Glioblastoma, the most common primary malignant brain tumor in adults, carries a poor prognosis, with a median survival of just 15 months, significantly impacting patients' quality of life. The aggressive growth of these highly vascularized tumors relies heavily on angiogenesis, driven primarily by vascular endothelial growth factor-A. Therefore, VEGF signaling pathway has become a prime therapeutic target in GBM treatment over the past decade. While anti-angiogenic treatment showed promise, agents like bevacizumab have ultimately failed to improve overall survival. This highlights the presence of compensatory angiogenic mechanisms that bypass VEGF inhibition, necessitating further investigation into resistance mechanisms and the development of more effective therapeutic strategies. This review examined the current landscape of anti-angiogenic agents for GBM, analyzed the mechanisms driving resistance to these therapies, and explored potential strategies for enhancing their effectiveness.

Background: The intermediate filament nestin was first described in stem and progenitor cells of neural and mesenchymal origin. Additionally, it is expressed in endothelial cells during wound healing and tumorigenesis. Thus, nestin is widely regarded as a marker for proliferative endothelium. However, little is known about its role in lymphatic endothelium. Methods: Here, we analyzed the expression of nestin in the endothelium of ten human haemangiomas and ten lymphangiomas in situ by immunohistochemistry. This study aimed to investigate the expression of nestin in haemangiomas and lymphangiomas to determine its potential role as a vascular marker. Specifically, we aimed to assess whether nestin expression is restricted to proliferating endothelial cells or also present in non-proliferative blood vessels. Results: Immunohistochemically, haemangiomas were positive for CD31 but negative for D2-40. The endothelial cells within these lesions showed a homogeneous expression of nestin. In contrast, the endothelium of lymphangiomas reacted positively for D2-40 and CD31 but did not show any nestin expression. Additionally, only a few endothelial cells of capillary haemangiomas showed a Ki-67 positivity. Conclusions: The differential expression of nestin in haemangiomas and lymphangiomas indicates a specificity of nestin for the endothelium of blood vessels. The Ki-67 negativity in the majority of the endothelial cells reveals the proliferative quiescence of these cells. These findings indicate that nestin could be used as a marker to differentiate between blood and lymphatic vessels.

Mathematical modelling has proven to be a valuable tool in predicting the delivery and efficacy of molecular, antibody-based, nano and cellular therapy in solid tumours. Mathematical models based on our understanding of the biological processes at subcellular, cellular and tissue level are known as mechanistic models that, in turn, are divided into continuous and discrete models. Continuous models are further divided into lumped parameter models - for describing the temporal distribution of medicine in tumours and normal organs - and distributed parameter models - for studying the spatiotemporal distribution of therapy in tumours. Discrete models capture interactions at the cellular and subcellular levels. Collectively, these models are useful for optimizing the delivery and efficacy of molecular, nanoscale and cellular therapy in tumours by incorporating the biological characteristics of tumours, the physicochemical properties of drugs, the interactions among drugs, cancer cells and various components of the tumour microenvironment, and for enabling patient-specific predictions when combined with medical imaging. Artificial intelligence-based methods, such as machine learning, have ushered in a new era in oncology. These data-driven approaches complement mechanistic models and have immense potential for improving cancer detection, treatment and drug discovery. Here we review these diverse approaches and suggest ways to combine mechanistic and artificial intelligence-based models to further improve patient treatment outcomes.

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers, characterized by high morbidity and mortality rates. Recently, immunotherapy has emerged as a crucial treatment modality for HCC, following surgery, locoregional therapies, and targeted therapies. This approach harnesses the body's immune system to target and eliminate cancer cells, potentially resulting in durable antitumor responses. However, acquired resistance and the tumor immunosuppressive microenvironment (TIME) significantly hinder its clinical application. Recently, advancements in nanotechnology, coupled with a deeper understanding of cancer biology and nano-biological interactions, have led to the development of various nanoparticles aimed at enhancing therapeutic efficacy through specific targeting of tumor tissues. These nanoparticles increase the accumulation of immunotherapeutic drugs within the tumor microenvironment, thereby transforming the TIME. In this review, we provide a concise overview of the fundamental principles governing the TIME landscape in HCC and discuss the rationale for and applications of nanoparticles in this context. Additionally, we highlight existing challenges and potential opportunities for the clinical translation of cancer nanomedicines.

BPC 157, known as the "Body Protection Compound", is a pentadecapeptide isolated from human gastric juice that demonstrated its pleiotropic beneficial effects in various preclinical models mimicking medical conditions, such as tissue injury, inflammatory bowel disease, or even CNS disorders. Unlike many other drugs, BPC 157 has a desirable safety profile, since only a few side effects have been reported following its administration. Nevertheless, this compound was temporarily banned by the World Anti-Doping Agency (WADA) in 2022 (it is not currently listed as banned by the WADA). However, it has not been approved for use in standard medicine by the FDA and other global regulatory authorities due to the absence of sufficient and comprehensive clinical studies confirming its health benefits in humans. In this review, we summarize information on the biological activities of BPC 157, with particular reference to its mechanism of action and probable toxicity. This generated the attention of experts, as BPC 157 has been offered for sale on many websites. We also present recent interest in BPC 157 as reflected in a number of patent applications and granted patents.

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.

Lung cancer remains an influential global health concern, necessitating the development of innovative therapeutic strategies. The tumour stroma, which is known as tumour microenvironment (TME) has a central impact on tumour expansion and treatment resistance. The stroma of lung tumours consists of numerous cells and molecules that shape an environment for tumour expansion. This environment not only protects tumoral cells against immune system attacks but also enables tumour stroma to attenuate the action of antitumor drugs. This stroma consists of stromal cells like cancer-associated fibroblasts (CAFs), suppressive immune cells, and cytotoxic immune cells. Additionally, the presence of stem cells, endothelial cells and pericytes can facilitate tumour volume expansion. Nanoparticles are hopeful tools for targeted drug delivery because of their extraordinary properties and their capacity to devastate biological obstacles. This review article provides a comprehensive overview of contemporary advancements in targeting the lung tumour stroma using nanoparticles. Various nanoparticle-based approaches, including passive and active targeting, and stimuli-responsive systems, highlighting their potential to improve drug delivery efficiency. Additionally, the role of nanotechnology in modulating the tumour stroma by targeting key components such as immune cells, extracellular matrix (ECM), hypoxia, and suppressive elements in the lung tumour stroma.

The high incidence of vascular and lymphatic metastasis is closely associated with poor prognosis and mortality in cancer. Finding effective inhibitors to prevent pathological angiogenesis and lymphangiogenesis relies on appropriate in vivo models. The chick embryo chorioallantoic membrane (CAM) is formed by the fusion of the chorion and allantois during embryonic development.

In this context, we primarily summarize the changes in vascular and lymphatic vessel formation in tumors under the action of drugs using this model, providing a preclinical model basis for effective tumor inhibitors.

Due to natural immunological defects, chick embryos accept various tissue and species transplants without immune response. The CAM model has been widely used in studying angiogenesis, antiangiogenesis, tumor growth, tumor metastasis, and drug efficacy. This review describes the use of CAM assays as a valuable method for testing the in vivo effects of drugs on vascular and lymphatic vessel formation before further investigating the effects of drugs on tumor vessels and lymphatic vessels in animal models.

