Cardio- and Vasoprotective Effects of Quinacrine in an In Vivo Rat Model of Myocardial Ischemia/Reperfusion Injury.

This study aimed to investigate the cardioprotective effect of quinacrine in an in vivo model of myocardial ischemia/reperfusion injury. A 30-min regional myocardial ischemia followed by a 2-h reperfusion was modeled in anesthetized Wistar rats. Starting at the last minute of ischemia and during the first 9 min of reperfusion the rats in the control (n=8) and experimental (n=9) groups were injected with 0.9% NaCl and quinacrine solution (5 mg/kg), respectively. The area at risk and infarct size were evaluated by "double staining" with Evans blue and triphenyltetrazolium chloride. To assess vascular permeability in the area at risk zone, indocyanine green (ICG) and thioflavin S (ThS) were injected intravenously at the 90th and 120th minutes of reperfusion, respectively, to assess the no-reflow zone. The images of ICG and ThS fluorescence in transverse sections of rat hearts were obtained using a FLUM multispectral fluorescence organoscope. HR tended to decrease by 13% after intravenous administration of quinacrine and then recovered within 50 min. Quinacrine reduced the size of the necrotic zone (p=0.01), vascular permeability in the necrosis region, and the no-reflow area (p=0.027); at the same time, the area at risk did not significantly differ between the groups. Intravenous administration of quinacrine at the beginning of reperfusion of the rat myocardium reduces no-reflow phenomenon and infarct size.

[Intraoperative near-infrared fluorescence imaging of peripheral lung tumors]. / Intraoperatsionnaya flyuorestsentnaya vizualizatsiya perifericheskikh opukholei legkikh v blizhnem infrakrasnom diapazone.

The main objective of surgical intervention in lung cancer is the radical removal of the entire tumor with the maximum possible preservation of healthy tissue. Although the area of the tumor lesion is known by the results of preoperative studies, it can be difficult to use this information to establish the exact boundaries of resection during surgery, especially with small sizes of the lump and when using minimally invasive approaches. There are several techniques to solve this problem. One of the latter is intraoperative fluorescence imaging in the infrared range, which makes it possible to detect a tumor not only with greater contrast than it can be done in white light, but also with its deep location. This review is devoted to the discussion of various aspects of this approach related to molecular imaging methods. The current situation based on the use of green indocyanine green, available for clinical use as a fluorescent agent is considered, the issues of using new targeted drugs are examined, as well as the possibility of increasing the depth of probing and combining with related treatment methods, which should contribute to a more radical operation and reduce the likelihood of local relapses.

[Intraoperative photodynamic therapy in complex treatment of malignant gliomas]. / Primenenie intraoperatsionnoi fotodinamicheskoi terapii v strukture kompleksnogo lecheniya zlokachestvennykh gliom.

Treatment of malignant gliomas is an extremely difficult objective associated with difficult choice of correct strategy. Photodynamic therapy is still not the treatment standard in these patients although this approach significantly improves treatment outcomes in surgery of gliomas. OBJECTIVE: To demonstrate the possibilities of chlorin e6-mediated photodynamic therapy for malignant glial tumors. MATERIAL AND METHODS: There were 161 patients with malignant supratentorial glial tumors who were treated at the Polenov Russian Neurosurgery Institute between 2009 and 2016. Eighty patients comprised the main group (photodynamic therapy), 81 ones - control group (without photodynamic therapy). RESULTS: Photodynamic therapy in complex treatment of malignant brain gliomas significantly increases overall survival in patients with Grade III gliomas up to 39.1±5.5 months (control group - 22.8±3.3 months) and Grade IV gliomas up to 20.7±4.7 months (control group - 13.5±2.3 months) (p=0.0002). This method also increases relapse-free period in patients with Grade III gliomas up to 21.7±3.4 months (control group - 15.8±3.1 months) (p=0.0002) and Grade IV gliomas up to 11.1±2.1 months (control group - 8.0±2.3 months) (p=0.0001).

[Comparative analysis of 5-ALA and chlorin E6 fluorescence-guided navigation in malignant glioma surgery]. / Sravnitel'nyi analiz fluorestsentnoi navigatsii v khirurgii zlokachestvennykh gliom s ispol'zovaniem 5-ALA i khlorina E6.

