Endocytosis of indium-tin-oxide nanoparticles by macrophages provokes pyroptosis requiring NLRP3-ASC-Caspase1 axis that can be prevented by mesenchymal stem cells.

The biological effects of indium-tin-oxide (ITO) are of considerable importance because workers exposed to indium compounds have been diagnosed with interstitial lung disease or pulmonary alveolar proteinosis; however, the pathophysiology of these diseases is undefined. Here, mice intraperitoneally inoculated with ITO-nanoparticles (ITO-NPs) resulted in peritonitis dependent in NLRP3 inflammasome, with neutrophils recruitment and interleukin-1ß (IL-1ß) production. Withal peritoneal macrophages exposed ex vivo to ITO-NPs caused IL-1ß secretion and cytolysis. Further, alveolar macrophages exposed to ITO-NPs in vitro showed ITO-NP endocytosis and production of tumor necrosis factor-α (TNF-α) and IL-1ß, ensued cell death by cytolysis. This cell death was RIPK1-independent but caspase1-dependent, and thus identified as pyroptosis. Endocytosis of ITO-NPs by activated THP-1 cells induced pyroptosis with IL-1ß/TNF-α production and cytolysis, but not in activated THP-1 cells with knockdown of NLRP3, ASC, or caspase1. However, exposing activated THP-1 cells with NLRP3 or ASC knockdown to ITO-NPs resulted in cell death but without cytolysis, with deficiency in IL-1ß/TNF-α, and revealing features of apoptosis. While, mesenchymal stem cells (MSCs) co-cultured with macrophages impaired both inflammation and cell death induced by ITO-NPs. Together, our findings provide crucial insights to the pathophysiology of respiratory diseases caused by ITO particles, and identify MSCs as a potent therapeutic.

Tailoring 99mTc-Macroaggregated Albumin Administration to Optimize Patient Dose Reduction.

UNLABELLED: In the ever-changing field of nuclear medicine, best-practice considerations cannot simply go unchallenged for months and years, with the need to minimize radiation exposure to patients highlighted in "as low as reasonably achievable" principles. The Australian Radiation Protection and Nuclear Safety Agency reports that the dose for (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) administered should be 180-200 MBq. An objective of imaging in pulmonary embolism, or indeed any diagnostic procedure involving radiation, is to minimize radiation exposure without sacrificing image quality and diagnostic accuracy. The amount of radiation involved must be considered together with imaging protocols. Our aim was to reduce the amount of (99m)Tc-MAA administered without compromising the diagnostic quality of the scan. METHODS: To achieve a ventilation-to-perfusion ratio of 1:4, we ventilated the patient as per standard protocol and then placed intravenous access into the patient. For the perfusion component, 180-200 MBq were prepared in a 2-mL injection. Aliquots of 0.5 mL of (99m)Tc-MAA were administered every 30 s followed by a 5-mL saline flush until the required ventilation-to-perfusion ratio was achieved. RESULTS: With this protocol, the average administered dose was 105 ± 20.7 MBq (vs. 180 ± 5.3 MBq, P < 0.0001). CONCLUSION: By individually tailoring the administered dose, diagnostic quality is maintained while achieving a significant dose reduction.

Sentinel lymph node identification with radiopharmaceuticals in patients with breast cancer: a comparison of 99mTc-tin colloid and 99mTc-phytate efficiency.