The high incidence of vascular and lymphatic metastasis is closely associated with poor prognosis and mortality in cancer. Finding effective inhibitors to prevent pathological angiogenesis and lymphangiogenesis relies on appropriate in vivo models. The chick embryo chorioallantoic membrane (CAM) is formed by the fusion of the chorion and allantois during embryonic development.

In this context, we primarily summarize the changes in vascular and lymphatic vessel formation in tumors under the action of drugs using this model, providing a preclinical model basis for effective tumor inhibitors.

Due to natural immunological defects, chick embryos accept various tissue and species transplants without immune response. The CAM model has been widely used in studying angiogenesis, antiangiogenesis, tumor growth, tumor metastasis, and drug efficacy. This review describes the use of CAM assays as a valuable method for testing the in vivo effects of drugs on vascular and lymphatic vessel formation before further investigating the effects of drugs on tumor vessels and lymphatic vessels in animal models.

This study explores the challenges associated with nanoparticle-based drug delivery to the tumor parenchyma, focusing on the widely utilized enhanced permeability and retention effect (EPR). While EPR has been a key strategy, its inconsistent clinical success lacks clear mechanistic understanding and is hindered by limited tools for studying relevant phenomena. This work introduces an approach that employs multiparametric dynamic contrast-enhanced ultrasound (CEUS) with a nanoscale contrast agent for noninvasive, real-time examination of tumor microenvironment characteristics. We demonstrate that CEUS imaging can: (1) evaluate tumor microenvironment features, (2) be used to help predict the distribution of doxorubicin-loaded liposomes in the tumor parenchyma, and (3) be used to predict nanotherapeutic efficacy. CEUS using nanobubbles (NBs) was carried out in two tumor types of high (LS174T) and low (U87) vascular permeability. LS174T tumors consistently showed significantly different time intensity curve (TIC) parameters, including area under the rising curve (AUCR, 2.7×) and time to peak intensity (TTP, 1.9×) compared to U87 tumors. Crucially, a recently developed decorrelation time (DT) parameter specific to NB CEUS dynamics successfully predicted the distribution of doxorubicin-loaded liposomes within the tumor parenchyma (r = 0.86 ± 0.13). AUCR, TTP, and DT were used to correlate imaging findings to nanotherapeutic response with 100% accuracy in SKOV-3 tumors. These findings suggest that NB-CEUS parameters can effectively discern tumor vascular permeability, serving as a biomarker for identifying tumor characteristics and predicting the responsiveness to nanoparticle-based therapies. The observed differences between LS174T and U87 tumors and the accurate prediction of nanotherapeutic efficacy in SKOV-3 tumors indicate the potential utility of this method in predicting treatment efficacy and evaluating EPR in diseases characterized by pathologically permeable vasculature. Ultimately, this research contributes valuable insights into refining drug delivery strategies and assessing the broader applicability of EPR-based approaches.

In this perspective, we highlight and reflect on the current knowledge with respect to serine/glycine metabolism in cancer, therapeutic resistance, and precision medicine opportunities for therapeutic targeting and treatment follow-up. Cancer subtypes with high mortality rates include lung cancer and glioblastomas. In order to improve future therapeutic opportunities, patient stratification need to be performed to select patients that might benefit from adjuvant serine/glycine targeting compounds. In an effort to identify the group of patients for stratification purposes, we analyzed publicly available TCGA patient datasets to test associations between serine/glycine metabolism enzyme expression and important cancer drivers in lung cancer and glioblastoma. These patients presenting serine/glycine pathway overexpression might benefit from adjuvant sertraline treatment in the future.

Colorectal cancer remains a major cause of cancer death and morbidity worldwide. Surgery is a major treatment modality for primary and, increasingly, secondary curative therapy. However, with more patients being diagnosed with early stage and premalignant disease manifesting as large polyps, greater accuracy in diagnostic and therapeutic precision is needed right from the time of first endoscopic encounter. Rapid advancements in the field of artificial intelligence (AI), coupled with widespread availability of near infrared imaging (currently based around indocyanine green (ICG)) can enable colonoscopic tissue classification and prognostic stratification for significant polyps, in a similar manner to contemporary dynamic radiological perfusion imaging but with the advantage of being able to do so directly within interventional procedural time frames. It can provide an explainable method for immediate digital biopsies that could guide or even replace traditional forceps biopsies and provide guidance re margins (both areas where current practice is only approximately 80% accurate prior to definitive excision). Here, we discuss the concept and practice of AI enhanced ICG perfusion analysis for rectal cancer surgery while highlighting recent and essential near-future advancements. These include breakthrough developments in computer vision and time series analysis that allow for real-time quantification and classification of fluorescent perfusion signals of rectal cancer tissue intraoperatively that accurately distinguish between normal, benign, and malignant tissues in situ endoscopically, which are now undergoing international prospective validation (the Horizon Europe CLASSICA study). Next stage advancements may include detailed digital characterisation of small rectal malignancy based on intraoperative assessment of specific intratumoral fluorescent signal pattern. This could include T staging and intratumoral molecular process profiling (e.g. regarding angiogenesis, differentiation, inflammatory component, and tumour to stroma ratio) with the potential to accurately predict the microscopic local response to nonsurgical treatment enabling personalised therapy via decision support tools. Such advancements are also applicable to the next generation fluorophores and imaging agents currently emerging from clinical trials. In addition, by providing an understandable, applicable method for detailed tissue characterisation visually, such technology paves the way for acceptance of other AI methodology during surgery including, potentially, deep learning methods based on whole screen/video detailing.

Skin metastases arise in 10% of cancer patients, but standardized dermoscopy diagnostic criteria for skin metastases remain poor. This study's objective was to analyze the dermoscopy features of skin metastases from advanced systemic and cutaneous cancers.

A retrospective study on 715 dermoscopy images of skin metastases from 33 patients with various primary cancers (breast, ovary, melanoma, non-melanoma skin cancer, and chronic leukemia) attending two academic centers between 2013 and 2023 was performed. Four independent observers blindly analyzed patterns, colors, vessels, and elementary lesions for each metastasis (30 parameters in total).

The structureless white pattern was the most prominent indicator of cutaneous metastasis (81.26%, p < 0.001). Regardless of the primary tumor, colors pink, red, white, and tan were identified. Elementary lesions were infrequent, except for melanoma metastases that displayed dots (13.23%) and globules (11.11%). Breast cancer metastases presented: blue (41.48%) and red (34.32%) colors, irregular vessels (13.58%), and a blue-naevus pattern (22.22%). Melanoma metastases displayed: a blue-naevus pattern (61.38%), a blue color (85.71%), and a structureless-blue combination pattern (79.37%). Non-melanoma skin cancer metastases were characterized by vascular (42.11%) and angioma-like (31.58%) patterns, pink (57.89%) and red (57.89%) colors, irregular (57.89%), thin hairpin (47.37%), comma (47, 37%), and thick hairpin (26, 32%) vessels and a red, white and irregular vessels combination pattern (52, 63%). A pink structureless combination pattern was frequent (61.05%) in chronic leukemia metastases. Ovarian cancer metastases displayed a white and tan structureless combination pattern (100%) and frequently had dotted vessels (42.85%).

