Developmental immunotoxicity of maternal exposure to yttrium nitrate on BALB/c offspring mice.

Yttrium is a typical heavy rare earth element with widespread use in numerous sectors. Only one previous study has indicated that yttrium has the potential to cause developmental immunotoxicity (DIT). Therefore, there remains a paucity of evidence on the DIT of yttrium. This study aimed to explore the DIT of yttrium nitrate (YN) and the self-recovery of YN-induced DIT. Dams were treated with 0, 0.2, 2, and 20 mg/kg bw/day YN by gavage during gestation and lactation. No significant changes were found in innate immunity between the control and YN-treated groups in offspring. In female offspring at postnatal day 21 (PND21), YN markedly inhibited humoral and cellular immune responses, the proliferative capacity of splenic T lymphocytes, and the expression of costimulatory molecules in splenic lymphocytes. Moreover, the inhibitory effect on cellular immunity in female offspring persisted to PND42. Unlike females, YN exposure did not change the adaptive immune responses in male offspring. Overall, maternal exposure to YN showed a strong DIT to offspring, with the lowest effective dose of 0.2 mg/kg in the current study. The toxicity of cellular immunity could persist throughout development into adulthood. There were sex-specific differences in YN-induced DIT, with females being more vulnerable.

Effectiveness of Nanohydroxyapatite on Demineralization of Enamel and Cementum Surrounding Margin of Yttria-Stabilized Zirconia Polycrystalline Ceramic Restoration.

INTRODUCTION: Prosthetic dentistry has shifted toward prevention of caries occurrence surrounding restorative margin through the anti-demineralization process. This study examines the ability of nanohydroxyapatite (NHA) gel and Clinpro (CP) on enhancing resistance to demineralization of enamel and cementum at margin of restoration. MATERIALS AND METHODS: Thirty extracted mandibular third molars were segregated at 1 mm above and below cementoenamel junction (CEJ) to separate CEJ portions and substituted with zirconia disks by bonding to crown and root portions with resin adhesive. The enamel and cementum area of 4 × 4 mm2 neighboring zirconia was applied with either NHA or CP, while one group was left no treatment (NT) before demineralized with carbopal. Vickers hardness (VHN) of enamel and cementum was evaluated before material application (B M), after material application (A M), and after demineralization (A D). Analysis of variance (ANOVA) and post hoc multiple comparisons were used to justify for the significant difference (α = 0.05). Scanning electron microscopy (SEM) and X-ray diffraction (XRD) were determined for surface evaluations. RESULTS: The mean ± SD of VHN for B M, A M, and A D for enamel and cementum was 393.24 ± 26.27, 392.89 ± 17.22, 155.00 ± 5.68 and 69.89 ± 4.59, 66.28 ± 3.61, 18.13 ± 0.54 for NT groups, respectively, 390.10 ± 17.69, 406.77 ± 12.86, 181.55 ± 7.99 and 56.01 ± 9.26, 62.71 ± 6.15, 19.09 ± 1.16 for NHA groups, respectively, and 387.90 ± 18.07, 405.91 ± 9.83, 188.95 ± 7.43 and 54.68 ± 7.30, 61.81 ± 4.30, 19.22 ± 1.25 for CP groups, respectively. ANOVA indicated a significant increase in anti-demineralization of enamel and cementum upon application of NHA or CP (p < 0.05). Multiple comparisons indicated the capability in inducing surface strengthening to resist demineralization for enamel and cementum of NHA which was comparable to CP (p > 0.05) as evidenced by SEM and XRD data indicating NHA and CP deposition and crystallinity accumulation. CONCLUSION: NHA and CP were capable of enhancing anti-demineralization for enamel and cementum. The capability in resisting the demineralization process of NHA was comparable with CP. NHA was highly recommended for anti-demineralization for enamel and cementum surrounding restorative margin.

Effect of brassica oleracea extract on the erythron state during chronic yttrium salt intake.