Sentinel lymph node biopsy with lymphoscintigraphy has become the standard method for the detection of axillary lymph node metastasis in breast cancer patients. However, there is no standardized radiopharmaceutical. For the detection of axillary lymph node metastasis by lymphoscintigraphy and sentinel node biopsy in patients with breast cancer, we compared the results between subareolar injection of (99m)Tc-tin colloid and injection of (99m)Tc-phytate. This study included 516 breast cancer patients who underwent surgery between 2001 and 2010. Among the 516 patients, (99m)Tc-tin colloid (37-185 MBq) was administered to 412 patients by subareolar injection, and (99m)Tc-phytate (37-185 MBq) was injected in 104 patients. Lymphoscintigraphy was performed with the patients in the supine position, and sentinel node identification was performed by hand-held gamma probe during surgery. Among 412 patients with (99m)Tc-tin colloid, the sentinel node was identified by lymphoscintigraphy in 364 cases (88.3%) and by a gamma probe in 369 cases (89.6%). Among 104 patients with (99m)Tc-phytate, 101 cases (97.1%) were identified by lymphoscintigraphy and 101 cases (97.1%) were identified by a gamma probe. The identification rates by lymphoscintigraphy and gamma probe were superior with (99m)Tc-phytate, as compared with (99m)Tc-tin colloid, with a statistically significant difference (P < 0.05 for both methods). (99m)Tc-phytate is a better choice than (99m)Tc-tin colloid for identification of the sentinel node in breast cancer patients.

Endonuclease IV is the main base excision repair enzyme involved in DNA damage induced by UVA radiation and stannous chloride.

Stannous chloride (SnCl(2)) and UVA induce DNA lesions through ROS. The aim of this work was to study the toxicity induced by UVA preillumination, followed by SnCl(2) treatment. E. coli BER mutants were used to identify genes which could play a role in DNA lesion repair generated by these agents. The survival assays showed (i) The nfo mutant was the most sensitive to SnCl(2); (ii) lethal synergistic effect was observed after UVA pre-illumination, plus SnCl(2) incubation, the nfo mutant being the most sensitive; (iii) wild type and nfo mutants, transformed with pBW21 plasmid (nfo(+)) had their survival increased following treatments. The alkaline agarose gel electrophoresis assays pointed that (i) UVA induced DNA breaks and fpg mutant was the most sensitive; (ii) SnCl(2)-induced DNA strand breaks were higher than those from UVA and nfo mutant had the slowest repair kinetics; (iii) UVA + SnCl(2) promoted an increase in DNA breaks than SnCl(2) and, again, nfo mutant displayed the slowest repair kinetics. In summary, Nfo protects E. coli cells against damage induced by SnCl(2) and UVA + SnCl(2).

Chronic pulmonary toxicity study of indium-tin oxide and indium oxide following intratracheal instillations into the lungs of hamsters.

OBJECTIVES: The aim of this study was to clarify the chronic toxicological effects of indium-tin oxide (ITO) and indium oxide (In(2)O(3)) on laboratory animals. METHODS: Male Syrian golden hamsters were intratracheally administered 3 mg/kg or 6 mg/kg of ITO particles, or 2.7 mg/kg or 5.4 mg/kg of In(2)O(3) particles, containing 2.2 mg/kg or 4.5 mg/kg of indium, twice a week, for 8 wk. Control hamsters were given vehicle of distilled water only. The hamsters were euthanized serially up to 78 wk after the final instillation and the toxicological effects were determined. RESULTS: Body weight gain was significantly suppressed in the ITO 6 mg/kg-treated hamsters compared with the control group, but not in the ITO 3 mg/kg-treated or In(2)O(3)-treated hamsters. Relative lung weights among all the indium-treated groups were significantly increased compared to that in the control group throughout the observation period. The serum indium concentration among all the indium-treated groups gradually increased up to the end of the observation period. Histopathologically, foci of slight to severe pulmonary inflammatory response with diffuse alveolar or bronchiolar cell hyperplasia, expansion of the alveolar spaces and interstitial fibrotic proliferation were present in all the indium-treated hamsters and the severity of these lesions worsened with the passage of time. Lung benign adenomas were only manifest in 3 out of 15 of the ITO 6 mg/kg-treated hamsters. CONCLUSIONS: The present results clearly demonstrate that ITO and In(2)O(3) particles caused chronic pulmonary toxicity when repeated intratracheal instillations were given to hamsters.

Comparison of subareolar injection lymphoscintigraphy with the 1-day and the 2-day protocols for the detection of sentinel lymph nodes in patients with breast cancer.

