Proportion of early-stage breast cancer at diagnosis in Ethiopia: a systematic review and meta-analysis.

BACKGROUND: Breast cancer is the most common cancer-affecting women globally, with disproportionally high mortality rates in lower-income countries, including Ethiopia. The stage at diagnosis is a well-defined predictive system that determines the likelihood of breast cancer mortality. Early-stage breast cancer at diagnosis is associated with better treatment outcomes as compared with late stage. Although there are numerous primary studies on women with breast cancer with different proportions of early-stage breast cancer, there is currently no summary data on what proportion of breast cancer was diagnosed at early-stage in Ethiopia. This study focused on a pooled proportion of early-stage breast cancer at diagnosis in Ethiopia. METHODS: By using key terms, Medline through Pub-Med, Google Scholar, Science Direct, HINARI and Medley were searched about breast cancer in Ethiopia, and a total of 288 articles were retrieved. After screening the articles and quality of each article was assessed using Newcastle-Ottawa Scale. Finally, 41 articles were used for the final pooled proportion. A random effects model was used to estimate the pooled prevalence and heterogeneity of included studies that were then assessed by using prediction interval. RESULTS: Pooled proportion of early-stage breast cancer at diagnosis in Ethiopian hospitals was found to be 36% with a 95% confidence interval ranging from 31 to 41% and a 95% prediction interval ranging from 28 to 45%. CONCLUSION: Most breast cancer patients (64%) in Ethiopia are diagnosed at a late-stage. This contributes to the high mortality rates of breast cancer among women in Ethiopia. Therefore, in line with recommendations by the World Health Organization, we recommend that there should be an emphasis in Ethiopia to focus on early detection of breast cancer.

Aptamer-functionalized MOFs and AI-driven strategies for early cancer diagnosis and therapeutics.

Metal-Organic Frameworks (MOFs) have exceptional inherent properties that make them highly suitable for diverse applications, such as catalysis, storage, optics, chemo sensing, and biomedical science and technology. Over the past decades, researchers have utilized various techniques, including solvothermal, hydrothermal, mechanochemical, electrochemical, and ultrasonic, to synthesize MOFs with tailored properties. Post-synthetic modification of linkers, nodal components, and crystallite domain size and morphology can functionalize MOFs to improve their aptamer applications. Advancements in AI and machine learning led to the development of nonporous MOFs and nanoscale MOFs for medical purposes. MOFs have exhibited promise in cancer therapy, with the successful accumulation of a photosensitizer in cancer cells representing a significant breakthrough. This perspective is focused on MOFs' use as advanced materials and systems for cancer therapy, exploring the challenging aspects and promising features of MOF-based cancer diagnosis and treatment. The paper concludes by emphasizing the potential of MOFs as a transformative technology for cancer treatment and diagnosis.

Magnifying endoscopy is superior at detecting easy-missed neoplastic lesions on the upper gastrointestinal tract.

Magnifying endoscopy is advantageous in detecting precancerous lesions. Our study aimed to clarify its ability to detect easily missed neoplastic lesions on the upper gastrointestinal tract. A retrospective analysis of clinical, endoscopic, and pathological data of cases undergoing gastroscopy was performed using magnifying and routine endoscopy. The detection rates of overall lesions, the ability to identify flat-type neoplastic lesions, and the easily missed neoplastic lesions were compared between the two groups. Endoscopic data from 32,367 patients was analyzed in this study. The use of magnifying endoscopy was an independent factor in identifying flat lesions (OR 2.236, 95% CI 1.969-2.540, p < 0.001), particularly type IIb lesions (OR 3.117, 95% CI 2.333-4.165, p < 0.001). For neoplastic lesions, magnifying endoscopy was also identified as having better sensitivity than routine endoscopy (sensitivity, 90.4% vs. 78.9%, p < 0.001). Similarly, magnifying endoscopy was an independent factor for identifying flat lesions (OR 2.927, 95% CI 2.365-3.621, p < 0.001), especially type IIc lesions (OR 4.415, 95% CI 3.076-6.339, p < 0.001). Magnifying endoscopy was also identified as having superior sensitivity (44.7% vs. 13.3%, p = 0.034) for early cancerous lesions. Compared to routine endoscopy, magnification endoscopy is advantageous in detecting and identifying neoplastic lesions in the upper gastrointestinal tract, especially flat neoplastic lesions and early cancers.