OBJECTIVE: Introduction: Yttrium compounds are known to be able to produce toxic effects on the body. This fact brings up the question of the development of preventive healthcare measures for those who can be exposed to the chemical element. The aim: The purpose of this work is to study the effect of broccoli extract on the state of erythron in animals exposed to chronic intake of a water-soluble yttrium compound. PATIENTS AND METHODS: Materials and methods: The series of experiments involved 16 white male rats, divided into 3 groups: intact rats; animals, which were administered yttrium acetate in a daily dose of 175 mg / kg body weight for 10 days; animals, which were given yttrium salt and dry extract of broccoli (Brassica oleracea L. var Italica Plenck) in a dose of 25 mg / kg body weight with food for 10 days. RESULTS: Results: Blood samples obtained were studied to evaluate red blood cells (RBC) count, hematocrit, total hemoglobin, RBC indices and reticulocyte content (Rt). The total number of karyocytes in the bone marrow of the femoral bone of the rats and their myelogram were investigated. The administration of yttrium acetate to the animals did not cause significant changes in "red" blood, but resulted in decreased Rt content compared with the intact control. There was a decrease in the karyocyte count in the bone marrow, the count of normoblasts and the total count of all erythroid cells. The use of the broccoli extract resulted in an increase in the blood Rt content in 1.4 times compared with the same level of yttrium loading without pharmacological correction. In the bone marrow of the animals of this group, the number of erythroid cells increased as well as the number of pro-normoblasts. CONCLUSION: Conclusions: The broccoli extract is able to reduce the negative effects produced by excess yttrium on erythropoiesis, contributing to the restoration of normal formation of reticulocytes and their release into the blood.

Epidermal grafting for leukoderma resulting from 1064-nm quality-switched neodymium-doped yttrium aluminium garnet laser toning.

Leukoderma secondary to Q-switched 1064-nm neodymium-doped yttrium aluminium garnet laser is usually refractory to treatment. The pathogenesis was cumulative phototoxic damage to melanocytes and eventually resulted in melanocytopenia. Wood's light or UV imaging can help observe early leukoderma before it becomes apparent clinically and determine the degree of melanocytopenia before conducting a biopsy. NB-UVB phototherapy and 308-nm excimer laser can potentially worsen the pre-existing melasma lesions and may not be effective if the lesions have already become melanocytopenic. Epidermal grafting can replenish the hypopigmented area with melanocytes without worsening melasma.

Effect of surface treatments on repair with composite resin of a partially monoclinic phase transformed yttrium-stabilized tetragonal zirconia.

STATEMENT OF PROBLEM: Studies of composite resin repairs of yttrium-tetragonal zirconia polycrystal (Y-TZP) are usually performed in its tetragonal phase, but it may be partially transformed into a monoclinic phase in a clinical fracture. PURPOSE: The purpose of this in vitro study was to evaluate the effect of airborne-particle abrasion (APA) and a bonding agent on the shear bond strength (SBS) between a composite resin and hydrothermally aged Y-TZP. MATERIAL AND METHODS: Specimens (7.0×7.0×1.7 mm, N=112) of Y-TZP Lava were obtained, and 50% were aged in an autoclave at 134°C at 300 kPa for 8 hours. The surfaces were treated with APA 50-µm Al2O3 particles (ALU) or Rocatec Soft (30 µm) (ROC) followed by Clearfil SE Bond Primer (10-methacryloyloxydecyl dihydrogen phosphate [10-MDP]) plus Clearfil porcelain bond activator (3-methacryloxypropyl-trimethoxy silane [3-MPS]) (CLE) or RelyX Ceramic Primer plus a layer of RelyX U100 adhesive-resin cement (REL). Composite resin cylinders were built on the Y-TZP treated surfaces. After thermocycling (6000 cycles, 5°C and 55°C, 30-second dwell time), an SBS test was carried out (n=14). Data were analyzed by 3-way ANOVA and the Tukey honest significant differences test (α=.05). The failure mode was analyzed. RESULTS: The 3-way ANOVA was not significant for aging (P>.05), but the APA (P<.001), bonding agent (P<.001), and their interaction (P<.001) were significant. APA with ALU or ROC did not influence the SBS of the groups bonded with CLE, but the REL APA with ROC provided higher SBS. The failure mode was adhesive for all specimens. CONCLUSIONS: Adhesion was not different on monoclinic partially transformed Y-TZP. The APA with ROC followed by REL was the most effective treatment for repairing Y-TZP.

