"Rigid-Flexible" Dual-Ferrocene Chimeric Nanonetwork for Simultaneous Tumor-Targeted Tracing and Photothermal/Photodynamic Therapy.

There is an urgent need to develop phototherapeutic agents with imaging capabilities to assess the treatment process and efficacy in real-time during cancer phototherapy for precision cancer therapy. The safe near-infrared (NIR) fluorescent dyes have garnered significant attention and are desirable for theranostics agents. However, until now, achieving excellent photostability and fluorescence (FL) imaging capability in aggregation-caused quenching (ACQ) dyes remains a big challenge. Here, for the only FDA-approved NIR dye, indocyanine green (ICG), we developed a dual-ferrocene (Fc) chimeric nanonetwork ICG@HFFC based on the rigid-flexible strategy through one-step self-assembly, which uses rigid Fc-modified hyaluronic acid (HA) copolymer (HA-Fc) and flexible octadecylamine (ODA) bonded Fc (Fc-C18) as the delivery system. HA-Fc reserved the ability of HA to target the CD44 receptor of the tumor cell surface, and the dual-Fc region provided a rigid space for securely binding ICG through metal-ligand interaction and π-π conjugation, ensuring excellent photostability. Additionally, the alkyl chain provided flexible confinement for the remaining ICG through hydrophobic forces, preserving its FL. Thereby, a balance is achieved between outstanding photostability and FL imaging capability. In vitro studies showed improved photobleaching resistance, enhanced FL stability, and increased singlet oxygen (1O2) production efficiency in ICG@HFFC. Further in vivo results display that ICG@HFFC had good tumor tracing ability and significant tumor inhibition which also exhibited good biocompatibility.. Therefore, ICG@HFFC provides an encouraging strategy to realize simultaneous enhanced tumor tracing and photothermal/photodynamic therapy (PTT/PDT) and offers a novel approach to address the limitations of ACQ dyes.

Intraoperative visualization of cranial nerve schwannomas using second-window indocyanine green: A case series.

BACKGROUND: Second Window Indocyanine Green (SWIG) is a novel intraoperative imaging technique that uses near-infrared (NIR) light for intra-operative tumor visualization using the well-known fluorophore indocyanine green (ICG). Because schwannomas often incorporate the nerve into the encapsulated tumor and impinge on surrounding neural structures, SWIG is a promising technique to improve tumor resection while sparing the nerve. OBJECTIVE: To demonstrate the use of SWIG in resection of cranial nerve schwannomas. METHODS: Three patients with cranial nerve schwannomas (i.e., trigeminal, vestibular, and vagus) underwent SWIG-guided resection. During surgery, NIR visualization was used intermittently used to detect fluorescence to guide resection. Signal-to-background ratio was then calculated to quantify fluorescence. RESULTS: Patients were infused with ICG at a dose of 5.0 mg/kg 24 hours before surgery. Each patient achieved total or near-total resection and relief of symptoms with lack of recurrence at six-month follow-up. The average SBR calculated was 3.79, comparable to values for SWIG-guided resection of other brain and spine tumors. CONCLUSION: This case series is the first published report of trigeminal and vagus nerve schwannoma resection using the SWIG technique and suggests that SWIG may be used to detect all schwannomas, alongside many other types of brain tumor. This paper also demonstrates the importance of preoperative ICG infusion timing and discusses the inverse pattern of NIR signal that may be observed when infusion occurs outside of the optimal timing. This provides direction for future studies investigating the administration of SWIG to resect cranial nerve schwannomas and other brain tumors.

Fluorinated Iron Metal-Organic Frameworks for Activatable 19F Magnetic Resonance Imaging and Synergistic Therapy of Tumors.

