel contrast agent for imaging early response to therapy. Clinical translation of our studies will enable precision imaging of response to therapy for patients with BRAF-mutant gliomas.

PET/CT radiomics and deep learning in the diagnosis of benign and malignant pulmonary nodules: progress and challenges

Lung cancer is currently the leading cause of cancer-related deaths, and early diagnosis and screening can significantly reduce its mortality rate. Since some early-stage lung cancers lack obvious clinical symptoms and only present as pulmonary nodules (PNs) in imaging examinations, accurately determining the benign or malignant nature of PNs is crucial for improving patient survival rates. 18F-FDG PET/CT is important in diagnosing PNs, but its specificity needs improvement. Radiomics can provide information beyond traditional visual assessment, overcoming its limitations by extracting high-throughput quantitative features from medical images. Radiomics features based on 18F-FDG PET/CT and deep learning methods have shown great potential in the noninvasive diagnosis of PNs. This paper reviews the latest advancements in these methods and discusses their contributions to improving diagnostic accuracy and the challenges they face.

Antibiotic adoption effects on nutrition and quality of life in lung cancer patients undergoing radiotherapy and chemotherapy: A meta-analysis.

Lung cancer (LC) is one of the leading causes of death worldwide. Treatment methodologies such as chemotherapy and radiotherapy have improved patient survival rates. Nevertheless, these treatments can also lead to adverse reactions and impact patients' nutritional status and quality of life (QOL). Antibiotics are commonly used for treating infections, but there is still controversy regarding their potential adverse effects on LC patients. This work aimed to investigate the impact of antibiotic adoption on the nutritional status and QOL of LC patients undergoing radiotherapy or chemotherapy, providing valuable insights for the clinical management of LC. A meta-analysis approach was employed to comprehensively evaluate the relationship by synthesizing relevant literature. Published studies were identified through searches in databases such as PubMed, EMBASE, Cochrane Library, Web of Science, and CNKI. The inclusion criteria encompassed randomized controlled trials, cohort studies, and cross-sectional studies. Assessment indicators included patient weight, BMI, hemoglobin levels, and QOL. Meta-analysis was conducted using software such as the Cochrane Collaboration and RevMan5.3. Heterogeneity was evaluated using the Higgins I2 index, where values between 25% and 50% indicate moderate heterogeneity, and values greater than 50% indicate substantial heterogeneity. 12 eligible studies involving 1,917 patients were finally included. LC patients who received antibiotics during radiotherapy or chemotherapy were found to have a higher risk of malnutrition. The antibiotic group exhibited a more significant decrease in body mass index (BMI) (P< 0.05) and lower serum albumin levels (P< 0.05) versus the control (C) group. Additionally, the overall QOL scores in the antibiotic group were dramatically lower than those in the C group, showing a significant difference with P< 0.05. Sensitivity analysis indicated that the overall conclusions of this work were robust and unbiased. Antibiotics in LC patients undergoing radiotherapy or chemotherapy may increase the risk of malnutrition and decrease their QOL. Hence, physicians should carefully consider antibiotics and take necessary preventive measures and supportive treatments to improve LC patients' nutritional status and QOL.

Ethical implications of artificial intelligence in skin cancer diagnostics: use-case analyses.