Targeted Yttrium 89-Doxorubicin Drug-Eluting Bead-A Safety and Feasibility Pilot Study in a Rabbit Liver Cancer Model.

The purpose of this article is to evaluate feasibility and safety of the cancer targeting (radio)-chemoembolization drug-eluting bead (TRCE-DEB) concept drug SW43-DOX-L-NETA(89Y) DEB for the intra-arterial treatment of VX2 rabbit liver tumors. The treatment compound comprises of the sigma-2 receptor ligand SW43 for cancer targeting, doxorubicin (DOX), and 89yttrium (89Y) as nonradioactive surrogate for therapeutic (yttrium-90, lutetium-177) and imaging (yttrium-86) radioisotopes via the chelator L-NETA. Ten New Zealand white rabbits with VX2 tumor allografts were used. SW43-DOX-89Y was synthesized, loaded onto DEB (100 µL; 100-300 µm), and administered intra-arterially in six rabbits at increasing doses (0.2-1.0 mg/kg). As controls, two rabbits each received either doxorubicin IV (0.3 mg/kg) or no treatment. Consecutive serum analysis for safety and histopathological evaluation after sacrifice were performed. One-Way ANOVA incl. Bonferroni Post-Hoc test was performed to compare groups. Targeted compound synthesis, loading onto DEB, and intra-arterial administration were feasible and successful in all cases. Serum liver enzyme levels increased in a dose dependent manner within 24 h and normalized within 3 days for 0.2/0.6 mg/kg SW43-DOX-89Y loaded onto DEB. The two rabbits treated with 1 mg/kg SW43-DOX-89Y had to be euthanized after 3/24 h due to worsening general condition. Histopathological necrosis increased over time in a dose depended manner with 95-100% tumor necrosis 3-7 days post treatment (0.6 mg/kg). SW43-DOX-89Y loaded onto DEB can be formulated and safely administered at a concentration of 0.6 mg/kg. Loading with radioactive isotopes (e.g., 86yttrium/90yttrium/177lutetium) to synthesize the targeted radio-chemoembolization drug-eluting bead (TRCE-DEB) concept drug is feasible.

Glass Microspheres 90Y Selective Internal Radiation Therapy and Chemotherapy as First-Line Treatment of Intrahepatic Cholangiocarcinoma.

PURPOSE OF THE REPORT: Intrahepatic cholangiocarcinoma's incidence is increasing. We studied the efficacy of Y selective internal radiation therapy (SIRT) as first-line treatment, with chemotherapy, and compared with the results of chemotherapy alone. PATIENTS AND METHODS: We retrospectively studied data from patients treated at our institution with glass microspheres SIRT for intrahepatic cholangiocarcinoma as part of first-line treatment in combination with chemotherapy. We compared results with those of similar patients treated in the ABC-02 study (a study in advanced biliary tract cancer that defined the current standard chemotherapy), assessed as not progressing after the first evaluation. We assessed progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty-four patients were treated with SIRT. Chemotherapy was given concomitantly in 10 (42%), as induction before SIRT in 13 (54%) or after SIRT in 1 (4%). Grade 3 adverse events were reported in 1 (4%). Median PFS after SIRT was 10.3 months. Longer PFS was observed when chemotherapy was given concomitantly than when chemotherapy was given before SIRT, with respective median of 20.0 versus 8.8 months (P = 0.001). Median OS after SIRT was not reached. Eleven patients went to surgery (46%). Thirty-three patients in ABC-02 had locally advanced nonextrahepatic cholangiocarcinoma, not progressing after first evaluation. From the start of any treatment, the median PFS was 16.0 months in our cohort versus 11.3 months in ABC-02 (P = 0.25), whereas the median OS was significantly higher in our cohort, not reached versus 17.9 months, respectively (P = 0.026). CONCLUSIONS: Selective internal radiation therapy combined with concomitant chemotherapy seems a promising strategy as first-line treatment for unresectable intrahepatic cholangiocarcinoma.

In intermediate stage hepatocellular carcinoma: radioembolization with yttrium 90 or chemoembolization?