Papules and nodules with a white structureless pattern suggest skin metastases, regardless of the primary tumor. A blue structureless lesion is indicative of melanoma metastasis and a vascular pattern with irregular vessels indicates a non-melanoma skin cancer metastasis. Dermoscopy stands as a reliable non-invasive diagnostic method for suspected cutaneous metastases in patients with a known cancer history.

Glioblastomas (GBM) are aggressive tumors known for their heterogeneity, rapid proliferation, treatment resistance, and extensive vasculature. Angiogenesis, the formation of new vessels, involves endothelial cell (EC) migration and proliferation. Various extracellular matrix (ECM) molecules regulate EC survival, migration, and proliferation. Culturing human brain EC (HBMEC) on GBM-derived ECM revealed a decrease in EC numbers compared to controls. Through in silico analysis, we explored ECM gene expression differences between GBM and brain normal glia cells and the impact of GBM microenvironment on EC ECM transcripts. ECM molecules such as collagen alpha chains (COL4A1, COL4A2, p < 0.0001); laminin alpha (LAMA4), beta (LAMB2), and gamma (LAMC1) chains (p < 0.0005); neurocan (NCAN), brevican (BCAN) and versican (VCAN) (p < 0.0005); hyaluronan synthase (HAS) 2 and metalloprotease (MMP) 2 (p < 0.005); MMP inhibitors (TIMP1-4, p < 0.0005), transforming growth factor beta-1 (TGFB1) and integrin alpha (ITGA3/5) (p < 0.05) and beta (ITGB1, p < 0.0005) chains showed increased expression in GBM. Additionally, GBM-influenced EC exhibited elevated expression of COL5A3, COL6A1, COL22A1 and COL27A1 (p < 0.01); LAMA1, LAMB1 (p < 0.001); fibulins (FBLN1/2, p < 0.01); MMP9, HAS1, ITGA3, TGFB1, and wingless-related integration site 9B (WNT9B) (p < 0.01) compared to normal EC. Some of these molecules: COL5A1/3, COL6A1, COL22/27A1, FBLN1/2, ITGA3/5, ITGB1 and LAMA1/B1 (p < 0.01); NCAN, HAS1, MMP2/9, TIMP1/2 and TGFB1 (p < 0.05) correlated with GBM patient survival. In conclusion, this study identified both established and novel ECM molecules regulating GBM angiogenesis, suggesting NCAN and COL27A1 are new potential prognostic biomarkers for GBM.

This literature review provides a comprehensive overview of triple-negative breast cancer (TNBC) and explores innovative targeted therapies focused on specific hallmarks of cancer cells, aiming to revolutionize breast cancer treatment. TNBC, characterized by its lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), presents distinct features, categorizing these invasive breast tumors into various phenotypes delineated by key elements in molecular assays. This article delves into the latest advancements in therapeutic strategies targeting components of the tumor microenvironment and pivotal hallmarks of cancer: deregulating cellular metabolism and the Warburg effect, acidosis and hypoxia, the ability to metastasize and evade the immune system, aiming to enhance treatment efficacy while mitigating systemic toxicity. Insights from in vitro and in vivo studies and clinical trials underscore the promising effectiveness and elucidate the mechanisms of action of these novel therapeutic interventions for TNBC, particularly in cases refractory to conventional treatments. The integration of targeted therapies tailored to the molecular characteristics of TNBC holds significant potential for optimizing clinical outcomes and addressing the pressing need for more effective treatment options for this aggressive subtype of breast cancer.

We developed a novel drug delivery system called hyperthermic pressurized intraperitoneal aerosol chemotherapy (HPIPAC) that hybridized Hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). The present study aims to assess the feasibility and safety of HPIPAC system in a large animal survival model.

Eleven pigs (eight non-survival models and three survival models) were used in the experiment. The heat module in the HPIPAC controller circulates hyperthermic CO2 in a closed-loop circuit and creates gas-based dry intraperitoneal hyperthermia. Three 12 mm trocars were placed on the abdomen. The afferent CO2 tube wound with heat generating coil was inserted into a trocar, and the efferent tube was inserted into another trocar. Heated CO2 was insufflated and circulated in a closed circuit until the intra-abdominal and peritoneal surface temperature reached 42 °C. 100 ml of 5% dextrose in water was nebulized for 5 min and the closed-loop circulation was resumed for 60 min at 42 °C. Tissue biopsies were taken from several sites from the pigs in the survival model.

The average change in core temperature of the pigs was 2.5 ± 0.08 °C. All three pigs displayed no signs of distress, and their vital signs remained stable, with no changes in their diet. In autopsy, inflammatory and fibrotic responses at the biopsy sites were observed without serious pathologic findings.

We successfully proved the feasibility and safety of our novel HPIPAC system in an in-vivo swine survival model.

Immunotherapy is a promising cancer therapeutic strategy. However, the "cold" tumor immune microenvironment (TIME), characterized by insufficient immune cell infiltration and immunosuppressive status, limits the efficacy of immunotherapy. Tumor vascular abnormalities due to defective pericyte coverage are gradually recognized as a profound determinant in "cold" TIME establishment by hindering immune cell trafficking. Recently, several vascular normalization strategies by improving pericyte coverage have been reported, whereas have unsatisfactory efficacy and high rates of resistance. Herein, a combinatorial strategy to induce tumor vasculature-targeted pericyte recruitment and zinc ion-mediated immune activation with a platelet-derived growth factor B (PDGFB)-loaded, cyclo (Arg-Gly-Asp-D-Phe-Lys)-modified zeolitic imidazolate framework 8 (PDGFB@ZIF8-RGD) nanoplatform is proposed. PDGFB@ZIF8-RGD effectively induced tumor vascular normalization, which facilitated trafficking and infiltration of immune effector cells, including natural killer (NK) cells, M1-like macrophages and CD8+ T cells, into tumor microenvironment. Simultaneously, vascular normalization promoted the accumulation of zinc ions inside tumors to trigger effector cell immune activation and effector molecule production. The synergy between these two effects endowed PDGFB@ZIF8-RGD with superior capabilities in reprogramming the "cold" TIME to a "hot" TIME, thereby initiating robust antitumor immunity and suppressing tumor growth. This combinatorial strategy for improving immune effector cell infiltration and activation is a promising paradigm for solid tumor immunotherapy.

Glioblastoma (GBM) is a highly aggressive type of primary brain cancer with a poor prognosis, and despite intensive research, survival rates have not significantly improved. Non-coding RNAs (ncRNAs) are emerging as critical regulators of GBM pathogenesis, including angiogenesis, which is essential for tumor growth and invasion. MicroRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) have been identified as regulators of angiogenesis in GBM. miRNAs such as miR-21, miR-10b, and miR-26a promote angiogenesis by targeting anti-angiogenic factors, while lncRNAs such as H19 and MALAT1 inhibit angiogenesis by regulating pro-angiogenic factors. CircRNAs, such as circSMARCA5 and circBACH2, also regulate angiogenesis through various mechanisms. Similarly, signaling pathways such as the vascular endothelial growth factor (VEGF) pathway play critical roles in angiogenesis and have been targeted for GBM therapy. However, resistance to anti-angiogenic therapies is a significant obstacle in clinical practice. Developing novel therapeutic strategies targeting ncRNAs and angiogenesis is a promising approach for GBM. Potential targets include miRNAs, lncRNAs, circRNAs, and downstream signaling pathways that regulate angiogenesis. This review highlights the critical roles of ncRNAs and angiogenesis in GBM pathogenesis and the potential for new therapeutic strategies targeting these pathways to improve the prognosis and quality of life for GBM patients.

