Prospective comparison of positron emission tomography (PET)/magnetic resonance and PET/computed tomography dosimetry in hepatic malignant neoplastic disease after 90Y radioembolization treatment.

Background: 90Y radioembolization is an established treatment modality for hepatic malignancies. Successful radioembolization requires optimal dose delivery to tumors while minimizing dosages to parenchyma. Post-treatment positron emission tomography (PET)/computed tomography (CT) dosimetry is the established benchmark, whereas PET/magnetic resonance (MR) is an emerging modality. The goal of this study was to assess the intermodality agreement between PET/MR and PET/CT 90Y dosimetry. Methods: In this single-institution study, 18 patients (20 treatment sessions) with a primary or metastatic hepatic malignancy underwent both PET/MR and PET/CT after 90Y radioembolization. Patients were randomized to undergo one modality first, followed by the other. The region of interest was delineated using MR images and tumor and liver dosimetry was calculated. Intermodality agreement was assessed using the Bland-Altman method. A generalized linear model was used to assess the effect of baseline variables on intermodality dose differences. Results: PET/MR underestimated tumor and liver absorbed doses when compared to PET/CT by -3.7% (P=0.042) and -5.8% (P=0.029), respectively. A coverage probability plot demonstrated that 80% and 90% of tumor dose measurements fell within intermodality differences of 11% and 18%, respectively. PET/MR underestimated tumor dose at both low (<1 GBq) and high (>3 GBq) injected activity levels (P<0.001) by -22.3 [standard deviation (SD) =13.5] and -24.3 (SD =18.7), respectively. Conclusions: Although PET/MR significantly underestimated the absorbed dose when compared to PET/CT, the intermodality agreement was high and the degree of underestimation was better than previously reported. Intermodality differences were more pronounced at low and high injected doses. Additional studies are required to assess the clinical implications of these findings.

Pleural effusion as a novel prognostic factor in metastatic thyroid carcinoma.

OBJECTIVE: To identify novel prognostic risk factors and compare them with other known prognostic risk factors in follicular-cell-derived thyroid carcinoma (FDTC) with distant metastases. METHODS: A retrospective review was conducted of adult patients with metastatic FDTC seen at a tertiary care center between January 1990 and December 2010. A 15-year Kaplan-Meier survival estimate was created for overall survival (OS) and cancer-specific survival (CSS). Hazard ratios (HR) and P values from Cox proportional hazard models were used with a 95% CI. RESULTS: There were 143 patients (60.1% male, 39.9% female), of whom 104 (72.7%) patients had papillary, 30 (21.0%) had follicular, 5 (3.5%) had poorly differentiated, and 4 (2.8%) had Hürthle cell cancers. Median length of follow-up was 80.0 months (range 1.0-564.0). The 15-year mortality rate was 32.2% and cancer-specific mortality was 25.2%, with OS and CSS having the same risk factors. Lung was the most common site of metastases in 53 patients (37.1%), and patients with pleural effusions had significantly lower CSS (HR = 5.21, CI = 1.79-15.12). Additional risk factors for a decreased CSS included: older age upon diagnosis (>45 years, HR = 4.15, CI = 1.43-12.02), multiple metastatic locations (HR = 3.75, CI = 1.32-10.67), and incomplete/unknown tumor resection (HR = 2.35, CI = 1.18-4.67). CONCLUSION: This study is the first to demonstrate that pleural effusion is a poor prognostic sign in patients with FDTC with distant metastases and compare this risk with other accepted prognostic variables.

Quiescent hepatic stellate cells induce toxicity and sensitivity to doxorubicin in cancer cells through a caspase-independent cell death pathway: Central role of apoptosis-inducing factor.