Nanobodies for the Early Detection of Ovarian Cancer.

Ovarian cancer ranks fifth in cancer-related deaths among women. Since ovarian cancer patients are often asymptomatic, most patients are diagnosed only at an advanced stage of disease. This results in a 5-year survival rate below 50%, which is in strong contrast to a survival rate as high as 94% if detected and treated at an early stage. Monitoring serum biomarkers offers new possibilities to diagnose ovarian cancer at an early stage. In this study, nanobodies targeting the ovarian cancer biomarkers human epididymis protein 4 (HE4), secretory leukocyte protease inhibitor (SLPI), and progranulin (PGRN) were evaluated regarding their expression levels in bacterial systems, epitope binning, and antigen-binding affinity by enzyme-linked immunosorbent assay and surface plasmon resonance. The selected nanobodies possess strong binding affinities for their cognate antigens (KD~0.1-10 nM) and therefore have a pronounced potential to detect ovarian cancer at an early stage. Moreover, it is of utmost importance that the limits of detection (LOD) for these biomarkers are in the pM range, implying high specificity and sensitivity, as demonstrated by values in human serum of 37 pM for HE4, 163 pM for SLPI, and 195 pM for PGRN. These nanobody candidates could thus pave the way towards multiplexed biosensors.

Highly sensitive and portable mRNA detection platform for early cancer detection.

Pancreatic cancer, at unresectable advanced stages, presents poor prognoses, which could be prevented by early pancreatic cancer diagnosis methods. Recently, a promising early-stage pancreatic cancer biomarker, extracellular vesicles (EVs) related glypican-1 (GPC1) mRNA, is found to overexpress in pancreatic cancer cells. Current mRNA detection methods usually require expensive machinery, strict preservation environments, and time-consuming processes to guarantee detection sensitivity, specificity, and stability. Herein, we propose a novel two-step amplification method (CHAGE) via the target triggered Catalytic Hairpin Assembly strategy combined with Gold-Enhanced point-of-care-testing (POCT) technology for sensitive visual detection of pancreatic cancer biomarker. First, utilizing the catalyzed hairpin DNA circuit, low expression of the GPC1 mRNA was changed into amplification product 1 (AP1, a DNA duplex) as the next detection targets of the paper strips. Second, the AP1 was loaded onto a lateral flow assay and captured with the gold signal nanoparticles to visualize results. Finally, the detected results can be further enhanced by depositing gold to re-enlarge the sizes of gold nanoparticles in detection zones. As a result, the CHAGE methodology lowers the detection limit of mRNA to 100 fM and provides results within 2 h at 37 °C. Furthermore, we demonstrate the successful application in discriminating pancreatic cancer cells by analyzing EVs' GPC1 mRNA expression levels. Hence, the CHAGE methodology proposed here provides a rapid and convenient POCT platform for sensitive detection of mRNAs through unique probes designs (COVID, HPV, etc.).

Machine learning enables detection of early-stage colorectal cancer by whole-genome sequencing of plasma cell-free DNA.

BACKGROUND: Blood-based methods using cell-free DNA (cfDNA) are under development as an alternative to existing screening tests. However, early-stage detection of cancer using tumor-derived cfDNA has proven challenging because of the small proportion of cfDNA derived from tumor tissue in early-stage disease. A machine learning approach to discover signatures in cfDNA, potentially reflective of both tumor and non-tumor contributions, may represent a promising direction for the early detection of cancer. METHODS: Whole-genome sequencing was performed on cfDNA extracted from plasma samples (N = 546 colorectal cancer and 271 non-cancer controls). Reads aligning to protein-coding gene bodies were extracted, and read counts were normalized. cfDNA tumor fraction was estimated using IchorCNA. Machine learning models were trained using k-fold cross-validation and confounder-based cross-validations to assess generalization performance. RESULTS: In a colorectal cancer cohort heavily weighted towards early-stage cancer (80% stage I/II), we achieved a mean AUC of 0.92 (95% CI 0.91-0.93) with a mean sensitivity of 85% (95% CI 83-86%) at 85% specificity. Sensitivity generally increased with tumor stage and increasing tumor fraction. Stratification by age, sequencing batch, and institution demonstrated the impact of these confounders and provided a more accurate assessment of generalization performance. CONCLUSIONS: A machine learning approach using cfDNA achieved high sensitivity and specificity in a large, predominantly early-stage, colorectal cancer cohort. The possibility of systematic technical and institution-specific biases warrants similar confounder analyses in other studies. Prospective validation of this machine learning method and evaluation of a multi-analyte approach are underway.