Glioblastoma (GB) is an intrusive and recurrent primary brain tumor with low survivability. The heterogeneity of the tumor microenvironment plays a crucial role in the stemness and proliferation of GB. The tumor microenvironment induces tumor heterogeneity of cancer cells by facilitating clonal evolution and promoting multidrug resistance, leading to cancer cell progression and metastasis. It also plays an important role in angiogenesis to nourish the hypoxic tumor environment. There is a strong interaction of neoplastic cells with their surrounding microenvironment that comprise several immune and non-immune cellular components. The tumor microenvironment is a complex network of immune components like microglia, macrophages, T cells, B cells, natural killer (NK) cells, dendritic cells and myeloid-derived suppressor cells, and non-immune components such as extracellular matrix, endothelial cells, astrocytes and neurons. The prognosis of GB is thus challenging, making it a difficult target for therapeutic interventions. The current therapeutic approaches target these regulators of tumor micro-environment through both generalized and personalized approaches. The review provides a summary of important milestones in GB research, factors regulating tumor microenvironment and promoting angiogenesis and potential therapeutic agents widely used for the treatment of GB patients.

Nanomedicine in oncology has not had the success in clinical impact that was anticipated in the early stages of the field's development. Ideally, nanomedicines selectively accumulate in tumor tissue and reduce systemic side effects compared to traditional chemotherapeutics. However, this has been more successful in preclinical animal models than in humans. The causes of this failure to translate may be related to the intra- and inter-patient heterogeneity of the tumor microenvironment. Predicting whether a patient will respond positively to treatment prior to its initiation, through evaluation of characteristics like nanoparticle extravasation and retention potential in the tumor, may be a way to improve nanomedicine success rate. While there are many potential strategies to accomplish this, prediction and patient stratification via noninvasive medical imaging may be the most efficient and specific strategy. There have been some preclinical and clinical advances in this area using MRI, CT, PET, and other modalities. An alternative approach that has not been studied as extensively is biomedical ultrasound, including techniques such as multiparametric contrast-enhanced ultrasound (mpCEUS), doppler, elastography, and super-resolution processing. Ultrasound is safe, inexpensive, noninvasive, and capable of imaging the entire tumor with high temporal and spatial resolution. In this work, we summarize the in vivo imaging tools that have been used to predict nanoparticle distribution and treatment efficacy in oncology. We emphasize ultrasound imaging and the recent developments in the field concerning CEUS. The successful implementation of an imaging strategy for prediction of nanoparticle accumulation in tumors could lead to increased clinical translation of nanomedicines, and subsequently, improved patient outcomes. This article is categorized under: Diagnostic Tools In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery Emerging Technologies.

The tumor microenvironment is characterized by dysfunctional endothelial cells, resulting in heightened vascular permeability. Many nanoparticle-based drug delivery systems attempt to use this enhanced permeability combined with impaired lymphatic drainage (a concept known as the 'enhanced permeability and retention effect' or EPR effect) as the primary strategy for drug delivery, but this has not proven to be as clinically effective as anticipated. The specific mechanisms behind the inconsistent clinical outcomes of nanotherapeutics have not been clearly articulated, and the field has been hampered by a lack of accessible tools to study EPR-associated phenomena in clinically relevant scenarios. While medical imaging has tremendous potential to contribute to this area, it has not been broadly explored. This work examines, for the first time, the use of multiparametric dynamic contrast-enhanced ultrasound (CEUS) with a novel nanoscale contrast agent to examine tumor microenvironment characteristics noninvasively and in real-time. We demonstrate that CEUS imaging can: (1) evaluate tumor microenvironment features and (2) be used to help predict the distribution of doxorubicin-loaded liposomes in the tumor parenchyma. CEUS using nanobubbles (NBs) was carried out in two tumor types of high (LS174T) and low (U87) vascular permeability, and time-intensity curve (TIC) parameters were evaluated in both models prior to injection of doxorubicin liposomes. Consistently, LS174T tumors showed significantly different TIC parameters, including area under the rising curve (2.7x), time to peak intensity (1.9x) and decorrelation time (DT, 1.9x) compared to U87 tumors. Importantly, the DT parameter successfully predicted tumoral nanoparticle distribution (r = 0.86 ± 0.13). Ultimately, substantial differences in NB-CEUS generated parameters between LS174T and U87 tumors suggest that this method may be useful in determining tumor vascular permeability and could be used as a biomarker for identifying tumor characteristics and predicting sensitivity to nanoparticle-based therapies. These findings could ultimately be applied to predicting treatment efficacy and to evaluating EPR in other diseases with pathologically permeable vasculature.

Colorectal cancer (CRC) is the third most common worldwide. Depending on its stage, chemotherapy is usually given after surgery when CRC has already metastasized to other organs like the liver or lungs. Unfortunately, the current antineoplastics used for CRC therapies involve toxicity and side effects due to their lack of site-specificity. To overcome the drawbacks of heavy chemotherapy, this study proposes to assess the efficacy of thymoquinone (TQ), a bioactive constituent of black seeds (Nigella sativa), as an antiproliferative and pro-apoptotic agent on an experimental CRC model in mice. TQ was encapsulated in lipid nanocapsules (LNCs), used as nanocarriers, in order to increase its specificity and cell absorption. TQ-loaded LNCs (TQ-LNCs) have a diameter of 58.3 ± 3.7 nm and 87.7 ± 4.5% TQ encapsulation efficiency. In turn, in vivo studies showed that the intratumoral administration of TQ-LNCs decreased the tumor size in colorectal cancer bearing mice compared to the control group. TQ-LNCs were more effective than free TQ for inducing tumor cell death. These results highlight the potential of TQ entrapped in LNCs as an anticancer agent for CRC treatment.

Biomicrofluidics, a subdomain of microfluidics, has been inspired by several ideas from nature. However, while the basic inspiration for the same may be drawn from the living world, the translation of all relevant essential functionalities to an artificially engineered framework does not remain trivial. Here, we review the recent progress in bio-inspired microfluidic systems via harnessing the integration of experimental and simulation tools delving into the interface of engineering and biology. Development of "on-chip" technologies as well as their multifarious applications is subsequently discussed, accompanying the relevant advancements in materials and fabrication technology. Pointers toward new directions in research, including an amalgamated fusion of data-driven modeling (such as artificial intelligence and machine learning) and physics-based paradigm, to come up with a human physiological replica on a synthetic bio-chip with due accounting of personalized features, are suggested. These are likely to facilitate physiologically replicating disease modeling on an artificially engineered biochip as well as advance drug development and screening in an expedited route with the minimization of animal and human trials.

