Laparoscopic nerve lysis for deep endometriosis improves quality of life and chronic pain levels: A pilot study.

OBJECTIVES: To assess the benefit of surgical management of patients with endometriosis infiltrating pelvic nerves in terms of pain, analgesic consumption, and quality of life (QOL). METHODS: We conducted a retrospective cohort study In an Endometriosis referral center at a tertiary care university affiliated medical center. Patients diagnosed with endometriosis that underwent laparoscopic neurolysis for chronic pain were included. Patients rated their pain before and after surgery and differentiated between chronic pain and acute crises. Patients were requested to maintain a record of analgesic consumption and to evaluate their quality-of-life (QOL). RESULTS: Of the 21 patients in our study 15 (71.5 %) had obturator nerve involvement, 2 (9.5 %) had pudendal nerve involvement and 4 (19 %) had other pelvic nerve involvement. Median postoperative follow - up was of 8 months. All but 2 patients (9.6 %) had significant chronic pain improvement with a mean decrease of VAS of 3.05 (±2.5). Analgesic habits changed postoperatively with a significant decrease of 66 % of patients' daily consumption of any analgesics. Surgery improved QOL in 12 cases (57.1 %) and two patients (9.6 %) completely recovered with a high QOL. CONCLUSION: Neurolysis and excision of endometriosis of pelvic nerves could results in significant improvement of quality of life.

Measurement properties of sexual function assessment questionnaires in women with endometriosis: A systematic review following COSMIN guidelines.

INTRODUCTION: Sexual function of patients with endometriosis should be assessed by patient-reported outcome measures (PROMs) that present high reliability and validity. The objective was to study the PROMs used to assess sexual function for patients with endometriosis to improve their selection for research and clinical practice. MATERIAL AND METHODS: We performed a systematic literature review from January 2000 to September 2023. All studies including women with confirmed endometriosis and assessing sexual quality of life or sexual function or sexual distress were retrieved. Different properties of PROMs used for sexual dysfunction were assessed according to the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) recommendations. Properties evaluated were: structural validity, internal consistency, cross-cultural validity, reliability, measurement error, criterion validity, construct validity, and responsiveness. This literature review was registered on Prospero as 2018 CRD42018102278. RESULTS: Seventy-four articles with evaluation of sexual function were included. Of the 25 PROMs assessing sexual function, the Female Sexual Function Index (FSFI) was the most frequently used (34/74 [45.9%] items), followed by the Female Sexual Distress Scale (9/74 [12.2%] items) and the Sexual Activity Questionnaire (SAQ) (8/74 [10.8%] items). The most commonly used measurement properties were "hypothesis testing" and "responsiveness". The PROMs with a high level of evidence for these two measurement properties were the FSFI, the SAQ, the Short Sexual Functioning Scale, the Sexual Satisfaction Scale for Women, Sexual Quality of Life-Female, the Brief Profile of Female Sexual Function, and the Sexual Health Outcomes in Women Questionnaire. The FSFI questionnaire appeared to be more relevant for evaluating medical treatment, and the SAQ for evaluating surgical treatment. Only one instrument was specific to endometriosis (the Subjective Impact of Dyspareunia Inventory [SIDI]). CONCLUSIONS: In this systematic literature review of sexual function assessment questionnaires in endometriosis, the FSFI and the SAQ questionnaires emerged as having the best measurement properties according to the COSMIN criteria. The FSFI questionnaire appears to be suited for evaluating medical treatment, and the SAQ for surgical treatment. The SIDI is the only specific questionnaire, but its responsiveness remains to be defined.

Developing a set of patient-centered outcomes for routine use in endometriosis: An international Delphi study.