BACKGROUND & AIMS: Transarterial chemoembolization (TACE) is one of the standard treatments recommended for intermediate stage hepatocellular carcinoma (HCC). At the same time, only little is known about the use of radioembolization with Yttrium-90 microspheres (TARE Y-90) for this subset of patients. To perform comparative analysis between both locoregional therapies in intermediate HCCs. Primary endpoint was overall survival (OS), while safety, response rate and time-to-progression (TTP) were considered as secondary endpoints. METHODS: We collected data of 86 HCC patients in two university hospitals at which conventional TACE with doxorubicin or TARE Y-90 using glass microspheres were performed. The median observation period was 10 months. Patients were followed up for signs of toxicity and response. They underwent imaging analysis at baseline and follow-up at regular time intervals. RESULTS: Eighty-six HCC patients with intermediate stage B (BCLC) were treated with either TACE (n = 42) or TARE Y-90 (n = 44). Despite a higher tumour burden in the TARE Y-90 group, the median OS (TACE: 18 months vs. TARE Y-90: 16.4 months) and the median TTP (TACE: 6.8 months vs. TARE Y-90: 13.3 months) were not statistically different. The number of treatment sessions, the average rate of treatment sessions per patient, total hospitalization time and rate of adverse events were significantly higher in the TACE cohort. CONCLUSION: In intermediate HCC stage patients, both treatments resulted in similar survival probabilities despite more advanced disease in the TARE Y-90 group. Still, TARE Y-90 was better tolerated and associated with less hospitalization and treatment sessions.

Analysis of early morbidity and functional outcome of thulium: yttrium-aluminum-garnet laser enucleation for benign prostate enlargement: patient age and prostate size determine adverse surgical outcome.

OBJECTIVE: To evaluate complications and functional outcome and to identify patient-associated risk factors, we analyzed consecutive patients undergoing thulium:yttrium-aluminum-garnet laser enucleation of the prostate (ThuLEP) in our department. METHODS: A total of 234 patients were prospectively analyzed. Preoperative data, postoperative complications, and outcome at 6, 12, and 24 months were recorded. Individual risk factors for complications and treatment failure were assessed by univariate and multivariate analyses. RESULTS: Mean age at surgery was 72.88 ± 7.83 years. Mean preoperative prostate size was 84.8 ± 34.9 mL. Thirty-day complication rate was 19.7%. Functional treatment failure occurred in 9.0% of all patients. Decline of mean International Prostate Symptom Score was -75%, quality of life index -76%, and postvoid residual -86% at 24 months. Maximum urine flow at 24 months was improved at +231%. In univariate analysis, age >80 years and prostate size <50 mL were significant predictors of complications, which was confirmed by multivariate analysis (P = .0277 and .0409, respectively). Age >80 years, prostate size <80 mL or <50 mL, and American Society of Anesthesiologists classification were significant predictors of functional treatment failure in univariate analysis. Prostate size <80 mL or <50 mL was significantly associated with treatment failure (P < .001) in multivariate analysis. CONCLUSION: ThuLEP is a safe and efficient surgical procedure, even in a patient cohort with high prostate volumes, age, and comorbidities. However, high patient age and small prostate size were significant determinants of adverse outcomes after surgery. To address the question of optimal therapy selection for patients with prostates smaller than 80 mL, further prospective randomized evaluation of ThuLEP and alternative surgical interventions is needed.

Safety and toxicity of radioembolization plus Sorafenib in advanced hepatocellular carcinoma: analysis of the European multicentre trial SORAMIC.