Due to their appealing physiochemical properties, metal-organic frameworks (MOFs) have been widely employed in biomedical fields. In this study, we utilize ferric ions and fluorine-containing organic ligands as both structural and functional units to develop a stimulus-responsive nanoagent, 19FIMOF-TA nanoparticles, for activatable 19F magnetic resonance imaging (MRI) and synergistic therapy of tumors. This nanoagent could respond to excess GSH in a tumor microenvironment, discharging fluorinated organic ligands and reduced ferrous ions. The release of these fluorine-containing small molecules results in boosting of the 19F MRI signals, which could be further enhanced by the photothermal effect of this nanoagent to achieve a responsive cascaded amplification of 19F MRI signals for tumor visualization. Meanwhile, ferroptosis promoted by the ferrous ions leads to significant tumor cell death, which is synergistically aggravated by the photothermal effect. The encouraging results illustrate the promising potential of our nanoagent for effective tumor imaging and combinative cancer therapy.

Recent advancements in the diagnosis and treatment of non-muscle invasive bladder cancer: Evidence update of surgical concept, risk stratification, and BCG-treated disease.

In the management of non-muscle invasive bladder cancer (NMIBC), disease progression and long-term control are determined by the intensity of delivered treatment and surveillance and the cancer cells' biological nature. This requires risk stratification-based postoperative management, such as intravesical instillation of chemotherapy drugs, Bacillus Calmette-Guérin (BCG), and radical cystectomy. Advancements in mechanical engineering, molecular biology, and surgical skills have evolved the clinical management of NMIBC. In this review, we describe the updated evidence and perspectives regarding the following aspects: (1) advancements in surgical concepts, techniques, and devices for transurethral resection of the bladder tumor; (2) advancements in risk stratification tools for NMIBC; and (3) advancements in treatment strategies for BCG-treated NMIBC. Repeat transurethral resection, en-bloc transurethral resection, and enhanced tumor visualization, including photodynamic diagnosis and narrow-band imaging, help reduce residual cancer cells, provide accurate diagnosis and staging, and sensitive detection, which are the first essential steps for cancer cure. Risk stratification should always be updated and improved because the treatment strategy changes over time. The BCG-treated disease concept has recently diversified to include BCG failure, resistance, refractory, unresponsiveness, exposure, and intolerance. A BCG-unresponsive disease is an extremely aggressive subset unlikely to respond to a rechallenge with BCG. Numerous ongoing clinical trials aim to develop a future bladder-sparing approach for very high-risk BCG-naïve NMIBC and BCG-unresponsive NMIBC. The key to improving the quality of patient care lies in the continuous efforts to overcome the clinical limitations of bedside management.

The application of fluorescein sodium for the resection of medulloblastoma.

INTRODUCTION: Surgical resection of medulloblastoma (MB) remains a challenge. At present, a variety of tracers have been used for intraoperative tumor visualization. However, there are few reports on the intraoperative visualization of MB. Hence, we reported our experience of applying fluorescein sodium (FS) in MB surgery. METHODS: We retrospectively analyzed the clinical information of patients with MB confirmed by surgery and pathology from January 2016 to December 2020 from Sun Yat-sen University Cancer Center. A total of 62 patients were enrolled, of which 27 received intraoperative FS and 35 did not. The intraoperative dose of FS was 3 mg/kg. RESULTS: Among the 62 patients, 42 were males, and twenty were females. The age of onset in the FS group was 9.588 ± 7.322, which in the non-fluorescein sodium group was 13.469 ± 10.968, p = 0.198. We did not find significant differences in tumor location, tumor size, tumor resection, tumor histology, and preoperative symptoms (hydrocephalus, headache, vomit, balance disorder) between the groups. There was no significant difference in the postoperative symptoms (hydrocephalus, headache, vomiting, balance disorder, and cerebellar mutism). However, patients in the FS group had a relatively low incidence of balance disorder and cerebellar mutism. There was definite fluorescence of tumor in all cases of the FS group, and even the tiny metastatic lesion was visible. No case had side effects related to the use of FS. CONCLUSIONS: FS is safe and effective in MB surgery. Whether the application of FS for surgery can reduce complications remains to be studied in the future.

Benefits of Zebrafish Xenograft Models in Cancer Research.