OBJECTIVE: To analyze specificity and sensitivity of 5-ALA and chlorin E6 fluorescence-guided navigation in malignant glioma surgery. MATERIAL AND METHODS: Fluorescence-guided navigation was analyzed in 50 patients (2 groups) with high-grade glioma. All patients were treated at the Polenov Russian Neurosurgery Institute. Chlorin E6 1 mg/kg intravenously (Photoditazin) was used as a fluorescence inducer in 25 patients (the 1st group), 5-ALA 20 mg/kg orally (Alasens) - in other 25 patients (the 2nd group). Each group included 10 patients with glioma grade III and 15 patients with glioma grade IV. Both groups were statistically representative (p>0.05). RESULTS: In patients with glioma grade III, sensitivity of chlorin E6 fluorescence-guided navigation was 83.8%, 5-ALA fluorescence - 82.5%. Specificity was 66.7% and 64.1%, respectively. In patients with glioma grade IV, sensitivity was 87.7% for chlorin E6 and 88.3% for 5-ALA. Specificity was 85.2% and 88.1%, respectively. CONCLUSION: Statistical analysis confirmed comparable high efficacy of both agents in surgery of malignant gliomas. Sensitivity and specificity of fluorescence-guided navigation with chlorin E6 and 5-ALA were similar (p>0.05).

[Morphological evaluation of the effectiveness of fluorescence navigation with chlorin e6 in surgery for malignant gliomas]. / Morfologicheskaya otsenka effektivnosti fluorestsentnoi navigatsii s khlorinom e6 v khirurgii zlokachestvennykh gliom.

OBJECTIVE: To evaluate the effectiveness of fluorescence navigation with chlorin e6 in surgery for malignant gliomas based on surgical material morphological and immunohistochemical data. MATERIAL AND METHODS: The surgical material obtained from patients with high-grade (Grade III-IV) anaplastic glioma was examined. Along with histological examination, the proliferation marker Ki-67, the cell cycle transcription factor protein p53, and vascular endothelial growth factor (VEGF) were determined. RESULTS: A significant direct correlation was found between the expression of Ki-67, p53, and VEGF and the fluorescence intensity of tumor tissues (p<0.05). CONCLUSION: The technique of fluorescence navigation using chlorin e6 in comparative morphopathological analysis has confirmed its effectiveness in surgery for malignant gliomas.

[Intraoperative fluorescence control with chlorin E6 in resection of glial brain tumors]. / Rezul'taty ispol'zovaniya intraoperatsionnogo flyuorestsentnogo kontrolya s khlorinom E6 pri rezektsii glial'nykh opukholei golovnogo mozga.

In recent years, fluorescence navigation has been increasingly used in surgery for gliomas. In most studies, 5-ALA derivatives are used as fluorescence inducers. However, there are few data regarding E6 chlorin for these purposes. OBJECTIVE: To evaluate an effectiveness and feasibility of fluorescence navigation with chlorin E6 in surgery of brain gliomas. MATERIAL AND METHODS: The study included 30 patients with glial brain tumors grade II-IV. All patients were operated at the Polenov Russian Neurosurgical Institute. We used surgical microscope (Leica OHS-1), D-Light AF System (Karl Storz, Germany), original fluorescence module (St. Petersburg LOMO, developed by G.V. Papayan) and special software RSS Cam - Endo 1.4.313 for visual analysis of fluorescence. Histological examination included hematoxylin-eosin staining of specimens and immunohistochemical studies. RESULTS: Fluorescence was weak in all patients with Grade II gliomas and strong in almost all patients with Grade III-IV gliomas. Sensitivity of fluorescence diagnosis with chlorin E6 was 72.2% for Grade II gliomas, 83.8% for Grade III gliomas and 87.7% for Grade IV. Specificity of this method was 60% for Grade II gliomas, 66.7% for Grade III gliomas and 85.2% for Grade IV. CONCLUSION: Certain method of fluorescence imaging ensured resection of glial brain tumors using chlorin E6. Intensity of tumor fluorescence correlated with glioma malignancy grade. These results indicate that chlorin E6 is an effective photosensitizer for intraoperative fluorescence diagnosis in surgery for glioma.

[Analysis of lymphatic drainage pathways using infrared fluorescence in patients with lung cancer]. / Izuchenie putei regionarnogo limfoottoka pri rake legkogo s pomoshch'iu infrakrasnoi fluorestsentsii.