BACKGROUND & AIMS: The benefits of combined systemic and liver-directed treatments in inoperable intermediate- or advanced-stage hepatocellular carcinoma (HCC) have yet to be defined. This article presents the planned safety analyses for the first 40 patients randomized to radioembolization with yttrium-90 ((90) Y) resin microspheres followed by sorafenib (n = 20) or sorafenib only (n = 20) in the SORAMIC study. METHODS: Patients identified for palliative treatment who were poor candidates for transarterial (chemo)embolization (including those failing TACE) with preserved liver function (Child-Pugh ≤B7) and ECOG performance status <2 were screened. Radioembolization was administered using a sequential lobar approach. On day 3 after the last radioembolization procedure, sorafenib 200 mg twice daily was initiated escalating to 400 mg twice daily 1 week later; a matching sorafenib dose schedule was initiated in the control arm. RESULTS: Patients were followed up for a median of 8.3 months. Median total implanted activity of (90) Y was 1.87 (range: 0.54-2.35) GBq. Patients received a similar intensity and duration of sorafenib in the combination-treatment arm (median daily dose 614 mg over 8.5 months) and control arm (557 mg over 9.6 months). The incidence of total (196 vs. 222) and grade ≥3 (43 vs. 47) adverse events was similar in combination-treatment arm and control arm respectively (P > 0.05). No significant differences in the number of total or grade 3/4 toxicities were recorded for: total bilirubin, albumin, liver enzymes, ascites, Child-Pugh, fatigue, hand-foot skin reaction, blood pressure or diarrhoea. CONCLUSIONS: Radioembolization followed by sorafenib appears to be as well tolerated as sorafenib alone.

Adverse events resulting from lasers used in urology.

OBJECTIVE: To collate world reports of adverse events (AEs) resulting from lasers used in urology. METHODS: The Manufacturer and User Facility Device Experience (MAUDE) database of the United States Food and Drug Administration (FDA) was searched using the term "Laser for gastro-urology use." In addition, the Rockwell Laser Industries (RLI) Laser Accident Database was searched for the following types of lasers: neodymium-doped yttrium aluminum garnet (Nd:YAG), holmium:yttrium aluminum garnet (Ho:YAG), potassium titanyl phosphate (KTP), diode and thulium:YAG (Tm:YAG). RESULTS: Both databases were last accessed on October 1, 2012. Overall, there were 433 AEs; 166 in MAUDE database (1992-2012) and 267 in RLI database (1964-2005). Most of the AEs (198/433 or 46%) resulted from generator failure or fiber tip breaking. Whereas there were 20 (4.6%) AEs harming medical operators, there were 159 (37%) AEs harming nonmedical operators using Nd:YAG, KTP, and diode lasers. Eye injuries ranging from mild corneal abrasions to total vision loss were reported in 164 AEs with the use of Nd:YAG, KTP, and diode lasers. Overall, there were 36 (8.3%) AEs resulting in patient harm, including 7 (1.6%) mortalities, 3 deaths from ureteral perforation using the Ho:YAG laser, and 4 deaths from air emboli using the Nd:YAG laser. Other reported patient injuries included bladder perforation resulting in urinary diversion in a patient, in addition to minor skin burns, internal burns, and bleeding in others. There were no AEs reported with the use of Tm:YAG laser. CONCLUSIONS: Most of the AEs reported relate to equipment failure. There were no eye injuries reported with the use of Ho:YAG lasers. Caution must be exercised when using lasers in urology, including wearing appropriate eye protection when using Nd:YAG, KTP, and diode lasers.

One-piece zirconia oral implants: one-year results from a prospective cohort study. 1. Single tooth replacement.

AIM: To investigate the clinical and radiographic outcome of a one-piece zirconia oral implant for single tooth replacement after 1 year. MATERIALS AND METHODS: A total of 65 patients received a one-stage implant surgery with immediate temporization. Standardized radiographs were taken at implant insertion and after 1 year to monitor peri-implant bone loss. A univariate analysis of the influence of different baseline parameters on marginal bone loss from implant insertion to 12 months was performed. Soft tissue parameters were evaluated at prosthesis insertion and at the 1-year follow-up. RESULTS: After 1 year, three implants were lost, giving a cumulative survival rate of 95.4%. The marginal bone loss after 1 year was 1.31 mm. Thirty-four per cent of the implants lost at least 2 mm bone, and 14% more than 3 mm. The univariate analysis could not depict any parameter influencing marginal bone loss. Probing depth, Clinical Attachment Level, Bleeding and Plaque Index decreased over 1 year. CONCLUSIONS: The cumulative survival rate of the presented ceramic implant was comparable to the reported survival rate of titanium implants when immediately restored. However, the frequency of increased radiographic bone loss (>2 mm) after 1 year was considerably higher as compared to conventional two-piece titanium implants. The presented zirconia implant can therefore not be recommended for clinical usage.