As a promising in vivo tool for cancer research, zebrafish have been widely applied in various tumor studies. The zebrafish xenograft model is a low-cost, high-throughput tool for cancer research that can be established quickly and requires only a small sample size, which makes it favorite among researchers. Zebrafish patient-derived xenograft (zPDX) models provide promising evidence for short-term clinical treatment. In this review, we discuss the characteristics and advantages of zebrafish, such as their transparent and translucent features, the use of vascular fluorescence imaging, the establishment of metastatic and intracranial orthotopic models, individual pharmacokinetics measurements, and tumor microenvironment. Furthermore, we introduce how these characteristics and advantages are applied other in tumor studies. Finally, we discuss the future direction of the use of zebrafish in tumor studies and provide new ideas for the application of it.

Second-Window Indocyanine Green for Visualization of Hemangioblastoma: A Case Report With Two-Dimensional Operative Video.

BACKGROUND AND IMPORTANCE: The proper differentiation of neoplastic tissue from adjacent brain parenchyma can pose a great challenge, especially in eloquent areas of the brain. With the novel technique, "Second-Window Indocyanine Green," injection of a near-infrared fluorophore (ICG) allows for intraoperative visualization of tumors by taking advantage of the compromised vasculature surrounding the tumor. Thus, such a technique may demonstrate utility for hemangioblastomas, which are hypervascular tumors of the central nervous system. CLINICAL PRESENTATION: Here we present the case of a 39-yr-old male with a demonstrated cystic mass in the left cerebellum, with additional edema spreading towards the vermis. A total of 5 mg/kg of ICG was delivered intravenously 24 h prior to the operation. The tumor was approached via the infratentorial suboccipital approach. We observed strong near-infrared fluorescence through the intact dura, consistent with the tumor location. Surgical pathology confirmed a final diagnosis of cerebellar hemangioblastoma. There was complete resection of the tumor, with the patient discharged uneventfully. CONCLUSION: We report the first successful case of fluorescence-guided surgery of a cerebellar hemangioblastoma using near-infrared fluorescence imaging with the Second-Window ICG technique. This joins a growing series of publications that demonstrate the efficacy of a novel application of ICG, a near-infrared fluorophore, in accurate intraoperative visualization of neoplastic tissue. While the use of a dedicated near-infrared platform (ie, the VisionSense Iridium [Visionsense, Philadelphia, Pennsylvania]) yields a higher signal-to-background ratio, a neurosurgical microscope (ie, the Leica OH6 [Leica Microsystems, Wetzlar, Germany]) may also provide a suitable option in cases where fluorescence is very strong.

Current European Trends in Endoscopic Imaging and Transurethral Resection of Bladder Tumors.

Purpose: The aim of this survey was to obtain an overview of current European standards in the endoscopic visualization and management of bladder tumors. Methods: An online survey was launched in July 2018 for a duration of 4 months. It was distributed to all members of the European Association of Urology (EAU) and included 23 questions divided into 3 thematic sections: general information, white light cystoscopy (WLC) and imaging, and transurethral resection of bladder tumor (TURBT) techniques. Results: Responses of 222 participants were included for analysis. The majority of physicians were between 30 and 40 years of age (48.2%, n = 107) and performed over 50 TURBT per year (52.2%, n = 115). Overall, 52.3% (n = 116) reported WLC findings in written form only, 23.8% (n = 53) added endoscopic footage, and 79.2% (n = 176) considered preliminary WLC/TURBT reports before performing a subsequent bladder intervention. About half of the participants (50.5%, n = 104) used additional tumor visualization methods (aTVMs), but aTVMs were utilized by a greater proportion of physicians from Western countries (58.1%, n = 90) compared with developing countries (20.0%, n = 7). Photodynamic diagnosis was the predominant aTVM technique employed (43.8%, n = 60). Bipolar current was the most common technique for TURBT (46.6%, n = 149). Most urologists in this study occasionally utilized techniques like resections in fractions (80%, n = 161) or en bloc resection (87.2%, n = 182). A repeated TURBT was performed when no muscle was found in the specimen (70.6%, n = 149) and/or if the tumor was stage pT1 (72.0%, n = 152) or high grade (63.0%, n = 133). Conclusion: Implementation of resection techniques or repeated TURBT within EAU guidelines is promising, but it can be further challenged. For example, WLC/TURBT reporting should be improved since urologists consistently consider previous documentation. Given the moderate application rate of aTVMs, an attempt to increase its utilization would lead to a better assessment of its potential benefit.