Label-Free Optical Technologies to Enhance Noninvasive Endoscopic Imaging of Early-Stage Cancers.

White light endoscopic imaging allows for the examination of internal human organs and is essential in the detection and treatment of early-stage cancers. To facilitate diagnosis of precancerous changes and early-stage cancers, label-free optical technologies that provide enhanced malignancy-specific contrast and depth information have been extensively researched. The rapid development of technology in the past two decades has enabled integration of these optical technologies into clinical endoscopy. In recent years, the significant advantages of using these adjunct optical devices have been shown, suggesting readiness for clinical translation. In this review, we provide an overview of the working principles and miniaturization considerations and summarize the clinical and preclinical demonstrations of several such techniques for early-stage cancer detection. We also offer an outlook for the integration of multiple technologies and the use of computer-aided diagnosis in clinical endoscopy.

An antibody-drug conjugate for endometrioid carcinoma based on the expression of cell adhesion molecule 1.

Cell adhesion molecule 1 (CADM1), an immunoglobulin superfamily member, is expressed in endometrial glandular cells highly during the proliferative phase but lowly during the secretory phase. Previously, a CADM1-targeting antibody-drug conjugate (ADC) was generated, in which a humanized anti-CADM1 ectodomain antibody h3E1 was linked with monomethyl auristatin E (h3E1-MMAE ADC). The present study aimed at probing whether this ADC could be useful for the treatment of endometrial neoplasm. Firstly, immunohistochemistry for CADM1 was conducted on proliferative-phase endometrium (n = 13), endometrial hyperplasia (n = 35), and endometrioid carcinoma at various stages (n = 166). CADM1 immunostaining intensity was highest in atypical endometrial hyperplasia and endometrioid carcinoma confined within the endometrium and was decreased stepwise as the carcinoma stage progressed. Next, h3E1-MMAE ADC was examined for its cytotoxicity in vitro using human endometrial adenocarcinoma cell lines expressing CADM1; HEC-1B, HEC-50B, JHUM-3, and OMC-2. The ADC killed these cells in a dose-dependent manner with half maximal inhibitory concentration (IC50) of 12.02 nM for HEC-1B and 2.04 nM for HEC-50B. Collectively, h3E1-MMAE ADC may serve as a noninvasive alternative to simple hysterectomy in the treatment of endometrioid carcinoma confined within the endometrium.

Impact of Cancer Localization on Symptom Burden and Quality of Life in Head and Neck Cancers: A Comparative Study.

Background: Head and neck cancer (HNC) is a critical concern in oncology, with notable disparities in survival rates. While the long-term symptom burden in HNC survivors and its impact on quality of life (QoL) has been explored, there is limited understanding of the influence of cancer localizations on these aspects. This study aims to elucidate the role of cancer localizations in shaping long-term outcomes in HNC patients. Methods: A cross-sectional study was conducted at the University Hospital Erlangen's Department of Otolaryngology, exploring the impact of cancer localization on symptom burden and QoL in 138 HNC patients using the University of Washington Quality of Life Questionnaire Version 4. Results: In our study of HNC patients, we investigated symptom burden across different cancer localizations, including oral cavity, oropharyngeal, hypopharyngeal, laryngeal, and cancer of unknown primary (CUP). While we found no significant variations in parameters such as pain, appearance, and activity, notable differences emerged in swallowing, speech, and salivation. Patients with oral cavity and laryngeal carcinomas had significantly higher swallowing and salivation scores compared to those with oropharyngeal carcinoma and CUP, while speech-related symptoms were lower for oral cavity and laryngeal carcinoma patients. Importantly, these symptom differences did not significantly impact health-related and overall QoL. These findings emphasize the nuanced interplay between symptomatology and QoL in different HNC cancer localizations. Conclusion: The research highlights significant disparities in post-treatment symptoms across different HNC localizations and underscores the need for personalized treatment and management strategies to address unique challenges associated with each HNC type, ultimately aiming to enhance post-treatment QoL.