Skin cancer is the most common cancer worldwide. Early diagnosis is crucial for improving patient survival and morbidity. Artificial intelligence (AI)-assisted smartphone applications (apps) for skin cancer potentially offer accessible, early risk assessment of suspicious skin lesions. However, the integration of novel technologies into dermatology pathways raises ethical concerns. Although ethical principles for AI governance are well known, how these principles should be applied to real-life AI apps readily available for public use is less well understood. We conducted an ethical use-case analysis of commercially available skin cancer apps to better understand the ethical issues arising from their development and use in a real-world context. Established methods for ethical analysis of clinical AI applications were applied to two popular skin cancer apps in the UK: SkinVision and Scanoma. Systematic searches of published literature, regulatory documents, and websites were conducted to review the evidence regarding app development, effectiveness, and use. Screening for inclusion was undertaken by two researchers independently. Ethical concerns were identified with reference to previously described ethical concerns and principles for AI-assisted healthcare. By conceptualising ethical principles within the use-context of skin cancer apps, we identified specific ethical issues arising throughout the AI lifecycle of both apps. One company provided extensive detail regarding algorithm development and decision-making, this information was insufficiently reported for the other app. Other concerns identified related to number, quality, and consistency of studies assessing algorithm efficacy. Limited efforts to address potential skin tone biases and exclusion of individuals with darker skin tones as target users by one app risks perpetuating existing inequalities. Inadequate regulatory oversight was identified. Findings from our ethical use-case analysis of two patient-facing AI-assisted skin cancer apps suggest inadequate incorporation of bioethical norms such as justice, responsibility and transparency into the development and deployment of both apps. Improved regulation should increase accountability. Ensuring ethics by design through integration between technology developers, dermatologists, ethicists, and the public is urgently needed to prevent the potential benefits of AI-assisted skin cancer apps being overshadowed by potential ethical harms.

Prognostic Implications and Reversibility of Pulmonary Vascular Resistance Derived by Echocardiography in Patients Undergoing Tricuspid Annuloplasty.

Pulmonary vascular resistance (PVR) intimately correlates with right ventricular afterload and the development of secondary tricuspid regurgitation (sTR). We sought to investigate the prognostic roles of PVR derived by echocardiography in patients with sTR undergoing tricuspid annuloplasty (TA). Data from 322 TA patients [median age (interquartile range): 65.0 (59.0-70.0) years; 35.7% males] were obtained from a prospective registry to determine the impact of PVR on the composite outcome (including all-cause mortality and heart failure hospitalization). PVR was calculated by dividing the peak TR velocity by time-velocity integral of the right ventricular outflow tract followed by adding 0.16. During a median follow-up of 5.2 years, 108 adverse events occurred including 48 deaths and 60 heart failure readmissions. Baseline PVR ≥2 WU was independently associated with a higher risk of composite outcome (HR:1.674, 95% CI: 1.028-2.726, P=0.038). Baseline PVR outperforms both pulmonary artery systolic pressure (PASP) and the ratio of tricuspid annulus plane systolic excursion to PASP in terms of outcome prediction, with pronounced improvement of global model fit, reclassification, and discrimination. In 150 patients who received short-term echocardiograms after surgery, the presence of postoperative PVR ≥2 WU (n=20, 13.3%) was independently associated with composite outcome (HR: 2.621, 95% CI: 1.292-5.319, P=0.008). PVR derived by echocardiography is an independent determinant of outcomes in patients undergoing TA for sTR. The inclusion of noninvasive PVR may provide valuable information to improve patient selection and postoperative management in this population.

Added value of pre-procedural magnetic resonance angiography in transarterial embolization for refractory musculoskeletal pain

BackgroundTransarterial microembolization (TAME) is a minimally invasive treatment for chronic musculoskeletal disorders. Identifying angiogenesis and the supplying vessels of the target joint is important but challenging. Although magnetic resonance imaging (MRI) is commonly used to diagnose musculoskeletal diseases, it typically excludes vascular imaging. Dynamic contrast-enhanced magnetic resonance angiography (DCE-MRA) has the ability to visualize lesion angiogenesis, identify supplying vessels, and evaluate the vasculature anatomy. We propose that incorporating DCE-MRA into pre-procedural assessments can help identify the culprit vessels, arterial anatomy, and variant assessment of the target joint before TAME.Materials and methodsWe investigated six cases, each presenting pain in different body parts: shoulder adhesive capsulitis, trapezius myalgia, combined tennis and golf elbow, knee osteoarthritis, refractory knee pain after osteotomy, and plantar fasciitis. All patients underwent MRI with DCE-MRA before undergoing TAME. DCE-MRA was performed using either 1.5 T or 3 T MRI scanners, employing 3D-TRICKS or 4D-TRAK XD techniques. The numerical rating scale for pain was evaluated at one, three, and six months after the procedure, and any adverse events were recorded over the entire six-month follow-up period.ResultsPre-procedural DCE-MRA helped to visualize angiogenesis at the lesion site in all patients and identify the supplying vessels, arterial vasculature anatomy, and branching variants. These findings corroborated the subsequent digital subtraction angiography (DSA) findings obtained during TAME. All patients experienced pain reduction and functional improvement after TAME without any complications. The average pain score reduced significantly after TAME treatment (p &amp;lt; 0.05). Two patients underwent a second MRI and DCE-MRA at the six-month follow-up and showed a significant reduction in angiogenesis.ConclusionDCE-MRA offers a valuable pre-procedural assessment tool for TAME procedures by facilitating the visualization of angiogenesis at the lesion site, supplying vessels, and arterial anatomic variants, including the variable orifice of the supplying branches. This information can potentially improve patient selection and pre-procedural planning, leading to better outcomes and reduced risk of complications.