Second Window Indocyanine Green (SWIG) Near Infrared Fluorescent Transventricular Biopsy of Pineal Tumor.

BACKGROUND: Second Window Indocyanine Green (SWIG) is a novel technique for real-time, intraoperative tumor visualization using a high-dose infusion of indocyanine green (ICG) 24 hours before surgery. Due to pathologic diversity found in the pineal region, tissue diagnosis in patients with pineal region mass is essential to optimize further clinical management. CASE DESCRIPTION: We present the case of a 75-year-old woman with known pineal region mass for 18 years, who presented with progressive classic signs and symptoms of obstructive hydrocephalus over the past 6 months. Preoperative imaging confirmed a contrast-enhancing pineal region tumor, which appeared to be obstructing the aqueduct of Sylvius, causing proximal obstructive hydrocephalus. We delivered 5 mg/kg of ICG intravenously 24 hours before the surgery. The patient underwent an endoscopic third ventriculostomy and a biopsy of the pineal lesion. The tumor demonstrated clear near-infrared fluorescence, which was distinct from surrounding third ventricle floor and ependyma. The signal-to-background ratio was 2.9. The final pathology report revealed a World Health Organization grade I pineocytoma. CONCLUSIONS: We report on a novel application of near-infrared fluorescence for tumor identification of pineal region tumors, using the "SWIG technique."

Application of Indocyanine green in visual treatment of oral cancer / 口腔疾病防治

@#Indocyanine green (ICG) is a fluorescence indicator characterized by low trauma, a long effect time, low cytotoxicity, and high imaging resolution. It has been widely used in biomedical applications. However, ICG is not widely used in the treatment of oral cancer. This article reviews the application of ICG in the diagnosis and treatment of oral cancer. The results of a literature review showed that in the diagnosis and treatment of oral cancer, ICG mainly plays a role through the enhanced permeability and retention (EPR) effect of fluorescent substances and in coupling with various tumor-specific antibodies. For tumor visualization, ICG can focus on the primary tumor and lymph node metastasis by coupling the specific tumor antibodies and the EPR effect to guide the complete resection of the primary tumor and the determination of neck lymphadenectomy. In the reconstruction of the oral, head and neck regions, semi-quantitative measurement of ICG fluorescence intensity can be used to design a guide for a vascularized flap during the operation, for early detection of flap crisis after the operation, and to guide clinical flap exploration opportunities. In nonsurgical treatments of oral cancer, such as photothermal therapy and photodynamic therapy, ICG, as an important component of photosensitive nanomaterials, has attracted the attention of many scholars. ICG has good application prospects in the resection, reconstruction, visualization and nonsurgical treatment of oral cancer.

The value of visible 5-ALA fluorescence and quantitative protoporphyrin IX analysis for improved surgery of suspected low-grade gliomas.