INTRODUCTION: There is large variation in individual patient care for endometriosis. A uniform approach to measure outcomes could be incorporated into routine clinical practice to personalize and monitor treatments and potentially improve the quality of care. The aim of this study is to identify a group of patient-centered outcomes for use in routine endometriosis care which are relevant to all patient profiles. MATERIAL AND METHODS: By means of a modified two-round Delphi study with international representation including healthcare professionals, researchers and patient representatives (51 participants, 16 countries) we developed a set of patient-centered measurements. The participants evaluated 47 Patient Reported Outcome Measures (PROMs) and 30 Clinician Reported Outcome Measures (CROMs) regarding their feasibility and relevance for their use in routine endometriosis care. After the two rounds of quotation, meetings of the experts were convened to participate in a final discussion to finalize the consensus of the final set of included measures. RESULTS: The final set of patient-centered outcomes includes six PROMs (measuring symptomatic impact, pain, work productivity and quality of life) and 10 CROMs (measuring clinical, imaging and surgical indicators). A supplementary list of outcomes was added to include important dimensions that were considered essential by the expert panel but are not relevant to all patients. In addition the need for development of specific tools (PROMs) measuring the psychological impact and the impact in sexual activity of endometriosis was highlighted. CONCLUSIONS: We have developed a set of patient-centered outcomes measures in endometriosis care. The selected outcomes comprise the common features for all patients suffering from endometriosis. adapted for use in routine practice. The list of outcomes has been adapted for use in routine practice from which clinicians can chose, depending on their needs.

Validation of the French version of the ICHOM adult oral health standard set.

INTRODUCTION: The ICHOM Adult Oral Health Standard Set (AOHSS) recently developed by the ICHOM Oral Adult Health Working Group is a standard set of outcomes designed for its collection in clinical practice in dental health. The outcome standard set is made up of clinical-reported outcome measures (CROMs) and patient-reported outcome measures (PROMs). The purpose of this study was to translate and cross-culturally adapt the PROM section of the Standard Set in French for France to enable comprehensive evaluation of the patients' oral health quality of life in a French population. METHODS: The questionnaire was translated following the guidelines of the International Society for Pharmacoeconomics and Outcome Research (ISPOR). We included patients consulting in a dentistry clinic (n = 127) and seeking dental care. The PROM and CROM data were collected from all patients. Both reliability and the internal consistency were evaluated. RESULTS: The ICHOM AOHSS was successfully translated into French. We sampled and surveyed 126 patients in a dentistry clinic in France using the French translation of the ICHOM AOHSS. Cronbach's α was calculated to measure the internal consistency. The resulting Cronbach's α was 0.8, indicating acceptable homogeneity. CONCLUSIONS: The French version of the ICHOM AOHSS shows acceptable psychometric properties in terms of reliability and internal consistency. This translation is suitable for its implementation in a French-speaking patient population.

Outcome of subsequent pregnancies post uterine rupture in previous delivery: A case series, a review, and recommendations for appropriate management.

OBJECTIVES: To provide clinicians with concrete solutions on the best management of and counseling for patients in a subsequent pregnancy following uterine rupture. METHODS: A retrospective analysis of patients treated between 2005 and 2020 at Sheba Medical Center was conducted. All patients who had undergone a complete uterine rupture and subsequently had a full-term pregnancy were included. A literature review was conducted using Pubmed database and including previously published literature reviews. RESULTS: Fifteen patients with subsequent pregnancies following uterine rupture were included in our cohort. Mean interval between rupture and subsequent pregnancy was 3.8 years (range 2.2-6.9 years). One patient had repeat uterine rupture of less than 2 cm at 36+5 weeksof pregnancy. A total of 17 studies were selected in this literature review, including a total of 774 pregnancies in 635 patients. The risk of repeated uterine rupture was 8.0% (62/774), ranging from 0% to 37.5%. Overall, the risk of maternal death was of 0.6% (4/635), with only four cases reported in three studies. CONCLUSION: The risk of recurrence after uterine rupture is significant but should not prevent patients from conceiving.

Correction: Ponzo et al. Nucleolin Therapeutic Targeting Decreases Pancreatic Cancer Immunosuppression. Cancers 2022, 14, 4265.

In the original publication [...].

Synergic Thermo- and pH-Sensitive Hybrid Microgels Loaded with Fluorescent Dyes and Ultrasmall Gold Nanoparticles for Photoacoustic Imaging and Photothermal Therapy.