In this review, we discuss the effectiveness of drug delivery system based on metal nanoparticles, and also, describe the problems associated with their delivery to tumor cells. Throughout recent years, more reports have appeared in the literature that demonstrate promising results for the treatment of various types of cancer using metal-based nanoparticles. Due to their unique physical and chemical properties, metal nanoparticles are effectively being used for the delivery of drug to the tumor cells, for cancer diagnosis and treatment. They can also be synthesized allowing the control of size and shape. However, the effectiveness of the metal nanoparticles for cancer treatment largely depends on their stability, biocompatibility, and ability to selectively affect tumor cells after their systemic or local administration. Another major problem associated with metal nanoparticles is their ability to overcome tumor tissue barriers such as atypical blood vessel structure, dense and rigid extracellular matrix, and high pressure of tumor interstitial fluid. The review also describes the design of tumor drug delivery systems that are based on metal nanoparticles. The mechanism of action of metal nanoparticles on cancer cells is also discussed. Considering the therapeutic safety and toxicity of metal nanoparticles, the prospects for their use for future clinical applications are being currently reviewed.

Immunotherapy has changed the way many cancers are being treated. Researchers in the field of immunotherapy and tumor immunology are investigating similar questions: How can the positive benefits achieved with immunotherapies be enhanced? Can this be achieved through combinations with other agents and if so, which ones? In our view, there is an urgent need to improve immunotherapy to make further gains in the overall survival for those patients that should benefit from immunotherapy. While numerous different approaches are being considered, our team believes that drug delivery methods along with appropriately selected small-molecule drugs and drug candidates could help reach the goal of doubling the overall survival rate that is seen in some patients that are given immunotherapeutics. This review article is prepared to address how immunotherapies should be combined with a second treatment using an approach that could realize therapeutic gains 10 years from now. For context, an overview of immunotherapy and cancer angiogenesis is provided. The major targets in angiogenesis that have modulatory effects on the tumor microenvironment and immune cells are highlighted. A combination approach that, for us, has the greatest potential for success involves treatments that will normalize the tumor's blood vessel structure and alter the immune microenvironment to support the action of immunotherapeutics. So, this is reviewed as well. Our focus is to provide an insight into some strategies that will engender vascular normalization that may be better than previously described approaches. The potential for drug delivery systems to promote tumor blood vessel normalization is considered.

Lipid shell-stabilized nanoparticles with a perfluorocarbon gas-core, or nanobubbles, have recently attracted attention as a new contrast agent for molecular ultrasound imaging and image-guided therapy. Due to their small size (∼275 nm diameter) and flexible shell, nanobubbles have been shown to extravasate through hyperpermeable vasculature (e.g., in tumors). However, little is known about the dynamics and depth of extravasation of intact, acoustically active nanobubbles. Accordingly, in this work, we developed a microfluidic chip with a lumen and extracellular matrix (ECM) and imaging method that allows real-time imaging and characterization of the extravasation process with high-frequency ultrasound. The microfluidic device has a lumen and is surrounded by an extracellular matrix with tunable porosity. The combination of ultrasound imaging and the microfluidic chip advantageously produces real-time images of the entire length and depth of the matrix. This captures the matrix heterogeneity, offering advantages over other imaging techniques with smaller fields of view. Results from this study show that nanobubbles diffuse through a 1.3 μm pore size (2 mg mL-1) collagen I matrix 25× faster with a penetration depth that was 0.19 mm deeper than a 3.7 μm (4 mg mL-1) matrix. In the 3.7 μm pore size matrix, nanobubbles diffused 92× faster than large nanobubbles (∼875 nm diameter). Decorrelation time analysis was successfully used to differentiate flowing and extra-luminally diffusing nanobubbles. In this work, we show for the first time that combination of an ultrasound-capable microfluidic chip and real-time imaging provided valuable insight into spatiotemporal nanoparticle movement through a heterogeneous extracellular matrix. This work could help accurately predict parameters (e.g., injection dosage) that improve translation of nanoparticles from in vitro to in vivo environments.

Medulloblastoma (MB) is the most prevalent brain tumor in children. Although the current cure rate stands at approximately 70%, the existing treatments that involve a combination of radio- and chemotherapy are highly detrimental to the patients' quality of life. These aggressive therapies often result in a significant reduction in the overall well-being of the patients. Moreover, the most aggressive forms of MB frequently relapse, leading to a fatal outcome in a majority of cases. However, MB is highly vascularized, and both angiogenesis and lymphangiogenesis are believed to play crucial roles in tumor development and spread. In this context, our objective is to provide a comprehensive overview of the current research progress in elucidating the functions of these two pathways.

Cancer continues to pose a severe threat to global health, making pursuing effective treatments more critical than ever. Traditional therapies, although pivotal in managing cancer, encounter considerable challenges, including drug resistance, poor drug solubility, and difficulties targeting tumors, specifically limiting their overall efficacy. Nanomedicine's application in cancer therapy signals a new epoch, distinguished by the improvement of the specificity, efficacy, and tolerability of cancer treatments. This review explores the mechanisms and advantages of nanoparticle-mediated drug delivery, highlighting passive and active targeting strategies. Furthermore, it explores the transformative potential of nanomedicine in tumor therapeutics, delving into its applications across various treatment modalities, including surgery, chemotherapy, immunotherapy, radiotherapy, photodynamic and photothermal therapy, gene therapy, as well as tumor diagnosis and imaging. Meanwhile, the outlook of nanomedicine in tumor therapeutics is discussed, emphasizing the need for addressing toxicity concerns, improving drug delivery strategies, enhancing carrier stability and controlled release, simplifying nano-design, and exploring novel manufacturing technologies. Overall, integrating nanomedicine in cancer treatment holds immense potential for revolutionizing cancer therapeutics and improving patient outcomes.

Globally, clear-cell renal cell carcinoma (ccRCC) represents the most prevalent type of kidney cancer. Surgery plays a key role in the treatment of this cancer, although one third of patients are diagnosed with metastatic ccRCC and about 25% of patients will develop a recurrence after nephrectomy with curative intent. Molecular-target-based agents, such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), are recommended for advanced cancers. In addition to cancer cells, the tumor microenvironment (TME) includes non-malignant cell types embedded in an altered extracellular matrix (ECM). The evidence confirms that interactions among cancer cells and TME elements exist and are thought to play crucial roles in the development of cancer, making them promising therapeutic targets. In the TME, an unfavorable pH, waste product accumulation, and competition for nutrients between cancer and immune cells may be regarded as further possible mechanisms of immune escape. To enhance immunotherapies and reduce resistance, it is crucial first to understand how the immune cells work and interact with cancer and other cancer-associated cells in such a complex tumor microenvironment.