OBJECTIVE: Lymphoscintigraphy and sentinel node biopsy are used for the detection of axillary lymph node metastasis in breast cancer patients. However, currently there is no standardized technique. For the detection of axillary lymph node metastasis by lymphoscintigraphy and sentinel node biopsy, in patients with breast cancer, we compared the results of subareolar injections administered on the day of surgery (1-day protocol) with injections administered on the day before surgery (2-day protocol). MATERIALS AND METHODS: This study included 412 breast cancer patients who underwent surgery between 2001 and 2004. For the 1-day protocol (1 h before surgery) 0.8 ml of Tc-99m Tin-Colloid (37 MBq) was injected in 203 in the subareolar region on the morning of the surgery. For the 2-day protocol (16 h before surgery) 0.8 ml of Tc-99m Tin-Colloid (185 MBq) was injected in 209 patients on the afternoon before surgery. Lymphoscintigraphy was performed in the supine position and sentinel node identification was performed by hand-held gamma probe during surgery. RESULTS: Among 203 patients with the 1-day protocol, 185 cases (91.1%) were identified by sentinel node lymphoscintigraphy, and 182 cases (89.7%) were identified by gamma probe. Among the 209 patients, in the 2-day protocol, 189 cases (90.4%) had the sentinel node identified by lymphoscintigraphy, and 182 cases (87.1%) by the gamma probe. There was no significant difference in the identification rate of the sentinel node between the 1-day and 2-day protocols by lymphoscintigraphy and the gamma probe (p > 0.05, p > 0.05). CONCLUSIONS: The results of the identification of the sentinel node by subareolar injection according to 1-day or 2-day protocol, in breast cancer patients, showed no significant differences. Because the 2-day protocol allows for an adequate amount of time to perform the lymphoscintigraphy, it is a more useful protocol for the identification of sentinel nodes in patients with breast cancer.

CT-guided lymphoscintigraphy in patients with squamous cell carcinoma of the head and neck: a feasibility study.

Accurate knowledge of lymphatic drainage facilitates planning of surgery for patients with squamous cell carcinoma of the head and neck. The aim of this study was to evaluate the feasibility of a new injection technique for lymph node detection in patients with squamous cell carcinoma of the hypopharynx and larynx, in whom simple peritumoural injection is hampered by the tumour localisation. Computed tomography (CT)-guided lymphoscintigraphy was performed in a total of 13 patients with squamous cell carcinoma of the hypopharynx and larynx who could not be injected by simple visual inspection. In a first step, contrast medium-enhanced axial 5-mm-thick CT slices of the neck were obtained. After tumour localisation on these CT images, 1-2 ml contrast medium and, in the event of appropriate distribution, subsequently 50 MBq technetium-99m colloid were injected at one to three peritumoural sites under CT guidance. Peritumoural tracer distribution was controlled by thin-slice CT. Subsequently, planar scintigrams from anterior, right and left lateral views were obtained. In all patients, peritumoural colloid application was feasible, as shown on control CT scans. Post injection, neither severe nor minor complications were noted. The patients complained of only low pain sensations with an average score of 1.8 on a pain scale from 0 to 10. Lymphatic drainage was identified in nine of the 13 patients, with a total of 14 detected lymph nodes. In six patients, ipsilateral sentinel lymph nodes were visualised; bilateral sentinel lymph nodes were identified in one patient and contralateral lymphatic drainage was observed in two patients. CT-guided lymphoscintigraphy is a feasible and minimally invasive diagnostic tool for sentinel lymph node detection in patients with squamous cell carcinoma of the hypopharynx and the larynx. In contrast to endoscopic colloid injection under general anaesthesia, this technique seems to be a well-tolerated method for lymphatic mapping prior to surgical procedures.

Lymphoscintigraphic visualization of internal mammary nodes with subtumoral injection of radiocolloid in patients with breast cancer.