Smart microgels (µGels) made of polymeric particles doped with inorganic nanoparticles have emerged recently as promising multifunctional materials for nanomedicine applications. However, the synthesis of these hybrid materials is still a challenging task with the necessity to control several features, such as particle sizes and doping levels, in order to tailor their final properties in relation to the targeted application. We report herein an innovative modular strategy to achieve the rational design of well-defined and densely filled hybrid particles. It is based on the assembly of the different building blocks, i.e., µGels, dyes, and small gold nanoparticles (<4 nm), and the tuning of nanoparticle loading within the polymer matrix through successive incubation steps. The characterization of the final hybrid networks using UV-vis absorption, fluorescence, transmission electron microscopy, dynamic light scattering, and small-angle X-ray scattering revealed that they uniquely combine the properties of hydrogel particles, including high loading capacity and stimuli-responsive behavior, the photoluminescent properties of dyes (rhodamine 6G, methylene blue and cyanine 7.5), and the features of gold nanoparticle assembly. Interestingly, in response to pH and temperature stimuli, the smart hybrid µGels can shrink, leading to the aggregation of the gold nanoparticles trapped inside the polymer matrix. This stimuli-responsive behavior results in plasmon band broadening and red shift toward the near-infrared region (NIR), opening promising prospects in biomedical science. Particularly, the potential of these smart hybrid nanoplatforms for photoactivated hyperthermia, photoacoustic imaging, cellular internalization, intracellular imaging, and photothermal therapy was assessed, demonstrating well controlled multimodal opportunities for theranostics.

Cationic Polyethyleneimine (PEI)-Gold Nanocomposites Modulate Macrophage Activation and Reprogram Mouse Breast Triple-Negative MET-1 Tumor Immunological Microenvironment.

Nanomedicines based on inorganic nanoparticles have grown in the last decades due to the nanosystems' versatility in the coating, tuneability, and physical and chemical properties. Nonetheless, concerns have been raised regarding the immunotropic profile of nanoparticles and how metallic nanoparticles affect the immune system. Cationic polymer nanoparticles are widely used for cell transfection and proved to exert an adjuvant immunomodulatory effect that improves the efficiency of conventional vaccines against infection or cancer. Likewise, gold nanoparticles (AuNPs) also exhibit diverse effects on immune response depending on size or coatings. Photothermal or photodynamic therapy, radiosensitization, and drug or gene delivery systems take advantage of the unique properties of AuNPs to deeply modify the tumoral ecosystem. However, the collective effects that AuNPs combined with cationic polymers might exert on their own in the tumor immunological microenvironment remain elusive. The purpose of this study was to analyze the triple-negative breast tumor immunological microenvironment upon intratumoral injection of polyethyleneimine (PEI)-AuNP nanocomposites (named AuPEI) and elucidate how it might affect future immunotherapeutic approaches based on this nanosystem. AuPEI nanocomposites were synthesized through a one-pot synthesis method with PEI as both a reducing and capping agent, resulting in fractal assemblies of about 10 nm AuNPs. AuPEI induced an inflammatory profile in vitro in the mouse macrophage-like cells RAW264.7 as determined by the secretion of TNF-α and CCL5 while the immunosuppressor IL-10 was not increased. However, in vivo in the mouse breast MET-1 tumor model, AuPEI nanocomposites shifted the immunological tumor microenvironment toward an M2 phenotype with an immunosuppressive profile as determined by the infiltration of PD-1-positive lymphocytes. This dichotomy in AuPEI nanocomposites in vitro and in vivo might be attributed to the highly complex tumor microenvironment and highlights the importance of testing the immunogenicity of nanomaterials in vitro and more importantly in vivo in relevant immunocompetent mouse tumor models to better elucidate any adverse or unexpected effect.

Nucleolin Therapeutic Targeting Decreases Pancreatic Cancer Immunosuppression.

Background: The pancreatic ductal adenocarcinoma (PDAC) microenvironment is highly fibrotic and hypoxic, with poor immune cell infiltration. Recently, we showed that nucleolin (NCL) inhibition normalizes tumour vessels and impairs PDAC growth. Methods: Immunocompetent mouse models of PDAC were treated by the pseudopeptide N6L, which selectively inhibits NCL. Tumour-infiltrating immune cells and changes in the tumour microenvironment were analysed. Results: N6L reduced the proportion of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and increased tumour-infiltrated T lymphocytes (TILs) with an activated phenotype. Low-dose anti-VEGFR2 treatment normalized PDAC vessels but did not modulate the immune suppressive microenvironment. RNAseq analysis of N6L-treated PDAC tumours revealed a reduction of cancer-associated fibroblast (CAF) expansion in vivo and in vitro. Notably, N6L treatment decreased IL-6 levels both in tumour tissues and in serum. Treating mPDAC by an antibody blocking IL-6 reduced the proportion of Tregs and MDSCs and increased the amount of TILs, thus mimicking the effects of N6L. Conclusions: These results demonstrate that NCL inhibition blocks the amplification of lymphoid and myeloid immunosuppressive cells and promotes T cell activation in PDAC through a new mechanism of action dependent on the direct inhibition of the tumoral stroma.