Radioembolization with use of yttrium-90 resin microspheres in patients with hepatocellular carcinoma and portal vein thrombosis.

PURPOSE: Intraarterial delivery of yttrium-90 ((90)Y)-bound microspheres (ie, radioembolization) is a promising treatment for hepatocellular carcinoma (HCC). An early concern was the "embolic" nature of the microspheres, and their potential to reduce hepatic arterial blood flow in patients with compromised portal blood flow secondary to portal vein thrombosis/occlusion (PVT). In this situation, the risk of liver failure could be enhanced, particularly in patients with cirrhosis who have increased hepatic arterial blood flow. This retrospective analysis was undertaken to assess the safety and clinical benefits of radioembolization with (90)Y resin microspheres in HCC with branch or main PVT. MATERIALS AND METHODS: A total of 25 patients presenting with unresectable HCC and compromised portal flow received segmental, lobar, or whole-liver infusion of (90)Y resin microspheres. For the analysis of tumor response, changes in target lesions, appearance of new lesions, and changes in portal vein thrombus were studied. Controlled disease was defined by absence of progression in all these components. RESULTS: Globally, controlled disease was achieved in 66.7% of patients at 2 months and 50% of patients at 6 months. No significant changes were observed in liver-related toxicities according to Common Toxicity Criteria (version 3.0) at 1 and 2 months after treatment. Median survival time was 10 months (95% CI, 6.6-13.3 months). CONCLUSIONS: Radioembolization of unresectable HCC and branch or main PVT with (90)Y resin microspheres was associated with minimal toxicity and a favorable median survival time. Further prospective studies are warranted to validate the findings in this clinically challenging patient population.

Safety of yttrium-90 microsphere radioembolization in patients with biliary obstruction.

PURPOSE: There are few data on radioembolization in the setting of biliary obstruction. The present study was performed to assess the safety of yttrium-90 ((90)Y) radioembolization in the setting of tumor-related biliary obstruction and total bilirubin levels of 2 mg/dL or lower. MATERIALS AND METHODS: Twelve patients with liver tumors underwent 19 treatment sessions with (90)Y to the obstructed liver lobe or segment. Initial bilirubin level was 2 mg/dL or lower in all cases. Measured outcomes included pre- and posttreatment white blood cell (WBC) count, total bilirubin level, and alkaline phosphatase (ALP) level. Bilirubin toxicities and biliary complications were assessed according to Common Toxicity Criteria, version 3.0. RESULTS: Lobar or segmental (90)Y was successful in all cases. Pre- and posttreatment median WBC counts (5.3 vs 5.3; P = .490), bilirubin levels (1.0 vs 1.1; P = .460), and ALP levels (195 vs 146; P = .712) showed no differences. One case of grade 3 bilirubin toxicity was noted in a patient with liver hilar nodal progression and subsequent biliary obstruction requiring external drainage. Complete resolution of biliary obstruction was seen after (90)Y treatment in one case of metastatic colorectal carcinoma at 1 month follow-up. No biliary complications (infection, sepsis, biliary necrosis, biloma formation, abscess development, or biliary stricture) were encountered in this cohort during an overall median follow-up time of 22.9 months. CONCLUSIONS: The use of (90)Y glass microspheres demonstrated a good safety profile in the setting of tumor-related biliary obstruction in patients with normal or near-normal bilirubin levels in this series, without evidence of therapy-related progressive leukocytosis, bilirubin increase, or infectious or biliary complications after treatment.

Computer modeling of controlled microsphere release and targeting in a representative hepatic artery system.