Neuroblastoma (NB) is a pediatric malignancy that accounts for 15% of cancer-related childhood mortality. High-risk NB requires an aggressive chemoradiotherapy regimen that causes significant off-target toxicity. Despite this invasive treatment, many patients either relapse or do not respond adequately. Recent studies suggest that improving tumor perfusion can enhance drug accumulation and distribution within the tumor tissue, potentially augmenting treatment effects without inflicting systemic toxicity. Accordingly, methods that transiently increase tumor perfusion prior to treatment may help combat this disease. Here, we show the use of gene therapy to confer inducible nitric oxide synthase (iNOS) expression solely in the tumor space, using focused ultrasound targeting. NOS catalyzes the reaction that generates nitric oxide (NO), a potent endogenous vasodilator. This study reports the development of a targeted non-viral image-guided platform to deliver iNOS-expressing plasmid DNA (pDNA) to vascular endothelial cells encasing tumor blood vessels. Following transfection, longitudinal quantitative contrast-enhanced ultrasound (qCEUS) imaging revealed an increase in tumor perfusion over 72 h, attributed to elevated intratumoral iNOS expression. Methods: To construct a gene delivery vector, cationic ultrasound-responsive agents (known as "microbubbles") were employed to carry pDNA in circulation and transfect tumor vascular endothelial cells in vivo using focused ultrasound (FUS) energy. This was followed by liposomal doxorubicin (L-DOX) treatment. The post-transfection tumor response was monitored longitudinally using qCEUS imaging to determine relative changes in blood volumes and perfusion rates. After therapy, ex vivo analysis of tumors was performed to examine the bioeffects associated with iNOS expression. Results: By combining FUS therapy with cationic ultrasound contrast agents (UCAs), we achieved selective intratumoral transfection of pDNA encoding the iNOS enzyme. While transitory, the degree of expression was sufficient to induce significant increases in tumoral perfusion, to appreciably enhance the chemotherapeutic payload and to extend survival time in an orthotopic xenograft model. Conclusion: We have demonstrated the ability of a novel targeted non-viral gene therapy strategy to enhance tumor perfusion and improve L-DOX delivery to NB xenografts. While our results demonstrate that transiently increasing tumor perfusion improves liposome-encapsulated chemotherapeutic uptake and distribution, we expect that our iNOS gene delivery paradigm can also significantly improve radio and immunotherapies by increasing the delivery of radiosensitizers and immunomodulators, potentially improving upon current NB treatment without concomitant adverse effects. Our findings further suggest that qCEUS imaging can effectively monitor changes in tumor perfusion in vivo, allowing the identification of an ideal time-point to administer therapy.

The central dogma that nanoparticle delivery to tumours requires enhanced leakiness of vasculatures is a topic of debate. To address this, we propose a single-vessel quantitative analysis method by taking advantage of protein-based nanoprobes and image-segmentation-based machine learning (nano-ISML). Using nano-ISML, >67,000 individual blood vessels from 32 tumour models were quantified, revealing highly heterogenous vascular permeability of protein-based nanoparticles. There was a >13-fold difference in the percentage of high-permeability vessels in different tumours and >100-fold penetration ability in vessels with the highest permeability compared with vessels with the lowest permeability. Our data suggest passive extravasation and transendothelial transport were the dominant mechanisms for high- and low-permeability tumour vessels, respectively. To exemplify the nano-ISML-assisted rational design of nanomedicines, genetically tailored protein nanoparticles with improved transendothelial transport in low-permeability tumours were developed. Our study delineates the heterogeneity of tumour vascular permeability and defines a direction for the rational design of next-generation anticancer nanomedicines.

Ultrapure silicon nanoparticles (SiNPs) produced by femtosecond laser ablation in water have attracted great interest in the area of cancer therapy as they are efficient as photosensitizers in photodynamic therapy modality and can induce cell hyperthermia under radiofrequency radiation. Recently, we showed that these biocompatible nanoparticles were not able to reach tumors after intravenous injection in mice due to their rapid clearance from the bloodstream. In order to increase their half-life time and therefore their chances to reach and accumulate in tumors by an enhanced permeation retention (EPR) effect, a capping agent on SiNP surface acting as a colloidal stabilizer suspension is required. In this regard, this work focuses for the first time on the functionalization of SiNPs through the modification of their surface by chitosan (SiNPs-CH) in order to enhance their therapeutic properties in cancer therapy. Here, in vivo experiments were carried out during 15 days on nude mice developing a subcutaneously grafted malignant human brain tumor (glioblastoma). The characterization of SiNPs-CH showed an average hydrodynamic size of around 142 ± 65 nm as well as a relatively neutral charge (-5.2 mV) leading to a high colloidal suspension stability. The point of our work concerns the improvement of the biodistribution of SiNPs-CH with regard to tumors, the bloodstream, and organs. After the intravenous administration of 20 mg kg^-1, all the studied parameters (animal behavior, organs' morphology, and histopathology) were in accord with the absence of toxicity due to SiNPs-CH, confirming their biocompatibility and even size and surface charge were modified compared to bare nanoparticles. Moreover an increased time in the bloodstream circulation of up to 7 days was observed, indicating the stealth of the nanoparticles, which could escape opsonization and premature elimination by macrophages and the reticuloendothelial system. As evidenced by silicon assessment, the interaction of the SiNPs-CH with the liver and spleen was significantly reduced compared to the bare nanoparticles. At the same time, SiNPs-CH were concentrated progressively in tumors from 12.03% after 1 day up to 39.55% after 7 days, confirming their uptake by the tumor microenvironment through the enhanced permeability retention effect. Subsequently, the silicon level declined progressively down to 33.6% after 15 days, evidencing the degradation of pH-sensitive SiNPs-CH under the acidic tumor microenvironment. Taken together, the stealthy SiNPs-CH exhibited an ideal biodistribution profile within the tumor microenvironment with a sustainable biodegradation and elimination profile, indicating their promising application in the nano-oncology field as a tumor-targeting system.

Angiogenesis is crucial for tumor growth and is one of the hallmarks of cancer. In this study, we analyzed microvessel density, vessel median size, and perivascular a-SMA expression as prognostic biomarkers in breast cancer.

Dual IHC staining was performed where alpha-SMA antibodies were used together with antibodies against the endothelial cell marker CD34. Digital images of stainings were analyzed to extract quantitative data on vessel density, vessel size, and perivascular alpha-SMA status.

The analyses in the discovery cohort (n = 108) revealed a statistically significant relationship between large vessel size and shorter disease-specific survival (p = 0.007, log-rank test; p = 0.01, HR 3.1; 95% CI 1.3-7.4, Cox-regression analyses). Subset analyses indicated that the survival association of vessel size was strengthened in ER + breast cancer. To consolidate these findings, additional analyses were performed on a validation cohort (n = 267) where an association between large vessel size and reduced survival was also detected in ER + breast cancer (p = 0.016, log-rank test; p = 0.02; HR 2.3, 95% CI 1.1-4.7, Cox-regression analyses).

Alpha-SMA/CD34 dual-IHC staining revealed breast cancer heterogeneity regarding vessel size, vessel density, and perivascular a-SMA status. Large vessel size was linked to shorter survival in ER + breast cancer.

Response assessment of targeted cancer therapies is becoming increasingly challenging, as it is not adequately assessable with conventional morphological and volumetric analyses of tumor lesions. The tumor microenvironment is particularly constituted by tumor vasculature which is altered by various targeted therapies. The aim of this study was to noninvasively assess changes in tumor perfusion and vessel permeability after targeted therapy in murine models of breast cancer with divergent degrees of malignancy.

Low malignant 67NR or highly malignant 4T1 tumor-bearing mice were treated with either the multi-kinase inhibitor sorafenib or immune checkpoint inhibitors (ICI, combination of anti-PD1 and anti-CTLA4). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with i.v. injection of albumin-binding gadofosveset was conducted on a 9.4 T small animal MRI. Ex vivo validation of MRI results was achieved by transmission electron microscopy, immunohistochemistry and laser ablation-inductively coupled plasma-mass spectrometry.