Patient-Reported Outcome Measures in Endometriosis.

Patient Reported Outcome Measures (PROM) evoke measurements that allow capturing patients' perspectives on their condition. In endometriosis care, physicians' understanding of the effect of the disease and the treatment on patients is often poor. The use of PROMs in endometriosis clinical practice can facilitate patient-provider communication and the implementation of patient-centered care, improve patients' quality of life, as well as provide a tool for patients' self-management of the disease. Today, PROMs are extensively used in research and clinical trials, however they are barely used in clinical practice. The development of digital tools facilitating capturing PROMs can contribute to their use by physicians in routine endometriosis care. However, all PROMs are not adapted to be used in routine care in the context of endometriosis. The objective of this study was to present a catalogue of available PROMs for routine endometriosis care and evaluate them according to selected criteria. To do so, we explored the different PROMs currently in the literature. Consequently, 48 PROM were identified as tools used to evaluate various dimensions of the impact of endometriosis on patients. The selected PROMs were evaluated for their potential to be used as a standard in clinical practice in endometriosis. The selected catalogue of PROMs is the starting point for the integration of digital tools to capture PROMs and the development of patient-centered dashboards to be used by patients and clinicians in endometriosis care and self-management to improve care processes, patient satisfaction, quality of life, and outcomes.

Two step promotion of a hot tumor immune environment by gold decorated iron oxide nanoflowers and light-triggered mild hyperthermia.

Nanoparticle-mediated photothermal therapy (PTT) is an emerging modality to treat tumors with both spatial and temporal control provided by light activation. Gold decorated iron oxide nanoflowers (GIONF) are good candidates for PTT due to their biocompatibility, biodegradability and light-to-heat conversion. Profound changes in the tumor immune environment might be early induced by the gold and iron oxide metallic agents in addition to the photothermal effects. This study aims to elucidate the outcome of GIONF on their own, and of GIONF-induced mild hyperthermia in the tumor immune infiltrate in a murine model of triple negative breast cancer. First we explored the effects of 24 h GIONF exposure on bone-marrow derived macrophages (BMDM), revealing significant effects on the BMDM phenotype and secretion, 6 days post-incubation, with important downregulation of several cytokines and MHCII expression, predominantly towards a pro-inflammatory response. Intratumoral administration of GIONF promoted an increase in monocyte recruitment at day 1 post-administration, shifting towards a pro-inflammatory anti-tumor microenvironment with lower Treg population and a 4 fold lower CD4/CD8 ratio compared to the control at day 12. On top of the GIONF effects, mild hyperthermia (43 °C for 15 min), although it does not induce significant changes in tumor growth, resulted in an additional increase of CD8+ T lymphocytes and pro-inflammatory cytokines. The combination of a timely controlled immune response to GIONF and to mild hyperthermia could be used as a remotely triggered adjuvant treatment to immunotherapy approaches at the best favorable time-window.

Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment.

Only a fraction of cancer patients benefits from immune checkpoint inhibitors. This may be partly due to the dense extracellular matrix (ECM) that forms a barrier for T cells. Comparing five preclinical mouse tumor models with heterogeneous tumor microenvironments, we aimed to relate the rate of tumor stiffening with the remodeling of ECM architecture and to determine how these features affect intratumoral T cell migration. An ECM-targeted strategy, based on the inhibition of lysyl oxidase, was used. In vivo stiffness measurements were found to be strongly correlated with tumor growth and ECM crosslinking but negatively correlated with T cell migration. Interfering with collagen stabilization reduces ECM content and tumor stiffness leading to improved T cell migration and increased efficacy of anti-PD-1 blockade. This study highlights the rationale of mechanical characterizations in solid tumors to understand resistance to immunotherapy and of combining treatment strategies targeting the ECM with anti-PD-1 therapy.