Endoscopic Submucosal Dissection for Treatment of Early-Stage Cancer or Precancerous Lesion in the Upper Gastrointestinal Tract in Patients with Liver Cirrhosis.

(1) Background: Endoscopic submucosal dissection (ESD) has been widely accepted as the standard method for treating early-stage cancer or precancerous lesions in the upper gastrointestinal tract; however, it may be difficult in patients with liver cirrhosis due to clinical challenges such as coagulation dysfunction, presence of gastroesophageal varices, etc. We aimed to demonstrate the safety and efficacy of ESD in these populations. (2) Methods: The clinical data of patients were retrospectively collected and analyzed. Inclusion criteria of the study were: a. patients with liver cirrhosis; b. patients who underwent ESD; c. patients who were diagnosed with early-stage cancer or precancerous lesions in the upper gastrointestinal tract. (3) Results: Eight patients were enrolled from April 2019 to April 2023, of whom three were male and five were female, with ages ranging from 43 to 70 years old. Seven lesions were located in the stomach and one other lesion was in the esophagus. ESD was performed successfully in all eight patients, and the resected lesion size ranged from 2 to 6 cm. Only one patient encountered postoperative complications, namely, chest pain and fever. No recurrence was noticed during a follow-up of 3 to 45 months. (4) Conclusions: ESD may serve as a safe and effective method for treating upper gastrointestinal early-stage cancer or precancerous lesions in patients with liver cirrhosis.

A case of rapidly progressing and poorly differentiated Ip-type early-stage colorectal adenocarcinoma.

A 36-year-old woman visited our hospital with a chief complaint of bleeding during defecation. Colonoscopy revealed a 20-mm pedunculated polyp in the sigmoid colon, which was en bloc resected under endoscopy. The histopathological diagnosis was adenoma cancer with a depth of invasion indicating mucosal cancer, no lymphovascular invasion, and negative at the resection margin. The poorly differentiated adenocarcinoma component comprised approximately 5% of the tumor. Although there were no recurrence signs in the computed tomography scans obtained 4 months post polypectomy, the patient experienced aggressive lower back pain at 6 months post polypectomy. Local recurrence, peritoneal dissemination, and liver metastasis were confirmed. Finally, the patient died following a rapid and aggressive deterioration of her general condition. Histological examination of the local recurrence revealed a poorly differentiated adenocarcinoma (por2), with immunostaining revealing a high Ki67 positivity rate of 95%. Moreover, the poorly differentiated adenocarcinoma region of the resected polyp had a Ki67 positivity rate of 90%, which suggested that they were the same tumors. These findings suggested that the recurrence could have occurred through implantation.

RUNX3 in Stem Cell and Cancer Biology.

The runt-related transcription factors (RUNX) play prominent roles in cell cycle progression, differentiation, apoptosis, immunity and epithelial-mesenchymal transition. There are three members in the mammalian RUNX family, each with distinct tissue expression profiles. RUNX genes play unique and redundant roles during development and adult tissue homeostasis. The ability of RUNX proteins to influence signaling pathways, such as Wnt, TGFß and Hippo-YAP, suggests that they integrate signals from the environment to dictate cell fate decisions. All RUNX genes hold master regulator roles, albeit in different tissues, and all have been implicated in cancer. Paradoxically, RUNX genes exert tumor suppressive and oncogenic functions, depending on tumor type and stage. Unlike RUNX1 and 2, the role of RUNX3 in stem cells is poorly understood. A recent study using cancer-derived RUNX3 mutation R122C revealed a gatekeeper role for RUNX3 in gastric epithelial stem cell homeostasis. The corpora of RUNX3R122C/R122C mice showed a dramatic increase in proliferating stem cells as well as inhibition of differentiation. Tellingly, RUNX3R122C/R122C mice also exhibited a precancerous phenotype. This review focuses on the impact of RUNX3 dysregulation on (1) stem cell fate and (2) the molecular mechanisms underpinning early carcinogenesis.

