Proposal of New Safety Limits for In Vivo Experiments of Magnetic Hyperthermia Antitumor Therapy.

BACKGROUND: Lately, major advances in crucial aspects of magnetic hyperthermia (MH) therapy have been made (nanoparticle synthesis, biosafety, etc.). However, there is one key point still lacking improvement: the magnetic field-frequency product (H × f = 4.85 × 108 Am-1s-1) proposed by Atkinson-Brezovich as a limit for MH therapies. Herein, we analyze both local and systemic physiological effects of overpassing this limit. METHODS: Different combinations of field frequency and intensity exceeding the Atkinson-Brezovich limit (591-920 kHz, and 10.3-18 kA/m) have been applied for 21 min to WAG/RijHsd male rats, randomly distributed to groups of 12 animals; half of them were sacrificed after 12 h, and the others 10 days later. Biochemical serum analyses were performed to assess the general, hepatic, renal and/or pancreatic function. RESULTS: MH raised liver temperature to 42.8 ± 0.4 °C. Although in five of the groups the exposure was relatively well tolerated, in the two of highest frequency (928 kHz) and intensity (18 kA/m), more than 50% of the animals died. A striking elevation in liver and systemic markers was observed after 12 h in the surviving animals, independently of the frequency and intensity used. Ten days later, liver markers were almost recovered in all of the animals. However, in those groups exposed to 591 kHz and 16 kA/m, and 700 kHz and 13.7 kA/m systemic markers remained altered. CONCLUSIONS: Exceeding the Atkinson-Brezovich limit up to 9.59 × 109 Am-1s-1 seems to be safe, though further research is needed to understand the impact of intensity and/or frequency on physiological conditions following MH.

Complications and diagnostic accuracy of CT-guided 18G tru-cut versus end-cut percutaneous core needle biopsy of solitary solid lung nodules.

PURPOSE: Percutaneous biopsy has demonstrated high accuracy in diagnosis of lung nodules, but the technique is not innocuous and a yield decrease in lesions smaller than 20 mm has been reported. We carried out a prospective study to evaluate and compare the complications and efficacy of percutaneous core needle biopsy (CNB) of solitary solid lung nodules, which were performed with two types of automatic guns. METHODS: 330 consecutive CT-guided CNB were included. Tru-cut or end-cut 18G devices were used alternatively. Nodules were categorized by their size: ≤10 mm, 11-20 mm and >20 mm. Incidence of complications such as pneumothorax or hemoptysis and factors influencing them (nodule size and depth within lung parenchyma) were evaluated. Diagnostic accuracy of CNB achieved in the three groups of nodules regarding the two different needles were calculated and statistically evaluated and compared. RESULTS: We performed 68 CNB in nodules ≤10 mm, 130 in 11-20 mm and 132 in >20 mm. Pneumothorax appeared in 24.2% of them, but only 5.7% required drainage. Hemoptysis was developed in 9.4% and abundant hemoptysis with hypoxemia was observed in only 4.2% of patients. Regarding appearance of complications between the two needle types, no significant differences were found. A higher risk of hemoptysis was observed in nodules ≤10 mm (OR = 3.87; 95% CI = 1.24-12.06, P = 0.019) and in those located deeper in pulmonary parenchyma (OR = 2.21; 95% CI = 1.04-4.69, P = 0.038). End-cut needles reached a diagnostic accuracy of 93.7%, 92.1% and 98.3%, in nodules sized ≤10 mm, 11-20 mm and >20 mm, respectively. Corresponding results for tru-cut were 84.7%, 88.5% and 92.1%. In spite of differences reaching up to 9% in smaller nodules, intra-group results were not significant. CONCLUSION: Both needles have similar complications rate. Despite not having observed statistically significant differences between the two types of needles, end-cut devices have demonstrated a higher diagnostic yield in the three groups of nodules and could be a more suitable option especially for CNB of nodules ≤10 mm.

Biochemical and Metabolomic Changes after Electromagnetic Hyperthermia Exposure to Treat Colorectal Cancer Liver Implants in Rats.