Tumor-Selective Immune-Active Mild Hyperthermia Associated with Chemotherapy in Colon Peritoneal Metastasis by Photoactivation of Fluorouracil-Gold Nanoparticle Complexes.

Peritoneal metastasis (PM) is considered as the terminal stage of metastatic colon cancer, with still poor median survival rate even with the best recent chemotherapy treatment. The current PM treatment combines cytoreductive surgery, which consists of resecting all macroscopic tumors, with hyperthermic intraperitoneal chemotherapy (HIPEC), which uses mild hyperthermia to boost the diffusion and cytotoxic effect of chemotherapeutic drugs. As HIPEC is performed via a closed circulation of a hot liquid containing chemotherapy, it induces uncontrolled heating and drug distribution in the whole peritoneal cavity with important off-site toxicity and a high level of morbidity. Here, we propose a safer precision strategy using near-infrared (NIR) photoactivated gold nanoparticles (AuNPs) coupled to the chemotherapeutic drug 5-fluorouracil (5-FU) to enable a spatial and temporal control of mild chemo-hyperthermia targeted to the tumor nodules within the peritoneal cavity. Both the 16 nm AuNPs and the corresponding complex with 5-FU (AuNP-5-FU) were shown as efficient NIR photothermal agents in the microenvironment of subcutaneous colon tumors as well as PM in syngeneic mice. Noteworthy, NIR photothermia provided additional antitumor effects to 5-FU treatment. A single intraperitoneal administration of AuNP-5-FU resulted in their preferential accumulation in tumor nodules and peritoneal macrophages, allowing light-induced selective hyperthermia, extended tumor necrosis, and activation of a pro-inflammatory immune response while leaving healthy tissues without any damage. From a translational standpoint, the combined and tumor-targeted photothermal and chemotherapy mediated by the AuNP-drug complex has the potential to overcome the current off-target toxicity of HIPEC in clinical practice.

Immune Reprogramming Precision Photodynamic Therapy of Peritoneal Metastasis by Scalable Stem-Cell-Derived Extracellular Vesicles.

The dissemination of tumor metastasis in the peritoneal cavity, also called peritoneal metastasis (PM) or carcinomatosis, represents a late stage of gastrointestinal and gynecological cancer with very poor prognosis, even when cytoreductive surgery is effective, due to residual microscopic disease. Photodynamic therapy (PDT) in the management of peritoneal metastasis has been clinically limited by the low tumor selectivity of photosensitizers (PS) and important adverse effects. Here, we propose extracellular nanovesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) as the fourth generation of immune active PS vectors that are able to target peritoneal metastasis with superior selectivity, potentiate PDT cytotoxicity at the tumor site without affecting healthy tissues, modulate the tumor microenvironment of immunocompetent colorectal and ovarian carcinomatosis models, and promote an antitumor immune response. A pioneering strategy was developed for high yield, large-scale production of MSC-EVs encapsulating the drug meta(tetrahydroxyphenyl)chlorin (mTHPC) (EVs-mTHPC) that is compatible with requirements of clinical translation and also preserves the topology and integrity of naturally produced EVs. Intraperitoneal injection of EVs-mTHPC showed an impressive enhancement of tumoral selectivity in comparison to the free drug and to the liposomal formulation Foslip (mean ratio of PS in tumors/organs of 40 for EVs-mTHPC versus 1.5 for the free PS and 5.5 for Foslip). PDT mediated by EVs-mTHPC permitted an important tumoral necrosis (55% of necrotic tumoral nodules versus 18% for Foslip (p < 0.0001)) and promoted antitumor immune cell infiltration, mainly proinflammatory M1-like CD80+ and CD8+ T cell effector. Intratumor proliferation was significantly decreased after PDT with EVs-mTHPC. Overall EVs vectorization of mTHPC afforded important tumoral selectivity while overcoming the PDT toxicity of the free drug and prolonged mice survival in the colorectal carcinomatosis model. MSC-EVs produced by our scalable manufacturing method appears like the clinically relevant fourth-generation PDT vehicle to overcome current limitations of PDT in the treatment of peritoneal metastasis and promote a hot tumor immune environment in PM.