Combating liver tumors via yttrium-90 ((90)Y) radioembolization is a viable treatment option of nonresectable liver tumors. Employing clinical (90)Y microparticles (i.e., SIR-Spheres and TheraSpheres) in a computational model of a representative hepatic artery system, laminar transient 3D particle-hemodynamics were simulated. Specifically, optimal particle release positions in the right hepatic (parent) artery as well as the best temporal release window were determined for the microspheres to exit specific outlet daughter vessels, potentially connected to liver tumors. The results illustrate the influence of a curved geometry on the velocity field and the particle trajectory dependence on the spatial and temporal particle injection conditions. The differing physical particle characteristics of the SIR-Spheres and the TheraSpheres had a subtle impact on particle trajectories in the decelerating portion of the arterial pulse, i.e., when the inertial forces on the particles are weaker. Conversely, particle characteristics and inelastic wall collisions had little effect on particles released during the accelerating phase of the arterial pulse, i.e., both types of microspheres followed organized paths to predetermined outlets. Such results begin paving the way towards directing 100% of the released microspheres to specific daughter vessels (e.g., those connected to tumors) under transient flow conditions in realistic geometries via a novel drug-particle targeting methodology.

Folate receptor targeted, rare-earth oxide nanocrystals for bi-modal fluorescence and magnetic imaging of cancer cells.

Targeted cancer imaging using rare-earth oxide nanocrystals, free from heavy metals (Cd, Se, Te, Hg and Pb), showing bright red-fluorescence and magnetic resonance imaging (MRI) is presented. Y(2)O(3) nanocrystals (YO NC) doped in situ with fluorescent (Eu(3+)) and paramagnetic (Gd(3+)) impurities and conjugated with a potential cancer targeting ligand, folic acid (FA), were prepared using an all-aqueous wet-chemical process. Structural, optical and magnetic properties of these multifunctional nanocrystals were investigated by X-ray diffraction, electron microscopy, photoluminescence and magnetization studies. Highly monodisperse nanocrystals of size approximately 20 nm with cubic bixbyite crystal structure showed bright red-fluorescence when doped with Eu(3+). Co-doping with Gd(3+) and mild air drying resulted significantly enhanced fluorescence quantum efficiency of approximately 60% together with paramagnetic functionality, enabling T(1)-weighted MR contrast with approximately 5 times higher spin-lattice relaxivity compared to the clinically used Gd(3+) contrast agent. Cytotoxicity and reactive oxygen stress studies show no toxicity by YO NC in both normal and cancer cells up to higher doses of 500 microm and longer incubation time, 48h. Cancer targeting capability of FA conjugated NCs was demonstrated on folate receptor positive (FR+) human nasopharyngeal carcinoma cells (KB) with FR depressed KB (FRd) and FR negative (FR-) lung cancer cells A549 as controls. Fluorescence microscopy and flow-cytometry data show highly specific binding and cellular uptake of large concentration of FA conjugated NCs on FR+ve cells compared to the controls. Thus, the present study reveals, unique bi-modal contrast imaging capability, non-toxicity and cancer targeting capability of multiple impurities doped rare-earth oxide nanocrystals that can find promising application in molecular imaging.

Genotoxic effects of 1064-nm Nd:YAG and 532-nm KTP lasers on fibroblast cell cultures.

BACKGROUND: Several different laser types are used in cutaneous surgery. The neodymium:yttrium-aluminium-garnet (Nd:YAG) and frequency-doubled Nd:YAG (KTP, potassium titanyl phosphate) lasers are widely used in dermatology. OBJECTIVES: To investigate the possible genotoxic effects on fibroblasts of irradiation with a 1064-nm Nd:YAG laser and a 532-nm KTP laser. METHODS: Fibroblast cell cultures were exposed to each of the lasers, using 10-mm spot size at 60 ms pulse duration with 10, 20, 40 J/cm(2) and 3, 6, 12 J/cm(2) fluences, respectively. Fibroblasts in passages 1-6 were used. During laser irradiation, 96-well microplate cultures were kept on a cooling block and transported on ice and in the dark, and processed immediately for single-cell gel electrophoresis (SCGE) assay (also known as a comet assay). RESULTS: DNA damage was determined by computerized assessment of comet assay. There was increasing damage with increasing numbers of passages. For the Nd:YAG laser, the greatest damage occurred on passages 5 and 6, whereas the greatest damage appeared at passages 3 and 4 for KTP and returned to baseline at passages 5 and 6. Damage also increased with each dose increment for both wavelengths. At the highest dose for both wavelengths (Nd:YAG 40 J/cm(2) and KTP 12 J/cm(2)), damage was higher with the Nd:YAG laser. CONCLUSIONS: Different patterns of cellular damage were seen for different cell-culture passages, treatment doses, and laser wavelengths. These dose ranges are generally used for the treatment of vascular and pigmented lesions and for rejuvenation purposes. As replicative ageing or cell senescence is one of the critical factors determining the extent of cell damage induced by laser therapy, these results may have important implications for clinical practice.