BACKGROUND: Hyperthermia (HT) therapy still remains relatively unknown, in terms of both its biological and therapeutic effects. This work aims to analyze the effects of exposure to HT, such as that required in anti-tumor magnetic hyperthermia therapies, using metabolomic and serum parameters routinely analyzed in clinical practice. METHODS: WAG/RigHsd rats were assigned to the different experimental groups needed to emulate all of the procedures involved in the treatment of liver metastases by HT. Twelve hours or ten days after the electromagnetic HT (606 kHz and 14 kA/m during 21 min), blood samples were retrieved and liver samples were obtained. 1H-nuclear-magnetic-resonance spectroscopy (1H-NMR) was used to search for possible diagnostic biomarkers of HT effects on the rat liver tissue. All of the data obtained from the hydrophilic fraction of the tissues were analyzed and modeled using chemometric tools. RESULTS: Hepatic enzyme levels were significantly increased in animals that underwent hyperthermia after 12 h, but 10 d later they could not be detected anymore. The metabolomic profile (main metabolic differences were found in phosphatidylcholine, taurine, glucose, lactate and pyruvate, among others) also showed that the therapy significantly altered metabolism in the liver within 12 h (with two different patterns); however, those changes reverted to a control-profile pattern after 10 days. CONCLUSIONS: Magnetic hyperthermia could be considered as a safe therapy to treat liver metastases, since it does not induce irreversible physiological changes after application.

Intra-Arterial Infusion of Magnetic Nanoparticle-Based Theragnostic Agent to Treat Colorectal Cancer Liver Implants in Rats.

INTRODUCTION: Nowadays, surgical excision remains the gold standard to treat liver metastases of colorectal cancer (CRCLM). However, as more than 50% of patients are not eligible for surgery, other alternatives such as percutaneous or intravascular interventional therapies (thermal ablation, chemoembolization, or radioembolization), are quite relevant. Recently, the use of magnetic nanoparticles (MNPs) has been suggested as an adjuvant for these therapies, as they could increase their necrotising effect on the tumour while reducing doses and exposure times of thermal therapies. To investigate the potential curative effect of these compounds, animal models are needed, both for the development of experimental interventional procedures and for MNPs toxicity and distribution assessment. Herein, we describe both an experimental infusion procedure in CRCLM-bearing rats and analytical and histological methods to evaluate MNPs deposits in the tissue. METHODS: Eighteen male WAG/RijHsd rats were subjected to intrahepatic injection of 250,000 colorectal cancer cells. Twenty-eight days later, half of the tumour-positive animals (n = 6) were administered with MNPs while the other half (n = 6) did not receive any injection and were used as control. Under microscope magnification, the splenic artery was carefully and completely dissected, and a catheter was inserted through the splenic artery to the common hepatic artery where 1 mL MNPs suspension was administered in 5 min; then STIR, DP*, and T2 MRI sequences were obtained (and signal intensity measured) and both tumour and liver tissue samples were collected for elemental and histological analyses. CONCLUSION: Our method for selective administration of MNPs is reproducible and well-tolerated and it fairly mimics the approach used in clinical practice when intravascular interventional therapies are applied.

Ureteroarterial fistula treated by endovascular stent placement.

A 69-year-old woman with changes secondary to pelvic radiotherapy presents repeated episodes of massive hematuria associated with double J catheter replacements. After several imaging tests, an uretero-arterial fistula is confirmed by angiography and treated with a coated stent. Uretero-arterial fistula poses a diagnostic challenge, requiring a multidisciplinary approach through clinical suspicion and interventional procedures.

Complications and hospital admission in the following 90 days after lung cryobiopsy performed in interstitial lung disease.

Transbronchial lung cryobiopsy (TBLC) is an emerging technique for the diagnosis of interstitial lung disease (ILD), but its risk benefit ratio has been questioned. The objectives of this research were to describe any adverse events that occur within 90 days following TBLC and to identify clinical predictors that could help to detect the population at risk. METHODS: We conducted an ambispective study including all patients with suspected ILD who underwent TBLC. Data were collected concerning the safety profile of this procedure and compared to various clinical variables. RESULTS: Overall, 257 TBLCs were analysed. Complications were observed in 15.2% of patients; nonetheless, only 5.4% of all patients required hospital admission on the day of the procedure. In the 30 and 90 days following the TBLC, rates of readmission were 1.3% and 3.5% and of mortality were 0.38%, and 0.78% respectively. Two models were built to predict early admission (AUC 0.72; 95% CI 0.59-0.84) and overall admission (AUC 0.76; 95% CI 0.67-0.85). CONCLUSIONS: Within 90 days after TBLC, 8.9% of patients suffered a complication serious enough to warrant hospital admission. Modified MRC dyspnoea score ≥2, FVC<50%, and a Charlson Comorbidity Index score ≥2 were factors that predicted early and overall admission.

Ultrasound Tumor Size Assessment, Histology and Serum Enzyme Analysis in a Rat Model of Colorectal Liver Cancer.