Therapy-induced changes in tumor vasculature differed between low and highly malignant tumors. Sorafenib treatment led to decreased tumor perfusion and endothelial permeability in low malignant 67NR tumors. In contrast, highly malignant 4T1 tumors demonstrated characteristics of a transient window of vascular normalization with an increase in tumor perfusion and permeability early after therapy initiation, followed by decreased perfusion and permeability parameters. In the low malignant 67NR model, ICI treatment also mediated vessel-stabilizing effects with decreased tumor perfusion and permeability, while ICI-treated 4T1 tumors exhibited increasing tumor perfusion with excessive vascular leakage.

DCE-MRI enables noninvasive assessment of early changes in tumor vasculature after targeted therapies, revealing different response patterns between tumors with divergent degrees of malignancy. DCE-derived tumor perfusion and permeability parameters may serve as vascular biomarkers that allow for repetitive examination of response to antiangiogenic treatment or immunotherapy.

Cancer is a public health problem, and it needs blood vessels to grow. Knowing more about the processes of vascular adaptation to cancer improves our chances of attacking it, since the tumor for its extension needs such adaptation to satisfy its progressive demand for nutrients. The main objective of this review is to present the reader with some fundamental molecular pathways for vascular adaptation to cancer, highlighting within them the regulatory role of homologous tensin and phosphatase protein (PTEN). Hence the review describes vascular adaptation to cancer through somewhat known processes, such as angiogenesis, but emphasizes others that are much less explored, namely the changes in vascular reactivity and remodeling of the vascular wall -intima-media thickness and adjustments in the extracellular matrix- The role of PTEN in physiological and pathological vascular mechanisms in different types of cancer is deepened, as a crucial mediator in vascular adaptation to cancer, and points pending further exploration in cancer vascularization are suggested.

To explore the diagnostic value and feasibility of shear wave elastography and superb microvascular imaging in the grading diagnosis of glioma intraoperatively.

Forty-nine patients with glioma were included in this study. B-mode ultrasonography, Young's modulus in shear-wave elastography (SWE) and vascular architecture in superb microvascular imaging(SMI) of tumor tissue and peritumoral tissue were analyzed. Receiver operating characteristic(ROC) curve analysis was used to evaluate the diagnostic effect of SWE. Logistic regression model was used to calculate the prediction probability of HGG diagnosis.

Compared with LGG, HGG was often characterized by peritumoral edema in B mode (P < 0.05). There was a significant difference in Young's modulus between HGG and LGG; the diagnostic threshold of HGG and LGG was 13.05 kPa, the sensitivity was 78.3%, and the specificity was 76.9%. The vascular architectures of the tumor tissue and peritumoral tissues of HGG and LGG were significantly different (P < 0.05). The vascular architectures of peritumoral tissue in HGG often characterized by distorted blood flow signals surrounding the tumor (14/26,53.8%); in the tumor tissue, HGG often presents as dilated and bent vessels(19/26,73.1%). The elasticity value of SWE and the tumor vascular architectures of SMI were correlated with the diagnosis of HGG.

Intraoperative ultrasound (ioUS), especially SWE, and SMI are beneficial for the differentiation of HGG and LGG and may help optimize clinical surgical procedures.

Breast cancer ranks second among the causes of cancer-related deaths in women. In spite of the recent advances achieved in the diagnosis and treatment of breast cancer, further study is required to overcome the risk of cancer resistance to treatment and thereby improve the prognosis of individuals with advanced-stage breast cancer. The existence of a hypoxic microenvironment is a well-known event in the development of mutagenesis and rapid proliferation of cancer cells. Tumor cells, purposefully cause local hypoxia in order to induce angiogenesis and growth factors that promote tumor growth and metastatic characteristics, while healthy tissue surrounding the tumor suffers damage or mutate. It has been found that these settings with low oxygen levels cause immunosuppression and a lack of immune surveillance by reducing the activation and recruitment of tumor infiltrating leukocytes (TILs). The immune system is further suppressed by hypoxic tumor endothelium through a variety of ways, which creates an immunosuppressive milieu in the tumor microenvironment. Non responsiveness of tumor endothelium to inflammatory signals or endothelial anergy exclude effector T cells from the tumor milieu. Expression of endothelial specific antigens and immunoinhibitory molecules like Programmed death ligand 1,2 (PDL-1, 2) and T cell immunoglobulin and mucin-domain containing-3 (TIM-3) by tumor endothelium adds fuel to the fire by inhibiting T lymphocytes while promoting regulatory T cells. The hypoxic microenvironment in turn recruits Myeloid Derived Suppressor Cells (MDSCs), Tumor Associated Macrophages (TAMs) and T regulatory cells (Treg). The structure and function of newly generated blood vessels within tumors, on the other hand, are aberrant, lacking the specific organization of normal tissue vasculature. Vascular normalisation may work for a variety of tumour types and show to be an advantageous complement to immunotherapy for improving tumour access. By enhancing immune response in the hypoxic tumor microenvironment, via immune-herbal therapeutic and immune-nutraceuticals based approaches that leverage immunological evasion of tumor, will be briefly reviewed in this article. Whether these tactics may be the game changer for emerging immunological switch point to attenuate the breast cancer growth and prevent metastatic cell division, is the key concern of the current study.

Previous studies have demonstrated that breast cancer cells deploy a myriad array of strategies to thwart the activity of anticancer drugs like docetaxel (DTX), including acquired drug resistance due to overexpression of drug-efflux pumps like P-glycoprotein (P-gp) and innate drug resistance by cancer stem cells (CSCs). As disulfiram (DSF) can inhibit both P-gp and CSCs, we hypothesized that co-treatment of DTX and DSF could sensitize the drug-resistant breast cancer cells. To deliver a fixed dose ratio of DTX and DSF targeted to the tumor, a tumor extracellular pH-responsive nanoparticle (NP) was developed using a histidine-conjugated star-shaped PLGA with TPGS surface decoration ([DD]NpH-T). By releasing the encapsulated drugs in the tumor microenvironment, pH-sensitive NPs can overcome the tumor stroma-based resistance against nanomedicines. In in-vitro studies, [DD]NpH-T exhibited increased drug release at pH 6.8, improved penetration in a 3D tumor spheroid, reduced serum protein adsorption, and enhanced cytotoxic efficacy against both innate and acquired DTX-resistant breast cancer cells. In in-vivo studies, a significant increase in plasma AUC and tumor drug delivery was observed with [DD]NpH-T, which resulted in an enhanced in-vivo anti-tumor efficacy against a mouse orthotopic breast cancer, with a significantly increased intratumoral ROS and apoptosis, while decreasing P-gp expression and prevention of lung metastasis. Altogether, the current study demonstrated that the DTX and DSF combination could effectively target multiple drug-resistance pathways in-vitro, and the in-vivo delivery of this drug combination using TPGS-decorated pH-sensitive NPs could increase tumor accumulation, resulting in improved anti-tumor efficacy.