OBJECTIVE: To determine whether subtumoral injection of radiocolloid is useful for lymphoscintigraphic visualization of the internal mammary node and in sentinel lymph node (SLN) biopsy of the axilla in breast cancer patients. SUMMARY BACKGROUND DATA: The presence of retromammary lymphatics connecting to the axillary and internal mammary basins has been demonstrated by early anatomic studies. Thus, it is hypothesized that some lymph, especially that from the parenchyma under the tumor, may drain into both the axillary and internal mammary basins. METHODS: Patients (n = 196) with T1-2, N0 breast cancer underwent preoperative lymphoscintigraphy with radiocolloid (technetium 99m tin colloid) injection into various sites of the breast, followed by SLN biopsy using the combined method with blue dye. Patients were divided into four groups: group A (n = 41), peritumoral injection of both radiocolloid and blue dye; group B (n = 70), periareolar radiocolloid and peritumoral blue dye; group C (n = 45), intradermal radiocolloid and periareolar blue dye; and group D (n = 40), subtumoral radiocolloid and intradermal blue dye. A retrospective analysis of 1,297 breast cancer patients who underwent extended radical mastectomy with internal mammary node dissection was also conducted to determine the relationship between vertical tumor location (superficial or deep) and frequency of axillary and internal mammary node metastases. RESULTS: One patient (2%) in group A, 3 (4%) in group B, 0 (0%) in group C, and 15 (38%) in group D exhibited hot spots in the internal mammary region on lymphoscintigraphy (P <.001, group D vs. the other groups). The concordance rate of radiocolloid and blue dye methods in detection of SLNs in the axillary basin was significantly lower in group D than in the other groups. In contrast, the mismatch rate (some SLNs were identified by radiocolloid and other SLNs were identified by blue dye, but no SLN was identified by both in the same patient) was significantly higher in group D than in the other groups. In patients treated with extended radical mastectomy, positivity of axillary and internal mammary metastases was significantly higher in patients (n = 215) with deep tumors than those (n = 368) with superficial tumors. CONCLUSIONS: These results suggest the presence of a retromammary lymphatic pathway from the deep portion of the breast to both axillary and internal mammary basins, which is distinct from the superficial pathway. Therefore, SLN biopsy with a combination of subtumoral and other (peritumoral, dermal, or areolar) injections of radiocolloid will improve both axillary and internal mammary nodal staging.

Intradermal radioisotope injection is superior to subdermal injection for the identification of the sentinel node in breast cancer patients.

BACKGROUND AND OBJECTIVES: The purpose of the present study was to evaluate whether the intradermal injection of radiocolloids would improve the identification rate of sentinel nodes over the subdermal injection in breast cancer patients. METHODS: Sentinel node biopsy was performed in T2 breast cancer patients with clinically negative nodes, using subdermal or intradermal injection of radioisotopes with the peritumoral dye injection. We used Tc-99m tin colloid, with a larger particle size (0.4-5 microm), rather than sulfur colloid and colloidal albumin. RESULTS: The initial 55 patients underwent subdermal injection of radiocolloids; the next 61 patients underwent intradermal injection of radiocolloids for sentinel node biopsy. The detection rate of sentinel nodes was significantly (P = 0.048) higher in the intradermal injection group (61/61, 100%) than in the subdermal injection group (51/55, 92.7%). False-negative rates were comparable between the two groups. Lymphoscintigraphy visualized the sentinel nodes significantly (P < 0.0001) more often in the intradermal injection group (59/61, 96.7%) than in the subdermal injection group (20/54, 37.0%). CONCLUSIONS: A significantly higher identification rate of sentinel node biopsy and lymphoscintigraphy can be achieved by intradermal injection of Tc-99m tin colloid with a large particle size than by subdermal injection.

Comparison between periareolar and peritumoral injection of radiotracer for sentinel lymph node biopsy in patients with breast cancer.