Hepatocellular carcinoma (HCC) is a major health problem worldwide and in the United States as its incidence has increased substantially within the past two decades. HCC therapy remains a challenge, primarily due to underlying liver disorders such as cirrhosis that determines treatment approach and efficacy. Activated hepatic stellate cells (A-HSCs) are the key cell types involved in hepatic fibrosis/cirrhosis. A-HSCs are important constituents of HCC tumor microenvironment (TME) and support tumor growth, chemotherapy resistance, cancer cell migration, and escaping immune surveillance. This makes A-HSCs an important therapeutic target in hepatic fibrosis/cirrhosis as well as in HCC. Although many studies have reported the role of A-HSCs in cancer generation and investigated the therapeutic potential of A-HSCs reversion in cancer arrest, not much is known about inactivated or quiescent HSCs (Q-HSCs) in cancer growth or arrest. Here we report that Q-HSCs resist cancer cell growth by inducing cytotoxicity and enhancing chemotherapy sensitivity. We observed that the conditioned media from Q-HSCs (Q-HSCCM) induces cancer cell death through a caspase-independent mechanism that involves an increase in apoptosis-inducing factor expression, nuclear localization, DNA fragmentation, and cell death. We further observed that Q-HSCCM enhanced the efficiency of doxorubicin, as measured by cell viability assay. Exosomes present in the conditioned media were not involved in the mechanism, which suggests the role of other factors (proteins, metabolites, or microRNA) secreted by the cells. Identification and characterization of these factors are important in the development of effective HCC therapy.

Folic acid conjugated polymeric drug delivery vehicle for targeted cancer detection in hepatocellular carcinoma.

Targeted therapies provide increased efficiency for the detection and treatment of cancer with reduced side effects. Folate receptor (alpha subunit) is overexpressed in multiple tumors including liver cancer. In this study, we evaluated the specificity and toxicity of a folic acid-containing drug delivery vehicle (DDV) in a hepatocellular carcinoma (HCC) model. The DDV was prepared with two units each of folic acid (FA) and fluorescein isothiocyanate (FITC) molecules and conjugated to a central poly (ethylene glycol) (PEG) core via a modified chemo-enzymatic synthetic process. Rat hepatoma (N1S1) and human monocytic (U937) cell lines were used for cell culture-based assays and tested for DDV uptake and toxicity. Folate receptor expressions in liver tissues and cell lines were verified using standard immunohistochemistry techniques. Rat HCC model was used for in vivo assessment. The DDV was injected via intra-arterial or intravenous methods and imaged with IVIS spectrum in vivo imaging system. Strong signals of FITC in the liver tumor region correlated to targeted DDV uptake. The use of PEG enhanced water-solubility and provided flexibility for the interaction of FA ligands with multiple cell surface folate receptors that resulted in increased specific uptake. Our study suggested that PEG incorporation and folate targeting via intra-arterial approach is an efficient strategy for targeted delivery in HCC therapy.

Independent usefulness of flow phase 99mTc-red blood cell scintigraphy in predicting the results of angiography in acute gastrointestinal bleeding.

OBJECTIVE:: In acute gastrointestinal bleeding, despite positive dynamic phase 99mTc-red blood cell scintigraphy, invasive catheter angiography (CA) is frequently negative. In this study, we investigated the value of flow phase scintigraphy in predicting extravasation on CA. METHODS:: Institutional review board approval with a waiver of informed consent was obtained for this retrospective study. A total of 173 scintigraphy procedures performed in 145 patients with GIB between January 2013 and August 2014 were analysed. Scintigraphy had two phases: flow (1 image/s for 1 min) followed by dynamic (1 image/30 s for 1 h). Patients who underwent CA within 24 hours of positive scintigraphy were assessed. Each scintigraphy phase was randomly and independently reviewed by two nuclear medicine physicians blinded to the outcomes of the other phase and of CA. RESULTS:: A total of 42 patients (29%) had positive scintigraphy. Of these patients, 29 underwent CA, and extravasation was seen in 6 (21%). In all, dynamic phase scintigraphy was positive. 13 of the 29 patients also had positive flow phase scintigraphy. The sensitivity, specificity, positive-predictive value, and negative-predictive value of flow phase scintigraphy for extravasation on CA were 100, 70, 46, and 100%, respectively. Specificity and positive predictive value were higher when CA was performed within 4 hours of positive flow phase scintigraphy. CONCLUSIONS:: Negative flow phase scintigraphy can identify patients who will not benefit from CA despite positive dynamic phase scintigraphy. The likelihood of extravasation on CA is higher when performed soon after positive flow phase scintigraphy. ADVANCES IN KNOWLEDGE:: Negative flow phase scintigraphy identifies patients who will not benefit from invasive catheter angiography despite positive results on subsequent dynamic phase scintigraphy. Increasing the delay between positive red blood cell scintigraphy and catheter angiography progressively reduces the likelihood of identifying extravasation, which is required to target embolization.