Single-cell RNA sequencing analysis identifies acute changes in the tumor microenvironment induced by interferon α gene therapy in a murine bladder cancer model

IntroductionNadofaragene firadenovec (Ad-IFNα/Syn3) is now approved for BCG-unresponsive bladder cancer (BLCA). IFNα is a pleiotropic cytokine that causes direct tumor cell killing via TRAIL-mediated apoptosis, angiogenesis inhibition, and activation of the innate and adaptive immune system. We established an immunocompetent murine BLCA model to study the effects of murine adenoviral IFNα (muAd-Ifnα) gene therapy on cancer cells and the tumor microenvironment using a novel murine equivalent of Nadofaragene firadenovec (muAd-Ifnα).MethodsTumors were induced by instilling MB49 cells into the bladders of mice; luciferase imaging confirmed tumor development. Mice were treated with adenovirus control (Ad-Ctrl; empty vector), or muAd-Ifnα (3x1011 VP/mL), and survival analysis was performed. For single-cell sequencing (scRNAseq) analysis (72h), bladders were harvested and treated with collagenase/hyaluronidase and TrypLE for cell dissociation. Single cells were suspended in PBS/1% FBS buffer; viability was assessed with Vicell cell counter. scRNAseq analysis was performed using 10X genomics 3’ sequencing. Raw RNAseq data were pre-processed using Cell Ranger single-cell software. Seurat (R package) was used to normalize and cluster the scRNA data. Pooled differential gene expression analysis in specific cell clusters was performed with DESeq2.ResultsWe identified 16 cell clusters based on marker expression which were grouped into epithelial (tumor), uroplakin-enriched, endothelial, T-cells, neutrophils, and macrophage clusters. Top differentially expressed genes between muAd-Ifnα and Ad-Ctrl were identified. Within the specific cell clusters, IPA analysis revealed significant differences between muAd-Ifnα and control. IFNα signaling and hypercytokinemia/chemokinemia were upregulated in all clusters. Cell death pathways were upregulated in tumor and endothelial clusters. T-cells demonstrated upregulation of the immunogenic cell death signaling pathway and a decrease in the Th2 pathway genes. Macrophages showed upregulation of PD1/PD-L1 pathways along with downregulation of macrophage activation pathways (alternate and classical). Multiplex immunofluorescence confirmed increased infiltration with macrophages in muAd-Ifnα treated tumors compared to controls. PD1/PD-L1 expression was reduced at 72h.DiscussionThis single-cell analysis builds upon our understanding of the impact of Ad-IFNα on tumor cells and other compartments of the microenvironment. These data will help identify mechanisms to improve patient selection and therapeutic efficacy of Nadofaragene firadenovec.