BACKGROUND: The technique of sentinel lymph node (SLN) biopsy in patients with breast cancer varies among reports, and the optimal method remains to be established, particularly with regard to the site of radiotracer injection. The aim of this study was to compare periareolar and peritumoral injection of radiotracer in detecting SLN in patients with breast cancer. METHODS: Patients with T1-2 breast cancer (n = 155) were enrolled in this study. In phase 1 (n = 62), SLN biopsy was performed by using peritumoral injection of blue dye alone followed by backup axillary lymph node dissection. In phase 2, SLN biopsy was performed by using peritumoral injection of blue dye and peritumoral (group A, n = 41) or periareolar (group B, n = 52) injection of technetium 99m tin colloid. RESULTS: In phase 1, the detection rate of SLN was 81% and the false-negative rate was 5.6%, indicating our skill in SLN biopsy. In phase 2, the success rate of lymphoscintigraphy was significantly (P <.001) higher in group B (90%) than in group A (51%). The mean ex vivo radioactivity of SLN in group B (117 counts per second; range, 5 to 900) was also significantly (P <.05) higher than in group A (51 counts per second; range, 8 to 260). In addition, the detection rate of SLN was significantly (P <.05) higher in group B (100%) than in group A (90%). CONCLUSIONS: Periareolar injection of radiotracer for SLN biopsy is superior to peritumoral injection because of its simplicity, achieving a high success rate in lymphoscintigraphy and SLN detection.

Ultratag RBC kit for combined cardiac first-pass and multigated acquisition studies.

UNLABELLED: The authors developed a procedure to use the in vitro Ultratag (Mallinckrodt, St. Louis, MO) red blood cell (RBC) labeling kit for both first-pass (FP) and multigated acquisition (MUGA) studies with a high specific activity in a reduced volume (50 mCi/0.5 ml) and a high labeling efficiency that can be used with a single-crystal camera to yield a quality study. METHODS: A packed red blood cell (PRBC) bolus was created by two methods: (a) reducing the volume of the components of the Ultratag kit and (b) centrifuging the final dose volume. The labeling efficiency of each bolus was evaluated, each PRBC bolus was visually inspected for clots and percent hemolysis was assessed using a hemocytometer at 30 min, 1 hr and 2 hr postcentrifugation. RESULTS: Use of the first method, the 50% kit, provided the best results. However, the resulting volume from this kit only approached 1 ml, which is not clinically adequate for a first-pass study. In the second method, the total volume was centrifuged to form a PRBC bolus, which appeared to be stable in the syringe for at least 2 hr. A combined FP/MUGA study from a centrifuged 50% reduced kit was performed in one normal subject as a preliminary assessment of the clinical utility of this procedure. The image quality of the scan is diagnostically adequate. CONCLUSION: By using the in vitro Ultratag kit, a compact PRBC bolus was created that was stable in the syringe and could be reinjected safely into the patient for combined cardiac FP/MUGA studies.

Gas chromatographic determination of inorganic tin in rat urine after a single oral administration of stannous chloride and mono-, di-, and triphenyltin chloride.

A method is described for the determination of inorganic tin by gas chromatography with flame photometric detection. The inorganic tins, stannous and stannic, were extracted with hydrochloric acid and n-hexane-benzene in the presence of 0.05% tropolone, and both inorganic tins were pentylated to tetrapentyltin with a Grignard reagent prior to gas chromatography. The absolute limit of detection for tetrapentyltin was 3 pg as tin. The recovery of stannous chloride added to rat urine samples was 80.2 +/- 2.4% (mean +/- S.D., n = 8). The application of this method to the study of urinary excretion of inorganic tin and organotin compounds in rats following oral administration of tin compounds is presented. The urinary excretion of tin compounds was observed over a period of 96 h following administration of stannous chloride or phenyltin compounds. Most of the inorganic tin was excreted into urine within 24 h after administration of stannous chloride. In the experiments on organotin administration, the level of the excretion as total tin for monophenyltin reached a maximum ca. 0-24 h after administration, whereas the maxima for di- and triphenyltin were found after 24-48 h and 48-72 h, respectively. The predominant excretion product of these tin compounds found in urine was monophenyltin.