During tumor development, tissue necrosis appears as a natural phenomenon directly associated with an increase in tumor size. The aim of this study was to assess the use of ultrasound (US) for predicting natural tumor necrosis in a rat liver implant model of colorectal cancer. To achieve this goal, we sought to establish a correlation between US-measured tumor volume, serum enzyme levels and histopathological findings, particularly those regarding necrosis phenomena in liver implants. Under US guidance, CC531 colorectal cancer cells were injected into the left liver lobe of WAG/RijHsd rats. Twenty-eight days after cell inoculation, tumor volume was measured by US, and rats were sacrificed to obtain samples of tumor tissue as well as blood serum. In hematoxylin and eosin-stained tumor samples, the percentage of tumor that was necrotic was estimated. The association between percentage tumor necrosis and US-measured tumor volume was assessed by univariate logistic regression analysis, and a linear regression equation was obtained. Serum enzyme levels did not differ significantly between tumor-bearing and tumor-free rats. Tumor implants appeared as well-defined hyper-echoic regions with a mean volume of 0.61 ± 0.39 mL and tumor necrosis percentage of 8.6 ± 7.7%. Linear regression analysis revealed a very strong relationship (Pearson correlation coefficient r = 0.911) between US-measured tumor volume and tumor necrosis percentage; the regression equation was tumor necrosis percentage = 21 × US-measured tumor volume (in mL) - 3.1. The study found US to be a useful tool in animal-based trials. Tumors inside the liver (ranging in volume from 0.24-1.37 mL) can be observed by US, and moreover, US-measured tumor volume on day 28 can be used to estimate tumor necrosis occurring as the natural evolution of tumor implants.

Usefulness of an angioplasty balloon as selective bronchial blockade device after transbronchial cryobiopsy.

BACKGROUND AND OBJECTIVE: Transbronchial cryobiopsy (TBCB) is a technique in which frozen samples of lung are obtained using a probe inserted through a bronchoscope. We performed a retrospective study to assess the performance of the TBCB procedure complemented by segmental bronchial blockade using an angioplasty balloon, in terms of diagnostic yield and safety in diffuse parenchymal lung disease (DPLD). METHODS: Data from 100 patients with suspected DPLD (clinical and radiological findings), who underwent TBCB in our institution to establish a definitive diagnosis, were reviewed. In our institution, TBCB is monitored with fluoroscopy and performed under general anaesthesia by a multidisciplinary team (an anaesthesiologist, a pulmonologist and an interventional radiologist). In each patient, four samples were collected using a 2.4-mm distal diameter cryoprobe. To control bleeding, the biopsied segmental bronchus was blocked with a 6-mm diameter angioplasty balloon, inserted over a 0.035-inch angled hydrophilic guidewire. After the cryoextraction, the balloon was inflated for 3 min intervals until bleeding stopped. RESULTS: Overall, 98% of samples had diagnostic value. In 85% of cases, DPLD was confirmed, while in 7%, cancer was diagnosed. Complications were observed in 16% of the patients: 13 patients developed moderate haemorrhage, and 3 developed pneumothorax. CONCLUSION: Transbronchial cryobiopsy had a high diagnostic yield for DPLD. Performing the procedure under fluoroscopy guidance and using angioplasty balloon for selective bronchial blockade achieved a low rate of iatrogenic complications directly associated with the technique.

Antitumor magnetic hyperthermia induced by RGD-functionalized Fe3O4 nanoparticles, in an experimental model of colorectal liver metastases.

This work reports important advances in the study of magnetic nanoparticles (MNPs) related to their application in different research fields such as magnetic hyperthermia. Nanotherapy based on targeted nanoparticles could become an attractive alternative to conventional oncologic treatments as it allows a local heating in tumoral surroundings without damage to healthy tissue. RGD-peptide-conjugated MNPs have been designed to specifically target αVß3 receptor-expressing cancer cells, being bound the RGD peptides by "click chemistry" due to its selectivity and applicability. The thermal decomposition of iron metallo-organic precursors yield homogeneous Fe3O4 nanoparticles that have been properly functionalized with RGD peptides, and the preparation of magnetic fluids has been achieved. The nanoparticles were characterized by transmission electron microscopy (TEM), vibrating sample magnetometry (VSM), electron magnetic resonance (EMR) spectroscopy and magnetic hyperthermia. The nanoparticles present superparamagnetic behavior with very high magnetization values, which yield hyperthermia values above 500 W/g for magnetic fluids. These fluids have been administrated to rats, but instead of injecting MNP fluid directly into liver tumors, intravascular administration of MNPs in animals with induced colorectal tumors has been performed. Afterwards the animals were exposed to an alternating magnetic field in order to achieve hyperthermia. The evolution of an in vivo model has been described, resulting in a significant reduction in tumor viability.