OBJECTIVE: To develop a method for analysis of lymphatic drainage pathways from the lobe of the lung affected by non-small cell lung cancer (NSCLC) using infrared fluorescence. MATERIAL AND METHODS: A study enrolled patients with NSCLC who underwent anatomic resection of the lung with systematic lymph node dissection and preliminary intraoperative peritumoral injection of indocyanine green conjugate with human albumin. Registration of fluorescence in regional lymph nodes (LN) was carried out immediately after excision of specimen using the FLUM-808 instrumental system. RESULTS: Infrared fluorescence was observed in 117 hilar and mediastinal lymph nodes from 43 patients (2.7 nodes per a patient). Comparison of localization of fluorescent LN with localization of tumor in various lobes established significant variability of lymphatic drainage pathways. CONCLUSION: The developed method of infrared fluorescent evaluation of lymphatic drainage in patients with NSCLC confirms the necessity of systematic lymph node dissection for adequate staging.

[Stereotactic photodynamic therapy for recurrent glioblastoma. Case report and literature review]. / Stereotaksicheskaya fotodinamicheskaya terapiya v lechenii retsidiva glioblastomy. Sluchai iz praktiki i obzor literatury.

We report a patient with recurrent glioblastoma in eloquent brain area. Stereotactic fluorescence biospectroscopy and stereotactic photodynamic therapy of tumor in opercular area of the left frontal lobe under neurophysiological monitoring were carried out. Literature data on this issue were analyzed.

Infrared Fluorescent Angiography during Experimental Trachea Transplantation.

Indocyanine green fluorescence was used for evaluation of the degree of trachea revascularization after its autotransplantation in rabbits (transplantation of 1- and 2-cm segment of the trachea). Intravenous administration of indocyanine green was followed by a significant fluorescence of the substance in microvessels of the trachea over 30-40 sec. Immediately after surgery, fluorescence in the implanted segment was absent, but within 7 days it was completely restored in rabbits receiving transplantation of a 1-cm segment. After transplantation of 2-cm segment of the trachea, fluorescence did not recover, which corresponded to the clinical picture and autopsy results. Thus, fluorescent angiography is an informative method for evaluation of trachea revascularization.

[Possibility of the use of the conjugate of indocyanine green with albumin for infrared fluorescent diagnosis of pathological processes in experiment].

An investigation of fluorescent diagnosis possibility in the near infrared range was performed on a rat model of the Pliss lymphosarcoma (30 rats) with the use of indocyanine green (ICG) as a fluorescent marker and photosensitizer. For conju- gates of ICG there were used bovine and human albumins as these proteins in solution strengthened and stabilized fluorescence and in intravenous administration promoted improving diagnosis while the diagnostic contrast after administration during the optimum time was no less than 6. It permitted to easily detect a pathological focus (tumor or inflammation).

[Examination of skin autofluorescence for the determination of glycation end-products in patients on chronic hemodialysis].

AIM: To assess the results of determination of glycation end-products (GEPs) by skin autofluorescence (AF) in patients on chronic hemodialysis (HD). SUBJECTS AND METHODS: A device made in Russia was used to estimate skin AF intensity in 40 apparently healthy individuals and in 76 patients treated with chronic HD. While analyzing the findings, comparisons were made in both groups; a relationship between skin AF intensity and clinical and laboratory parameters was also investigated in patients on HD. RESULTS: The intensity of AF in the patients treated with chronic HD proved to be significantly higher than that in the control group. There was a direct correlation of the intensity of AF with age in both groups and that with the duration of dialysis treatment in patients on HD. In patients with coronary heart disease, the intensity of AF was significantly higher than in those without this condition. The intensity of AF directly correlated with the Charlson comorbidity index in the patients on HD. There were no correlations of skin AF intensity with main generally detected laboratory blood indicators, body mass index, and the nature of drug therapy in the patients on HD. CONCLUSION: Tissue GEP levels may serve as a cumulative index of metabolic stress in HD patients. The determination of GEP by measuring the intensity of skin AF may be used to assess prognosis in patients treated with chronic HD.

ENDOBRONCHIAL PHOTODYNAMIC THERAPY UNDER FLUORESCENCE CONTROL: PHOTODYNAMIC THERANOSTICS.