Role of endoscopic ultrasound for pre-intervention evaluation in early esophageal cancer.

BACKGROUND: Endoscopic ultrasound (EUS) stands as an accurate imaging modality for esophageal cancer staging, however utilization of EUS in early-stage cancer management remains controversial. Identification of non-applicability of endoscopic interventions with deep muscular invasion with EUS in pre-intervention evaluation of early-stage esophageal cancer is compared to endoscopic and histologic indicators. AIM: To display the role of EUS in pre-intervention early esophageal cancer staging and how the index endoscopic features of invasive esophageal malignancy compare for prediction of depth of invasion and cancer management. METHODS: This was a retrospective study of patients who underwent pre-resection EUS after a diagnosis of esophageal cancer at a tertiary medical center from 2012 to 2022. Patient clinical data, initial esophagogastroduodenoscopy/biopsy, EUS, and final resection pathology reports were abstracted, and statistical analysis was conducted to assess the role of EUS in management decisions. RESULTS: Forty nine patients were identified for this study. EUS T stage was concordant with histological T stage in 75.5% of patients. In determining submucosal involvement (T1a vs T1b), EUS had a specificity of 85.0%, sensitivity of 53.9%, and accuracy of 72.7%. Endoscopic features of tumor size > 2 cm and the presence of esophageal ulceration were significantly associated with deep invasion of cancer on histology. EUS affected management from endoscopic mucosal resection/submucosal dissection to esophagectomy in 23.5% of patients without esophageal ulceration and 6.9% of patients with tumor size < 2 cm. In patients without both endoscopic findings, EUS identified deeper cancer and changed management in 4.8% (1/20) of cases. CONCLUSION: EUS was reasonably specific in ruling out submucosal invasion but had relatively poor sensitivity. Data validated endoscopic indicators suggested superficial cancers in the group with a tumor size < 2 cm and the lack of esophageal ulceration. In patients with these findings, EUS rarely identified a deep cancer that warranted a change in management.

Primary and Metastatic Lung Cancer: Rationale, Indications, and Outcomes of Thermal Ablation.

The widespread use of imaging as well as the efforts conducted through screening campaigns has dramatically increased the early detection rate of lung cancer. Historically, the management of lung cancer has heavily relied on surgery. However, the increased proportion of patients with comorbidities has given significance to less invasive therapeutic options like minimally invasive surgery and image-guided thermal ablation, which could precisely target the tumor without requiring general anesthesia or a thoracotomy. Thermal ablation is considered low-risk for lung tumors smaller than 3 cm that are located in peripheral lung and do not involve major blood vessels or airways. The rationale for ablative therapies relies on the fact that focused delivery of energy induces cell death and pathologic necrosis. Image-guided percutaneous thermal ablation therapies are established techniques in the local treatment of hepatic, renal, bone, thyroid and uterine lesions. In the lung, and specifically in the setting of metastatic disease, the 3 main indications for lung ablation are to serve as (1) curative intent, (2) as a strategy to achieve a chemo-holiday in oligometastatic disease, and (3) in oligoprogressive disease. Following these premises, the current paper aims to review the rationale, indications, and outcomes of thermal ablation as a form of local therapy in the treatment of primary and metastatic lung disease.

Benefit Finding and Related Factors of Patients with Early-Stage Cancer in China.