The concept of the Myc (c-myc, n-myc, l-myc) oncogene as a canonical, DNA-bound transcription factor has consistently changed over the past few years. Indeed, Myc controls gene expression programs at multiple levels: directly binding chromatin and recruiting transcriptional coregulators; modulating the activity of RNA polymerases (RNAPs); and drawing chromatin topology. Therefore, it is evident that Myc deregulation in cancer is a dramatic event. Glioblastoma multiforme (GBM) is the most lethal, still incurable, brain cancer in adults, and it is characterized in most cases by Myc deregulation. Metabolic rewiring typically occurs in cancer cells, and GBM undergoes profound metabolic changes to supply increased energy demand. In nontransformed cells, Myc tightly controls metabolic pathways to maintain cellular homeostasis. Consistently, in Myc-overexpressing cancer cells, including GBM cells, these highly controlled metabolic routes are affected by enhanced Myc activity and show substantial alterations. On the other hand, deregulated cancer metabolism impacts Myc expression and function, placing Myc at the intersection between metabolic pathway activation and gene expression. In this review paper, we summarize the available information on GBM metabolism with a specific focus on the control of the Myc oncogene that, in turn, rules the activation of metabolic signals, ensuring GBM growth.

Having a hypoxic microenvironment is a common and salient feature of most solid tumors. Hypoxia has a profound effect on the biological behavior and malignant phenotype of cancer cells, mediates the effects of cancer chemotherapy, radiotherapy, and immunotherapy through complex mechanisms, and is closely associated with poor prognosis in various cancer patients. Accumulating studies have demonstrated that through normalization of the tumor vasculature, nanoparticle carriers and biocarriers can effectively increase the oxygen concentration in the tumor microenvironment, improve drug delivery and the efficacy of radiotherapy. They also increase infiltration of innate and adaptive anti-tumor immune cells to enhance the efficacy of immunotherapy. Furthermore, drugs targeting key genes associated with hypoxia, including hypoxia tracers, hypoxia-activated prodrugs, and drugs targeting hypoxia-inducible factors and downstream targets, can be used for visualization and quantitative analysis of tumor hypoxia and antitumor activity. However, the relationship between hypoxia and cancer is an area of research that requires further exploration. Here, we investigated the potential factors in the development of hypoxia in cancer, changes in signaling pathways that occur in cancer cells to adapt to hypoxic environments, the mechanisms of hypoxia-induced cancer immune tolerance, chemotherapeutic tolerance, and enhanced radiation tolerance, as well as the insights and applications of hypoxia in cancer therapy.

Selected patients with colorectal cancer peritoneal metastases (CRPM) could be offered a curative-intent strategy based on complete cytoreductive surgery (CRS), potentially combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and perioperative systemic chemotherapy. The impact of different neoadjuvant systemic chemotherapy (NACT) regimens remains unclear due to a lack of comparative data.

Consecutive CRPM patients from a monocentric database who were treated with complete CRS after single-line NACT were included in this study. Chemotherapy regimens were tailored as a doublet drug (FOLFOX/FOLFIRI) with/without targeted therapy (anti-epidermal growth factor receptor/bevacizumab) and triplet-drug combination (FOLFIRINOX). Morphological response (MR) was assessed using the Response Evaluation Criteria in Solid Tumors criteria, and pathological response (PR) was assessed using the Peritoneal Regression Grading Score (PRGS). Long-term oncologic outcomes were compared.

The cohort comprised 388 patients, including 127, 202, and 59 patients in the doublet, doublet + targeted, and triplet groups, respectively. MR rates were higher in the triplet (68.0%) and doublet + targeted groups (64.2%) when compared with the doublet group (42.4%, p = 0.003). Complete and major PRs were observed in 13.6% and 32.0% of patients, respectively. Higher MR rates were observed after doublet + targeted or triplet regimens, while no difference was observed for PR rates. In multivariate analysis, FOLFIRINOX was independently associated with better overall survival (hazard ratio 0.49, 95% confidence interval 0.25-0.96; p = 0.037). FOLFIRINOX also resulted in a higher rate of severe postoperative complications.

In this retrospective study, a FOLFIRINOX regimen as NACT seemed to result in better long-term outcomes for CRPM patients after complete CRS/HIPEC, although with higher morbidity. Prospective studies are needed, including groups without NACT and those with FOLFIRINOX + bevacizumab.

Sarcomas comprise a vast and heterogenous group of rare tumors. Because of their diversity, it is challenging to study sarcomas as a whole with regard to their biological and molecular characteristics. This diverse set of tumors may also possess differences related to their tumor-associated vasculature, which in turn may impact the ability to deliver systemic therapies (e.g., chemotherapy, targeted therapies, and immunotherapy). Consequently, response to systemic treatment may also be variable as these depend on the ability of the therapy to reach the tumor target via the tumor-associated vasculature. There is a paucity of data regarding sarcoma-related tumor vessels, likely in part to the rarity and heterogeneity of this cancer as well as the previously limited ability to image tumor-associated vessels in real time. Our group has previously utilized confocal fluorescent imaging technology to observe and characterize tumor-associated vessels in real time during surgical resection of tumors, including cutaneous melanoma and carcinomatosis implants derived from gastrointestinal, gynecological, or primary peritoneal (e.g., mesothelioma) tumors. Our prior studies have demonstrated the feasibility of real-time, human intravital microscopy in the study of these tumor types, leading to early but important new data regarding tumor vessel characteristics and their potential implications on drug delivery and efficacy. In this brief report, we present our latest descriptive findings in a cohort of patients with sarcoma who underwent surgical resection and real-time, intravital microscopy of their tumors. Overall, intravital imaging was feasible during the surgical resection of large sarcomas.

ClinicalTrials.gov, identifier NCT03517852; ClinicalTrials.gov, identifier NCT03823144.

Breast cancer is the most frequent cancer in women worldwide. However, its diagnosis mostly depends on visual examination of radiologic images, leading to an overdiagnosis with substantial costs. Therefore, a quantitative approach such as dynamic contrast enhanced (DCE)-magnetic resonance imaging (MRI) through pharmacokinetic (PK) modeling is required for reliable analysis. As PK parameters lack information on parameter heterogeneity, texture-based analysis is required to quantify PK parameter heterogeneity. Therefore, this study focused on determining the usefulness of fractal dimension (FD) as a potential imaging biomarker of tumor heterogeneity for discriminating benign and malignant breast lesions.

Parametric maps for PK parameters, extravasation rate of contrast agent from blood plasma to extravascular extracellular space (K^trans) and volume fraction of extravascular extracellular space (v_e), were generated for the regions of interest (ROIs) under the standard model using 18 lesions. Then, tumor ROI and pixel DCE-MRI time-course data were analyzed to extract pixel values of K^trans and v_e. For each ROI, FD values of K^trans and v_e were computed using the blanket method.

The FD values of K^trans for benign and malignant lesions varied from 2.96 to 3.49 and from 2.37 to 3.16, respectively, whereas FD values of v_e for benign and malignant lesions varied from 3.01 to 5.15 and 2.42 to 3.44, respectively. There were significant differences in FD values derived from K^trans parametric maps (P = .0053) and v_e parametric maps (P = .0271) between benign and malignant lesions according to the statistical analysis.

Incorporating texture heterogeneity changes in breast lesions captured by FD with quantitative DCE-MRI parameters generated under the standard model is a potential marker for prediction of malignant lesions.