Effect of Acridine Orange and Zoledronic Acid on Bone Metastasis in Renal Cell Carcinoma.

BACKGROUND/AIM: The increasing incidence of renal cell carcinoma (RCC) and its associated bone metastasis pose challenges in surgical interventions, warranting the exploration of novel therapeutic approaches. Therefore, this study aimed to assess the impact of hematogenously administering acridine orange (AO) alone and in combination with zoledronic acid (ZA) on bone metastasis in RCC. MATERIALS AND METHODS: RENCA cells (1.0×106 cells/10 µl) were directly injected into the right femur of male BALB/c mice. The mice were categorized into four groups based on the applied therapeutic intervention and were euthanized after five weeks. Micro-computed tomography was performed to quantify the extent of periosteal reaction, indicative of bone metastasis, along the entire length of the femur. Tumor weight and volume were measured at euthanization. Hematoxylin and eosin staining was used to examine the extent of tumor development in the bone. Apoptotic cell, osteoclast, and vascular endothelial growth factor (VEGF)-positive cell counts were assessed using TdT-mediated dUTP-biotin nick end labeling, tartrate-resistant acid phosphatase staining, and VEGF staining, respectively. RESULTS: The periosteal reaction was significantly reduced in the intervention groups compared to the control group (p<0.05). The apoptotic cell numbers in the intervention groups surpassed that in the control group (p<0.05), whereas those of osteoclasts and VEGF-positive cells in the intervention groups were lower than those in the control group (p<0.05). CONCLUSION: AO hinders bone metastasis progression in RCC, and combination therapy with ZA may be more effective than AO administration alone.

Development of a New Focal Mouse Model of Bone Metastasis in Renal Cell Carcinoma.

BACKGROUND/AIM: Developing animal models of bone metastasis in renal cell carcinoma (RCC) is challenging as immunodeficient mice are required. The aim of this study was to develop a simple immune model of RCC bone metastasis. MATERIALS AND METHODS: RENCA tumor cells were injected into the right femurs of BALB/c mice. Sixty mice were grouped into each twenty-mouse group according to the tumor cell concentration, and the presence or absence and extent of bone metastasis in the total length of the femur were compared using hematoxylin and eosin staining of the excised tissues. RESULTS: Bone metastasis was significantly higher in the high concentration group than in the other groups (p<0.05), with 10 mice developing bone metastasis at two weeks and nine mice developing bone metastasis at three weeks. The extent of bone metastasis was significantly greater in the high concentration group than in the other groups (p<0.05). Multiple logistic regression analysis was performed to examine the factors influencing bone metastasis, and only the high concentration was a significant factor (p<0.05). CONCLUSION: We developed a normal immunity mouse model of local bone metastasis from RCC. This model could prove valuable for research into the treatment of bone metastases in RCC.

Dysphagia Secondary to Myotonic Dystrophy Unveiled in a Case of Destructive Spondylitis With Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis (SAPHO) Syndrome Presenting As Torticollis.

To report an instructive case involving destructive spondylitis and synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome, presenting with torticollis and postoperative dysphagia without hoarseness, attributed to hidden myotonic dystrophy (DM). A 51-year-old male patient with a cervical deformity, who was previously managed conservatively for a metastatic tumor, underwent reconstruction surgery and subsequently experienced postoperative dysphagia. The presence of destructive spondylitis with torticollis, warranting prompt assessment to prevent paralysis, adds complexity to the delayed identification of DM. Given the rarity of DM, peculiar neurological symptoms and other systemic comorbidities did not lead to a preoperative diagnosis without prior knowledge. The patient's dysphagia induced respiratory arrest and required reintubation. Challenges in extubation and ventilator weaning arose due to hypercapnia. Superimposed COVID-19 infection elongated the duration of intubation. Extubation failed due to aspiration pneumonia and required a tracheotomy. Despite laryngeal elevation and preservation of the relaxation of the oesophageal entrance, the sensation and movement of the tracheopharynx were disturbed. The patient exhibited an oropharyngeal propulsive disorder, predominantly indicative of motor neuron disease. The patient's mother stated that his brother had been hospitalized for a long time after abdominal surgery. Finally, the patient was diagnosed with DM, which is known to cause post-anesthetic dysphagia. Recognizing the existence of severe destructive cervical spondylitis associated with SAPHO is crucial. Although DM is not very common, it is not classified as extremely rare. Therefore, surgeons should be mindful of the potential risks associated with general anesthesia in patients with DM. The complexity of preoperative conditions may hinder an accurate diagnosis. Recognizing and establishing preoperative expectations can assist surgeons in preventing complications, even if complex spinal surgery is required for patients with DM.

Effects of Soft Tissue Sarcoma and Doxorubicin on Bone Metabolism in Mice.