(1) Background: Although the research on benefit finding (BF) in China has increased in recent years, it remains in its infancy. Few previous studies have focused on early-stage cancer patients. Therefore, this research study aimed to explore BF and its influencing factors for early-stage cancer patients in China. (2) Methods: From April to August 2019, 319 patients with early-stage cancer in the treatment period were selected by the convenience sampling method and evaluated using the Benefit Finding of Cancer Patients Scale-Chinese (BFS-C), Perceived Social Support Scale (PSSS), and Medical Coping Modes Questionnaire (MCMQ). (3) Results: The mean BF score was 47.57 (SD = 12.26). The results of the correlation analysis show that benefit finding was positively correlated with social support, but negatively correlated with acceptance-resignation. In addition, social support was negatively correlated with avoidance and acceptance-resignation. The results of the multiple linear regression indicate that the variables of self-assessment of disease severity, exercise time, coping mode (acceptance-resignation), and social support, affect BF. Finally, social support was shown to exert an intermediary effect on acceptance-resignation and BF. (4) Conclusions: In this study, the score of BF of patients with early-stage cancer was low. Medical staff should be more aware of the health behavior of patients with early-stage cancer, guide them to actively face the disease, and fully mobilize the social support of patients' friends and family, so as to help patients increase their disease BF.

Selective isolation of extracellular vesicles from minimally processed human plasma as a translational strategy for liquid biopsies.

BACKGROUND: Intercellular communication is mediated by extracellular vesicles (EVs), as they enclose selectively packaged biomolecules that can be horizontally transferred from donor to recipient cells. Because all cells constantly generate and recycle EVs, they provide accurate timed snapshots of individual pathophysiological status. Since blood plasma circulates through the whole body, it is often the biofluid of choice for biomarker detection in EVs. Blood collection is easy and minimally invasive, yet reproducible procedures to obtain pure EV samples from circulating biofluids are still lacking. Here, we addressed central aspects of EV immunoaffinity isolation from simple and complex matrices, such as plasma. METHODS: Cell-generated EV spike-in models were isolated and purified by size-exclusion chromatography, stained with cellular dyes and characterized by nano flow cytometry. Fluorescently-labelled spike-in EVs emerged as reliable, high-throughput and easily measurable readouts, which were employed to optimize our EV immunoprecipitation strategy and evaluate its performance. Plasma-derived EVs were captured and detected using this straightforward protocol, sequentially combining isolation and staining of specific surface markers, such as CD9 or CD41. Multiplexed digital transcript detection data was generated using the Nanostring nCounter platform and evaluated through a dedicated bioinformatics pipeline. RESULTS: Beads with covalently-conjugated antibodies on their surface outperformed streptavidin-conjugated beads, coated with biotinylated antibodies, in EV immunoprecipitation. Fluorescent EV spike recovery evidenced that target EV subpopulations can be efficiently retrieved from plasma, and that their enrichment is dependent not only on complex matrix composition, but also on the EV surface phenotype. Finally, mRNA profiling experiments proved that distinct EV subpopulations can be captured by directly targeting different surface markers. Furthermore, EVs isolated with anti-CD61 beads enclosed mRNA expression patterns that might be associated to early-stage lung cancer, in contrast with EVs captured through CD9, CD63 or CD81. The differential clinical value carried within each distinct EV subset highlights the advantages of selective isolation. CONCLUSIONS: This EV isolation protocol facilitated the extraction of clinically useful information from plasma. Compatible with common downstream analytics, it is a readily implementable research tool, tailored to provide a truly translational solution in routine clinical workflows, fostering the inclusion of EVs in novel liquid biopsy settings.

Aptamer-Based Sandwich Assay Formats for Detection and Discrimination of Human High- and Low-Molecular-Weight uPA for Cancer Prognosis and Diagnosis.

Urokinase-type plasminogen activator (urokinase, uPA) is a frequently discussed biomarker for prognosis, diagnosis, and recurrence of cancer. In a previous study, we developed ssDNA aptamers that bind to different forms of human urokinase, which are therefore assumed to have different binding regions. In this study, we demonstrate the development of aptamer-based sandwich assays that use different combinations of these aptamers to detect high molecular weight- (HMW-) uPA in a micro titer plate format. By combining aptamers and antibodies, it was possible to distinguish between HMW-uPA and low molecular weight- (LMW-) uPA. For the best performing aptamer combination, we calculated the limit of detection (LOD) and limit of quantification (LOQ) in spiked buffer and urine samples with an LOD up to 50 ng/mL and 138 ng/mL, respectively. To show the specificity and sequence dependence of the reporter aptamer uPAapt-02-FR, we have identified key nucleotides within the sequence that are important for specific folding and binding to uPA using a fluorescent dye-linked aptamer assay (FLAA). Since uPA is a much-discussed marker for prognosis and diagnosis in various types of cancers, these aptamers and their use in a micro titer plate assay format represent a novel, promising tool for the detection of uPA and for possible diagnostic applications.