One of the disadvantages of photodynamic therapy is impossibility to specify the method according to biological features of malignant tumor such as a degree of blood supply, accumulation of photosensibilizator in tumorous tissue, proliferative activity and etc. The authors aimed to develop a mode of individualization of endobronchial photodynamic therapy of central non-small cell carcinoma of lung and assessment of method efficacy. The suggested method is based on fluorescent diagnostics of degree of accumulation of photosensibilizator in timorous tissue and the rate of its expenditure in process of performing of photodynamic therapy. There was made a comparison of parameters of methods and results of photodynamic therapy in 2 randomized groups. Each group consisted of 45 patients. The research method was applied in the main group and the standard method was used in the comparison group. It was found that the research method allowed significant reduction of duration of irradiation compared with conventional method (at the average from 690±65sec to 470±45sec, p=0,02), though the treatment results were the same. The suggested method allowed separation of group of patients with absence of fluorescence of timorous tissue. Performance of photodynamic therapy is unreasonable for these patients.

[Intraoperative detection of the sentinel lymph nodes in lung cancer].

An analysis of the scientific data was made. It was used the literature devoted to the intraoperative visualization of the sentinel lymph nodes in patients with lung cancer. Correct detection of such lymph nodes with following pathologic investigation allowed limiting the volume of lympho-dissection in a number of patients. There is the possibility of maximal in-depth study of the sentinel lymph nodes by purposeful application of most sensible pathologic and molecular methods for detection their micrometastatic lesions. At the same time the treatment strategy and prognosis could be determined. The authors present the results of an application of dye techniques, radioactive preparation and fluorescence imaging for sentinel lymph node detection. Advantages and disadvantages of the methods are shown in the article. There are validated the prospects of technical development, study of information value of new applications and the most perspective method of fluorescence indocyanine green visualization by lymph outflow.

[INTRAOPERATIVE DETECTION OF SENTINEL LYMPH NODES USING INFRARED IMAGING SYSTEM IN LOCAL NON-SMALL CELL CARCINOMA OF LUNG].

The article presents the results of the first domestic experience of intraoperative fluorescence mapping of sentinel lymph nodes in lung cancer. The research included 10 patients, who underwent surgery over the period of time from September 2013 to May 2014. After performing thoracotomy, the solution of indocyanine green (ICG) was injected using subpleural position above the tumor in 3-4 points. Fluorescence (ICG) image guided surgery was carried out by using infrared radiation (wave length 808 nm) on lung surface, root of lung, mediastinum in real time. Fluorescence lymph nodes were mapped. In case that metastatic lesions weren't revealed in sentinel lymph nodes, they weren't noted in other nodes. Method specificity consisted of 100%. Biopsy and histological study of sentinel lymph nodes mapped during fluorescence (ICG) image guided surgery could be useful for prevention of lymphodissection in patients with non-small cell carcinoma of lung.

Passive and active target delivery of drugs to ischemic myocardium.

Silica nanoparticles as carriers for targeted drug delivery to the heart were studied. Studies of hemodynamic parameters of rats after intravenous infusion of silica nanoparticles showed no acute toxicity. Intravenous infusion of silica nanoparticles to animals with ischemia-reperfusion of the myocardium led to accumulation of the nanoparticles in the focus of injury, which attests to possibility of passive targeted drug delivery to the myocardium.

Photodynamic Theranostics of Central Lung Cancer: Capabilities of Early Diagnosis and Minimally Invasive Therapy (Review).

The aim of the study was to assess the prospects for central lung cancer (CLC) screening using fluorescent diagnostics and its treatment by endobronchial photodynamic therapy (PDT). Bronchoscopic fluorescent diagnostics using chlorin e6 photosensitizers and a developed instrumental system enable to reveal tumor changes in large bronchi mucosa at early stages, and a developed PDT technique performed under fluorescent control helps achieve personalized treatment. Such an approach is considered as a theranostic technique - photodynamic theranostics. central lung cancer screening requires a fluorescent dye characterized by availability and can be used directly within the examination. Indocyanine green can be used as a dye, its peculiarity is the necessity to excite and record fluorescence in the near-infrared (NIR) wavelength band. First experiments using NIR bands to diagnose a bronchoscopic system showed the detectability of tumor areas using on-site bronchoscopic photodynamic theranostics, which consists in NIR imaging of tumor foci when a standard dose of indocyanine green is administered during the examination. Conclusion: Further progress of early diagnostics and minimally invasive CLC therapy will be determined by the development of new photosensitizers, which should be characterized by a high absorption band in NIR area, quick accumulation in a tumor, high yield of single oxygen in NIR illumination, bright fluorescence, high potential in terms of the induction of an anti-tumor immune response.