Local administration of stem cell-derived extracellular vesicles in a thermoresponsive hydrogel promotes a pro-healing effect in a rat model of colo-cutaneous post-surgical fistula.

Extracellular vesicles (EVs), especially from stem/stromal cells (SCs), represent a cell-free alternative in regenerative medicine holding promises to promote tissue healing while providing safety and logistic advantages in comparison to cellular counterparts. Herein, we hypothesize that SC EVs, administered locally in a thermoresponsive gel, is a therapeutic strategy for managing post-surgical colo-cutaneous fistulas. This disease is a neglected and challenging condition associated to low remission rates and high refractoriness. Herein, EVs from a murine SC line were produced by a high-yield scalable method in bioreactors. The post-surgical intestinal fistula model was induced via a surgical cecostomy communicating the cecum and the skin in Wistar rats. Animals were treated just after cecostomy with PBS, thermoresponsive Pluronic F-127 hydrogel alone or containing SC EVs. A PET-monitored biodistribution investigation of SC EVs labelled with 89Zr was performed. Fistula external orifice and output assessment, probe-based confocal laser endomicroscopy, MRI and histology were carried out for therapy follow-up. The relevance of percutaneous EV administration embedded in the hydrogel vehicle was indicated by the PET-biodistribution study. Local administration of SC EVs in the hydrogel reduced colo-cutaneous fistula diameter, output, fibrosis and inflammation while increasing the density of neo-vessels when compared to the PBS and gel groups. This multi-modal investigation pointed-out the therapeutic potential of SC EVs administered locally and in a thermoresponsive hydrogel for the management of challenging post-surgical colon fistulas in a minimally-invasive cell-free strategy.

Endocytosis-driven gold nanoparticle fractal rearrangement in cells and its influence on photothermal conversion.

Cellular endocytosis and intracellular trafficking of nanoparticles induce dynamic rearrangements that profoundly modify the physical properties of nanoparticle and govern their biological outcomes when activated by external fields. The precise structure, organization, distribution, and density of gold nanoparticles (AuNPs) confined within intracellular compartments such as lysosomes have not been studied comprehensively, hampering the derivation of predictive models of their therapeutic activity within the cells of interest. By using transmission electron microscopy and small-angle X-ray scattering, we have determined that canonical spherical citrate-coated AuNPs in the 3-30 nm size range form fractal clusters in endolysosomes of macrophages, endothelial cells, and colon cancer cells. Statistical analysis revealed that the cluster size and endolysosome size are correlated but do not depend on the size of AuNPs unless larger preformed aggregates of AuNPs are internalized. Smaller AuNPs are confined in greater numbers in loose aggregates covering a higher fraction of the endolysosomes compared to the largest AuNPs. The fractal dimensions of intracellular clusters increased with the particle size, regardless of the cell type. We thus analyzed how these intracellular structure parameters of AuNPs affect their optical absorption and photothermal properties. We observed that a 2nd plasmon resonance band was shifted to the near-infrared region when the nanoparticle size and fractal dimensions of the intracellular cluster increased. This phenomenon of intracellular plasmon coupling is not directly correlated to the size of the intralysosomal cluster or the number of AuNPs per cluster but rather to the compacity of the cluster and the size of the individual AuNPs. The intracellular plasmon-coupling phenomenon translates to an efficient heating efficiency with the excitation of the three cell types at 808 nm, transforming the NIR-transparent canonical AuNPs with sizes below 30 nm into NIR-absorbing clusters in the tumor microenvironment. Harnessing the spontaneous clustering of spherical AuNPs by cells might be a more valuable strategy for theranostic purposes than deploying complex engineering to derive NIR-absorbent nanostructures out of their environment. Our paper sheds light on AuNP intracellular reorganization and proposes a general method to link their intracellular fates to their in situ physical properties exploited in medical applications.

Photothermal Depletion of Cancer-Associated Fibroblasts Normalizes Tumor Stiffness in Desmoplastic Cholangiocarcinoma.