Fibroblast Growth Factor-1 vs. Fibroblast Growth Factor-2 in Ischemic Skin Flap Survival in a Rat Animal Model.

BACKGROUND: One of the main challenges in skin flap surgery is tissue ischemia and following necrosis. The present study compares the effects of fibroblast growth factors 1 and 2 on increasing cutaneous vasculature, improving ischemia, and preventing distal necrosis in ischemic skin flaps in rat model. METHODS: Thirty rats were allocated into 3 groups (n=10) and 2×8 cm dorsal random-pattern skin flaps were raised after four daily subdermal injections of normal saline (control group), fibroblast growth factor 1 (FGF-1 group; 2.5 µg/day), or fibroblast growth factor 2 (FGF-2 group; 2.5 µg/day) at designated flap areas. Skin flap viability and number of blood vessels were evaluated on day 10 after elevation by planimetric analysis and histological examination. RESULTS: It was shown that administrations of FGF-1 and FGF-2 significantly decreased the percentage of flap necrosis and improved the percentage of ischemic survivable area, compared to the control samples. Meanwhile, the differences between these factors in terms of preventing skin flap necrosis and improving ischemia were also significant. The number of visible blood vessel sections was also higher in FGF-1 and FGF-2 groups than in the control group. CONCLUSION: These findings suggest that, while FGF-2 is still much more potent than FGF-1, treatment with either of these drugs could be very effective in increasing the survival of surgical flaps at risk (length to width ratio>3) in situations that other therapeutic options could not be considered.

Acceleration of skin wound healing with tragacanth (Astragalus) preparation: an experimental pilot study in rats.

Gum tragacanth is a natural complex mixture of polysaccharides and alkaline minerals extracted from species of Astragalus plant, which is found widely in arid regions of the Middle East. In a pilot experimental study we examined the effects of its topical application on wound healing in ten albino adult male rats. Two similar parasagittal elliptical full-thickness wounds (control vs. test samples) were created on the dorsum of each animal. Test group samples were fully covered by a thin layer of gum tragacanth daily. The extent of wound healing was evaluated by planimetric analysis on multiple occasions during the 10-day study period. On the 7th day of the study, the percent of wound closure was significantly higher in gum tragacanth-treated specimens compared to the control samples (87%±2% vs. 70%±4%, P<0.001). The majority of wounds in the test group were completely closed by the 10th day of the study. The difference in wound healing index measured by histological examination on day 10 of the study was also statistically meaningful between the two groups (0.624±0.097 vs. 0.255±0.063, P<0.05). The results of this study clearly showed the useful effects of topical application of gum tragacanth in acceleration of skin wound contraction and healing. More studies are encouraged to identify the implicating agents and precisely understand the mechanism by which they exert their wound healing effects.

A comparative study of recombinant human basic fibroblast growth factor (bFGF) and erythropoietin (EPO) in prevention of skin flap ischemic necrosis in rats.

BACKGROUND: Impaired wound healing in ischemic tissues such as skin flaps resulting from inefficient perfusion is one major cause of complications in plastic surgery. In present experimental study, we investigated the effects of fibroblast growth factor-2 (FGF-2 or bFGF) and erythropoietin (EPO) in prevention of skin flap necrosis in rats. METHODS: 30 adult albino rats were randomized into 3 groups: in control group, normal saline solution; in EPO group, erythropoietin (100U/kg/day); and in FGF-2 group, fibroblast growth factor-2 (2.5µg/day) were injected subcutaneously in 3 daily consecutive doses in the designated flap areas before creating 4:1 random pattern skin flaps on the dorsum of animals. Areas of ischemic (SI) and necrotic (SN) zones were measured and compared in all groups one week after the flap creations. RESULTS: The necrotic zone (SN), as well as the ratio of the necrotic zone to the total discolored zone (SN/[SI+SN]) were substantially larger in the control group (41%±7%, 90%±6%) compared to the EPO (20%±2%, 42%±4%)  and the FGF-2 (8%±2%, 19%±3%) groups (p<0.001). The differences in these values were also meaningful between the EPO and FGF-2 groups (p<0.001).Vascular density in ischemic area of the control group was less than those in the EPO and the FGF-2 groups; however, the differences were not statistically significant between any of the groups (p>0.05). CONCLUSIONS: Local administration of erythropoietin or fibroblast growth factor-2 in skin flaps could remarkably increase tissue viability and accelerate the wound healing process. However, the therapeutic effect of fibroblast growth factor-2 in preventing the necrotic event in ischemic zones of skin flaps is much more considerable than that of erythropoietin.