Association between KRAS mutation and alcohol consumption in Brazilian patients with colorectal cancer

Colorectal cancer (CRC) is a leading cause of morbidity and mortality worldwide. Detection before metastasis and efficient treatment of disease significantly improve patient survival and quality of life. However, limitations in diagnosis and postoperative surveillance are associated with low CRC detection and survival rates. Thus, this project aimed to evaluate the molecular profile of patients diagnosed with CRC, as molecular biomarkers constitute a new frontier for diagnosis, treatment and prognosis. Methods and Results: 42 patients were included in the study, predominantly male (59.5%), with a median age of 63 years (SD: 10.0; min: 41; max: 83). The majority of primary tumors were located in the rectum (38.1%), in the sigmoid (33.3%) and in the ascending (21.4%) colon. We evaluated the genes KRAS, NRAS, BRAF, EGFR and TP53 using Sanger sequencing. Somatic and germline mutations were found in the KRAS, EGFR and TP53 genes, with the most common somatic alteration being rs121913529 in KRAS. This variant was also strongly associated with alcoholism (p = 0.002). Furthermore, patients with somatic mutations in TP53 had significantly higher mortality compared to those with wild-type alleles (OR: 11.2; 95% CI 1.25–2.45). Conclusions: Our findings support a relationship between alcohol consumption and the rs121913529 mutation, which is classified as pathogenic for colorectal cancer. Thus, further studies investigating the link between alcohol consumption, colorectal carcinogenesis and tumor progression ought to be conducted.

ASO Visual Abstract: Insight into Predictors of Cytoreduction Score Following Cytoreductive Surgery-Hyperthermic Intraperitoneal Chemotherapy for Gastric Peritoneal Carcinomatosis Improves Patient Selection and Prognostic Outcomes.

ASO Visual Abstract: Insight into Predictors of Cytoreduction Score Following Cytoreductive Surgery-Hyperthermic Intraperitoneal Chemotherapy for Gastric Peritoneal Carcinomatosis Improves Patient Selection and Prognostic Outcomes.

Intraoperative Guidance of Pancreatic Cancer Resection Using a Toll-like Receptor 2-Targeted Fluorescence Molecular Imaging Agent.

Human TLR2 is broadly expressed among pancreatic adenocarcinomas, and the highly specific TLR2L-800 fluorescence molecular imaging agent has potential for use in fluorescence-guided surgery to increase R0 margins and improve patient survival.

Leveraging machine learning for preoperative prediction of supramaximal ablation in laser interstitial thermal therapy for brain tumors.

Maximizing safe resection in neuro-oncology has become paramount to improving patient survival and outcomes. Laser interstitial thermal therapy (LITT) offers similar survival benefits to traditional resection, alongside shorter hospital stays and faster recovery times. The extent of ablation (EOA) achieved using LITT is linked to patient outcomes, with greater EOA correlating with improved outcomes. However, the preoperative predictors for achieving supramaximal ablation (EOA ≥ 100%) are not well understood. By leveraging machine learning (ML) techniques, this study aimed to identify these predictors to enhance patient selection and therefore outcomes. The objective was to explore preoperative predictors for supramaximal EOA using ML in patients with glioblastoma. A retrospective study was conducted on the medical records of 254 patients undergoing LITT from 2013 to 2023 at a single tertiary center. Cohort criteria included age ≥ 18 years, diagnosis of glioblastoma, single-trajectory ablation, and a complete dataset. The study assessed preoperative clinical and radiographic factors, using EOA ≥ 100% as the endpoint. Five ML models were used: logistic regression, random forest (RF), gradient boosting, Gaussian naive Bayes, and support vector machine. Training and testing cohorts were subsequently assessed across ML models with fivefold cross-validation. Models were optimized using hyperparameter tuning. Performance was primarily quantified using the area under the curve (AUC) of the receiver operating characteristic curve. The final cohort consisted of 72 patients. Among the ML models, RF achieved the highest AUC (mean ± SD 0.94 ± 0.06). The leading models identified that lower preoperative volume, history of prior radiation therapy, history of prior craniotomy, preoperative neurological deficits, history of preoperative seizures, and distance from intracranial heat sinks were predictive of successful ablations in patients. Additionally, RF had the best mean metrics: accuracy 0.88, precision 0.87, specificity 0.87, and sensitivity 0.89. This is the first study to investigate the role of ML for optimizing ablation volumes in LITT. These ML models suggest that low preoperative volumes, previous craniotomy, previous radiation therapy, no previous neurological deficits, larger catheter-heat sink distance, and the presence of preoperative seizures are important prognostic factors for predicting successful supramaximal ablations with LITT.