Cancer-derived EVs show tropism for tissues at early stage of neoplastic transformation.

From the past decade, extracellular vesicles (EVs) have attracted considerable attention as tools for the selective delivery of anti-neoplastic drugs to cancer tissues. Compared to other nanoparticles, EVs display interesting unique features including immune compatibility, low toxicity and the ability to encapsulate a large variety of small- and macro-molecules. However, in virtually all studies, investigations on EVs have been focused on fully transformed cancers: the possibility to apply EV technology also to early-stage tumors has never been explored. Methods: Herein, we studied the ability of cancer-derived EVs to recognize and deliver their cargo also to incipient cancers. To this purpose, EV biodistribution was studied in MMTV-NeuT genetically modified mice during early mammary transformation, in fully developed breast tumors and in the normal gland of wild type syngeneic mice. EVs were loaded with indocyanine green (ICG), a near-infrared (NIR) dye together with oncolytic viruses and i.v. injected in mice. The nanoparticle biodistribution was assayed by in vivo and ex vivo optical imaging (detecting the ICG) and semiquantitative real-time PCR (measuring the adenoviral genome) in different tissues. Results: Our results demonstrate the ability of cancer-derived EVs to recognize early-stage neoplastic tissues opening the possibility to selectively deliver theranostics also for tumor prevention. Conclusions: Taken together our study demonstrates the ability of EVs to recognize and deliver diagnostic and therapeutic agents not only to fully transformed tissues but also to early stage tumors. These findings pave the way for the synthesis of "universal" EVs-based formulation for targeted cancer therapy.

Curative-Intent Treatment with Durvalumab in Early-Stage Cancers.

The introduction of immunotherapy has fundamentally transformed the treatment landscape in cancer, providing long-term survival benefit for patients with advanced disease across multiple tumor types, including non-small cell lung cancer (NSCLC). In the placebo-controlled phase 3 PACIFIC trial, the PD-L1 inhibitor durvalumab demonstrated significant improvements in progression-free survival and overall survival in patients with unresectable, stage III NSCLC who had not progressed after platinum-based chemoradiotherapy (CRT). These findings have led to the widespread acceptance of the 'PACIFIC regimen' (durvalumab after CRT) as the standard of care in this setting. Moreover, the PACIFIC trial is the first study to demonstrate a proven survival advantage with an immunotherapy in a curative-intent setting, thereby providing a strong rationale for further investigation of durvalumab in early-stage cancers. Herein, we describe the extensive clinical development program for durvalumab across multiple tumor types in curative-intent settings, outlining the scientific rationale(s) for its use and highlighting the innovative research (e.g., personalized cancer monitoring) advanced by these trials.

Force-dependent extracellular matrix remodeling by early-stage cancer cells alters diffusion and induces carcinoma-associated fibroblasts.

It is known cancer cells secrete cytokines inducing normal fibroblasts (NFs) to become carcinoma-associated fibroblasts (CAFs). However, it is not clear how the CAF-promoting cytokines can effectively navigate the dense ECM, a diffusion barrier, in the tumor microenvironment to reach NFs during the early stages of cancer development. In this study, we devised a 3D coculture system to investigate the possible mechanism of CAF induction at early stages of breast cancer. We found that in a force-dependent manner, ECM fibrils are radially aligned relative to the tumor spheroid. The fibril alignment enhances the diffusion of exosomes containing CAF-promoting cytokines towards NFs. Suppression of force generation or ECM remodeling abolishes the enhancement of exosome diffusion and the subsequent CAF induction. In summary, our finding suggests that early-stage, pre-metastatic cancer cells can generate high forces to align the ECM fibrils, thereby enhancing the diffusion of CAF-promoting exosomes to reach the stroma and induce CAFs.