Safety and efficacy of Y-90 microsphere treatment in patients with primary and metastatic liver cancer: the tumor selectivity of the treatment as a function of tumor to liver flow ratio.

BACKGROUND: Treatment records and follow-up data on 40 patients with primary and metastatic liver malignancies who underwent a single whole-liver treatment with Y-90 resin microspheres (SIR-Spheres Sirtex Medical, Lake Forest, IL) were retrospectively reviewed. The objective of the study was to evaluate the anatomic and physiologic determinants of radiation dose distribution, and the dose response of tumor and liver toxicity in patients with liver malignancies who underwent hepatic arterial Y-90 resin microsphere treatment. METHODS: Liver and tumor volume calculations were performed on pre-treatment CT scans. Fractional tumor and liver flow characteristics and lung shunt fractions were determined using hepatic arterial Tc-99m MAA imaging. Absorbed dose calculations were performed using the MIRD equations. Liver toxicity was assessed clinically and by liver function tests. Tumor response to therapy was assessed by CT and/or tumor markers. RESULTS: Of the 40 patients, 5 had hepatocellular cancer (HCC), and 35 had metastatic liver tumors (15 colorectal cancer, 10 neuroendocrine tumors, 4 breast cancer, 2 lung cancer, 1 ovarian cancer, 1 endometrial cancer, and 2 unknown primary adenocarcinoma). All patients were treated in a salvage setting with a 3 to 80 week follow-up (mean: 19 weeks). Tumor volumes ranged from 15.0 to 984.2 cc (mean: 294.9 cc) and tumor to normal liver uptake ratios ranged from 2.8 to 15.4 (mean: 5.4). Average administered activity was 1.2 GBq (0.4 to 2.4 GBq). Liver absorbed doses ranged from 0.7 to 99.5 Gy (mean: 17.2 Gy). Tumor absorbed doses ranged from 40.1 to 494.8 Gy (mean: 121.5 Gy). None of the patients had clinical venoocclusive disease or therapy-induced liver failure. Seven patients (17.5 %) had transient and 7 patients (17.5 %) had persistent LFT abnormalities. There were 27 (67.5%) responders (complete response, partial response, and stable disease). Tumor response correlated with higher tumor flow ratio as measured by Tc-99m MAA imaging. CONCLUSION: Doses up to 99.5 Gy to uninvolved liver are tolerated with no clinical venoocclusive disease or liver failure. The lowest tumor dose producing a detectable response is 40.1 Gy. The utilization of MAA-based imaging techniques to determine tumor and liver blood flow for clinical treatment planning and the calculation of administered activity may improve clinical outcomes.

Effect of calcium trisodium DTPA in rats with puncture wound contaminated by 90Y-chloride.

The efficacy of diethylenetriaminepentaacetate calcium trisodium (CaNa(3)DTPA) in a dose of 34.7 micromol kg(-1) as a function of its route of administration was investigated in rats with a puncture wound contaminated by (90)Y-chloride at a concentration of 2.55 MBq kg(-1). Approximately 60% of (90)Y-chloride at a puncture wound was absorbed into the body of rats over 72 h post-puncture and radioactivity in femoral bone increased during the timed-release of (90)Y. Intravenous administration of CaNa(3)DTPA (systemic treatment) at 15 min post-puncture reduced (90)Y at a puncture wound and in bone up to 75.6 and 84.3% of controls, respectively. Direct infiltration of CaNa(3)DTPA into a puncture wound site (local treatment) at 15 min post-puncture diminished radioactivity at the puncture wound and in bone up to 34.9 and 52.5% of controls, respectively. Thus, prompt local treatment may be effective for removing (90)Y from a puncture wound and minimising (90)Y-distribution to bone compared with systemic treatment.