Physical oncology recognizes tissue stiffness mediated by activation of cancer-associated fibroblasts (CAF) and extracellular matrix remodeling as an active modulator of tumorigenesis, treatment resistance, and clinical outcome. Cholangiocarcinoma (CCA) is a highly aggressive and chemoresistant desmoplastic cancer enriched in CAF. CCA's stroma mechanical properties are considered responsible for its chemoresistant character. To normalize tumor mechanics, we propose a physical strategy based on remotely light-activated nanohyperthermia to modulate the tumor microenvironment. In this study, we report the use of multifunctional iron oxide nanoflowers decorated with gold nanoparticles (GIONF) as efficient nanoheaters to achieve complete tumor regression following three sessions of mild hyperthermia. The preferential uptake of GIONF by CAF allowed targeting this cell population, which resulted in a significant early reduction of tumor stiffness followed by tumor regression. In conclusion, our study highlights a spatially and temporally controlled physical strategy, GIONF-mediated photothermal therapy to deplete CAF and normalize the tumor mechanics that may apply to desmoplastic cancer and CCA treatment.

Tailored ultra-small Prussian blue-based nanoparticles for MRI imaging and combined photothermal/photoacoustic theranostics.

Ultrasmall sub-10 nm nanoparticles of Prussian blue analogues incorporating GdIII ions at their periphery revealed longitudinal relaxivities above 40 mM-1 s-1 per GdIII regardless of the nature of the core and the polymer coating. Large T1-weighted contrast enhancements were achieved in addition to a highly efficient photothermal effect and in vivo photoacoustic imaging in tumors.

Obstacles to T cell migration in the tumor microenvironment.

These last years, significant progress has been made in the design of strategies empowering T cells with efficient anti-tumor activities. Hence, adoptive T cell therapy and the use of monoclonal antibodies against the immunosuppressive surface molecules CTLA-4 and PD-1 appear as the most promising immunotherapies against cancer. One of the challenges ahead is to render these therapeutic interventions even more effective as a still elevated fraction of cancer patients is refractory to these treatments. A frequently overlooked determinant of the success of T cell-based immunotherapy relates to the ability of effector T cells to migrate into and within tumors, as well as to have access to tumor antigens. Here, we will focus on recent advances in understanding T cell trafficking into and within tumors. Both chemoattractant molecules and structural determinants are essential for regulating T cell motile behavior along with cellular interactions-mediated antigen recognition. In addition, we will review evidence that the microenvironment of advanced tumors creates multiple obstacles limiting T cells from migrating and making contact with their malignant targets. We will particularly focus on the extracellular matrix and tumor-associated macrophages that make tumors a hostile environment for T cell ability to contact and kill malignant cells. Finally, we will discuss possible strategies to restore a tumor microenvironment more favorable to T cell migration and functions with a special emphasis on approaches targeting the dysregulated extracellular matrix of growing tumors.

Polyethyleneimine-assisted one-pot synthesis of quasi-fractal plasmonic gold nanocomposites as a photothermal theranostic agent.

Gold nanoparticles have been thoroughly used in designing thermal ablative therapies and in photoacoustic imaging in cancer treatment owing to their unique and tunable plasmonic properties. While the plasmonic properties highly depend on the size and structure, controllable aggregation of gold nanoparticles can trigger a plasmonic coupling of adjacent electronic clouds, henceforth leading to an increase of light absorption within the near-infrared (NIR) window. Polymer-engraftment of gold nanoparticles has been investigated to achieve the plasmonic coupling phenomenon, but complex chemical steps are often needed to accomplish a biomedically relevant product. An appealing and controllable manner of achieving polymer-based plasmon coupling is a template-assisted Au+3 reduction that ensures in situ gold reduction and coalescence. Among the polymers exploited as reducing agents are polyethyleneimines (PEI). In this study, we addressed the PEI-assisted synthesis of gold nanoparticles and their further aggregation to obtain fractal NIR-absorbent plasmonic nanoaggregates for photothermal therapy and photoacoustic imaging of colorectal cancer. PEI-assisted Au+3 reduction was followed up by UV-visible light absorption, small-angle X-ray scattering (SAXS), and photo-thermal conversion. The reaction kinetics, stability, and the photothermal plasmonic properties of the as-synthesized nanocomposites tightly depended on the PEI : Au ratio. We defined a PEI-Au ratio range (2.5-5) for the one-pot synthesis of gold nanoparticles that self-arrange into fractal nanoaggregates with demonstrated photo-thermal therapeutic and imaging efficiency both in vitro and in vivo in a colorectal carcinoma (CRC) animal model.