OBJECTIVE: In patients with suspected diffusely infiltrating low-grade gliomas (LGG), the prognosis is dependent especially on extent of resection and precision of tissue sampling. Unfortunately, visible 5-aminolevulinic acid (5-ALA) fluorescence is usually only present in high-grade gliomas (HGGs), and most LGGs cannot be visualized. Recently, spectroscopic probes were introduced allowing in vivo quantitative analysis of intratumoral 5-ALA-induced protoporphyrin IX (PpIX) accumulation. The aim of this study was to intraoperatively investigate the value of visible 5-ALA fluorescence and quantitative PpIX analysis in suspected diffusely infiltrating LGG. METHODS: Patients with radiologically suspected diffusely infiltrating LGG were prospectively recruited, and 5-ALA was preoperatively administered. During resection, visual fluorescence and absolute tissue PpIX concentration (CPpIX) measured by a spectroscopic handheld probe were determined in different intratumoral areas. Subsequently, corresponding tissue samples were safely collected for histopathological analysis. Tumor diagnosis was established according to the World Health Organization 2016 criteria. Additionally, the tumor grade and percentage of tumor cells were investigated in each sample. RESULTS: All together, 69 samples were collected from 22 patients with histopathologically confirmed diffusely infiltrating glioma. Visible fluorescence was detected in focal areas in most HGGs (79%), but in none of the 8 LGGs. The mean CPpIX was significantly higher in fluorescing samples than in nonfluorescing samples (0.693 µg/ml and 0.008 µg/ml, respectively; p < 0.001). A significantly higher mean percentage of tumor cells was found in samples with visible fluorescence compared to samples with no fluorescence (62% and 34%, respectively; p = 0.005), and significant correlation of CPpIX and percentage of tumor cells was found (r = 0.362, p = 0.002). Moreover, high-grade histology was significantly more common in fluorescing samples than in nonfluorescing samples (p = 0.001), whereas no statistically significant difference in mean CPpIX was noted between HGG and LGG samples. Correlation between maximum CPpIX and overall tumor grade was highly significant (p = 0.005). Finally, 14 (40%) of 35 tumor samples with no visible fluorescence and 16 (50%) of 32 LGG samples showed significantly increased CPpIX (cutoff value: 0.005 µg/ml). CONCLUSIONS: Visible 5-ALA fluorescence is able to detect focal intratumoral areas of malignant transformation, and additional quantitative PpIX analysis is especially useful to visualize mainly LGG tissue that usually remains undetected by conventional fluorescence. Thus, both techniques will support the neurosurgeon in achieving maximal safe resection and increased precision of tissue sampling during surgery for suspected LGG.Clinical trial registration no.: NCT01116661 (clinicaltrials.gov).

Transurethral resection of bladder tumours: established and new methods of tumour visualisation.

Transurethral resection (TUR) of bladder tumours does not only serve diagnostic purposes by securing histological proof of the disease but might also resemble the final therapy. During recent years, technical innovations improved the intraoperative detection and visibility of tumourous lesions during TUR. The most important techniques, which have individually found their way into international guidelines, are photodynamic imaging (PDI) and narrowband imaging (NBI). Furthermore, there are more or less experimental approaches such as optical coherence tomography (OCT), confocal laser endomicroscopy (CLE), red/green/blue analysis (RGB) of WLC. Moreover, the combination of two or more techniques in a multiparametric setting is another development in improving intraoperative imaging. The aim of this review is to describe today's knowledge of the more established methods and to depict the most recent developments in intraoperative imaging.

Application of indocyanine green fluorescence endoscopic system in transsphenoidal surgery for pituitary tumors.

BACKGROUND: For the precise removal of pituitary tumors, preserving the surrounding normal structures, we need real-time intraoperative information on tumor location, margins, and surrounding structures. The aim of this study was to evaluate the benefits of a new intraoperative real-time imaging modality using indocyanine green (ICG) fluorescence through an endoscopic system during transsphenoidal surgery (TSS) for pituitary tumors. METHODS: Between August 2013 and October 2014, 20 patients with pituitary and parasellar region tumors underwent TSS using the ICG fluorescence endoscopic system. We used a peripheral vein bolus dose of 6.25 mg/injection of ICG, started with a time counter, and examined how each tissue type increased and decreased in fluorescence through time. RESULTS: A total of 33 investigations were performed for 20 patients: 9 had growth hormone secreting adenomas, 6 non-functioning pituitary adenomas, 3 Rathke's cleft cysts, 1 meningioma, and 1 pituicytoma. After the injection of ICG, the intensity of fluorescence of tumor and normal tissues under near-infrared light showed clear differences. We could differentiate tumor margins from adjacent normal tissues and define clearly the surrounding normal structures using the different fluorescent intensities time changes and tissue-specific fluorescence patterns. CONCLUSIONS: The ICG endoscopic system is simple, user-friendly, quick, cost-effective, and reliable. The method offered real-time information during TSS to delimit pituitary and parasellar region tumor tissue from surrounding normal structures. This method can contribute to the improvement of total removal rates of tumors, reduction of complications after TSS, saving surgical time, and preserving endocrinological functions.