Endonasal laser-assisted microscopic dacryocystorhinostomy: surgical technique and follow-up results.

PURPOSE: Endonasal dacryocystorhinostomy is known as an increasingly attractive and effective approach for the surgical treatment of nasal duct obstruction with minimal complications and best cosmetic consequences. In a relatively large-scale case-series study over a 5-year period, we describe the surgical technique and 12-month follow-up results of microscopic laser dacryocystorhinostomy with particular regard to the effect of various pre-/postoperational factors (ie, patients' sex, age, symptoms chronicity, previous interventions, duration of silicone intubation) on the surgical outcome. MATERIALS AND METHODS: A total of 162 cases in 151 patients with chronic epiphora, mucocele, or recurrent episodes of dacryocystitis were included in the study. Endonasal laser dacryocystorhinostomy was performed using a surgical microscope with transcanalicular lacrimal sac illumination. The laser types used were potassium-titanyl-phosphate and neodymium:yttrium-aluminum-garnet for ablation of nasal mucosa and application to bone, respectively. Patients were evaluated 6 months and 1 year later. Data were analyzed by chi(2) tests. RESULTS: There were no major complications during or after the operations. Complete cure occurred in 89.5% (after 6 months) and 74.2% (after 1 year) of the cases. Anatomical patency was shown by lacrimal system irrigation with fluorescein in 81.5% of the cases after the 12-month follow-up. It was found that patients younger than 55 years, with symptoms lasting less than 1 year, and without history of nasal problems, had significantly higher surgical success rates (P < .05). Moreover, rates of failure were significantly lower in cases whose canaliculi were intubated for 5 to 6 months (P < .05). CONCLUSIONS: Endonasal microscopic laser dacryocystorhinostomy is a safe and minimally invasive procedure with reasonable results. It has many advantages over external or other conventional approaches. Successful results could be further enhanced by more wisely selecting the patients and by silicone extubation after 6 months.

Development of an ovine model of myocardial infarction.

BACKGROUND: We report experimental myocardial infarction by occluding coronary arteries in ovine models. METHODS: Twelve ewes were included in the study. After the chest was opened by left lateral thoracotomy incision, the second diagonal branch of the left anterior descending coronary artery was ligated at a point approximately 40% distant from its base. Prophylactic anti-arrhythmics were given. Animals were mechanically ventilated during surgery and stayed in intensive care unit for 24 h postoperation. Experiments were then evaluated by echocardiographic, electrocardiographic, haemodynamic, serological and morphological investigations. Echocardiographic measurements were repeated after 2 months and animals were then killed for post-mortem cardiac examinations. RESULTS: All animals survived the surgical procedure. Cyanotic discoloration and hypokinesia in the cardiac tissue in an area of (30 +/- 2) x (4 +/- 2) mm plus ST-segment elevations was detected immediately after vessel ligation. Moreover, there were pathological Q-waves 2 months later. Echocardiographic evaluations showed an average of 30% relative decrease in cardiac ejection fraction. Wall motion analysis showed anteroseptal hypokinesia and akinesia in all animals 1 day and 2 months after operation, respectively. Thin-walled infarcted areas with tissue fibrosis were evident in pathological investigations 2 months after surgery. CONCLUSION: In conclusion, we developed a practical and safe method for producing myocardial infarction in large animal models.