BACKGROUND/AIM: This study aimed to evaluate the effects of doxorubicin (Dox) on bone microstructure and metabolism in a mouse model of soft tissue sarcoma. MATERIALS AND METHODS: CCRF S-180II cells (2-4×105 cells/0.2 ml) were injected subcutaneously into the back of mice. The mice were divided into four groups according to tumor and treatment status and were reared and sacrificed after 2 or 4 weeks. Micro-computed tomography (CT) was performed to calculate the architecture of the femoral bone. The proximal tibia was double stained with tartrate-resistant acid phosphatase (TRACP) and alkaline phosphatase (ALP), and bone morphometry was performed. RESULTS: Trabecular bone mass was significantly reduced in the Sarcoma and Sarcoma+Dox groups. Cortical bone thickness was reduced in the DOX group, with a stronger effect observed in the Sarcoma+Dox group. In bone morphometry, osteoclast number at the bone surface (Oc.N/BS) was significantly lower in the Dox, Sarcoma, and Sarcoma+Dox groups than in the Control group at 2 weeks. The osteoblast surface at the bone surface (Ob.S/BS) was significantly lower in the Dox and Sarcoma groups than in the Control group at 2 weeks. At 4 weeks, the differences were smaller for both Oc.N/BS and Ob.S/BS. CONCLUSION: The use of doxorubicin alone worsened the cortical bone structure; however, the presence of both soft-tissue sarcoma and doxorubicin use worsened both cortical and trabecular bone structures from an early stage.

Intravascular Administration of Acridine Orange and Zoledronate in a Bone Metastasis Model of Breast Cancer.

BACKGROUND/AIM: This study evaluated the effect of haematogenous administration of acridine orange (AO) alone and in combination with zoledronate (ZOL) on bone metastases. MATERIALS AND METHODS: E0771 cells (1.0×105 cells/10 µl) were injected directly into the right femur of female mice. The mice were divided into five groups according to treatment (drugs and irradiation) and were reared and sacrificed after 6 weeks. Micro-computed tomography (µCT) was performed to calculate the destruction rate of the femur bone. We measured tumour weight and volume at sacrifice and performed terminal deoxynucleotidyl transferase dUTP Nick-End Labelling staining of tumours. RESULTS: At 4 weeks, the bone destruction rate was lower in the AO+ZOL group than in the radiation group. At 6 weeks, the AO+ZOL group had a lower bone destruction rate than the control and radiation groups; the ZOL group had a lower rate than the radiation group. The AO and AO+ZOL groups had suppressed tumour weight and volume compared to the control and radiation groups. The number of extraosseous apoptotic cells was higher in the AO+ZOL group than in all other groups except the AO group. CONCLUSION: In a model of local bone metastasis of breast cancer, haematogenous administration of AO reduced tumour size and more so when combined with ZOL.

Development of New Mouse Breast Cancer Model of Local Bone Metastasis and Verification Using Bisphosphonates.

BACKGROUND/AIM: Local tumor injection models require complicated procedures. The purpose was to establish a simple local bone metastasis model using normal mice, and to study the usefulness of the model with bisphosphonates (BP). MATERIALS AND METHODS: This study used a versatile C57BL/6 mouse model and E0771 cells. Tumor cells were injected into the right femur. Mice were divided into groups depending on the concentration of cells injected and the use of BP or not. The degree of bone destruction between the different conditions was compared using micro-computed tomography (µCT). RESULTS: Bone destruction was confirmed in four mice in the high-concentration group at 3 weeks, and in all other mice at 4 and 6 weeks. At 6 weeks post-injection, bone destruction was significantly suppressed in the BP group (p<0.05). CONCLUSION: We created a breast cancer mouse model of local bone metastasis. Zoledronate showed the same usefulness as in previous models. It may be an effective model for evaluating treatments for bone metastasis.

The efficacy and safety of nab paclitaxel plus gemcitabine in elderly patients over 75 years with unresectable pancreatic cancer compared with younger patients.

PURPOSE: To evaluate the efficacy and safety of nab paclitaxel (nab-P) plus gemcitabine (GEM) in elderly patients ≥ 75 years old with unresectable pancreatic cancer (PC) compared with younger patients. METHODS: The data of 27 unresectable PC patients treated with nab-P plus GEM as first-line chemotherapy were retrospectively analyzed. The patients were divided into two groups according to their age at inclusion: an elderly group (9 patients ≥ 75 years old) and a younger group (18 patients <75 years old). We compared the disease control rate, median overall survival (OS), and adverse events (AEs) between the two groups. Predictive factors for the OS were also evaluated. RESULTS: The clinical characteristics of patients of the two groups were not significantly different except for the age. The respective values for the disease control rate (66.7% vs. 77.8%, P = 0.542) and median OS (277 days vs. 312 days, P = 0.722) were also not significantly different between the elderly and younger group, although the relative dose intensity of GEM/nab-P in the elderly group (56.6%/53.1%) was significantly lower than that in the younger group (67.3%/63.1%) (P = 0.016/0.04). The absence of biliary drainage and CEA ≥ 6.5 were found to be poor prognostic factors in a multivariate analysis. The most common grade ≥ 3 AE was neutropenia (44% in both groups). No significant differences in the frequency of all AEs were observed between the two groups. CONCLUSIONS: Nab-P plus GEM appears effective and well-tolerated for elderly patients ≥ 75 years old with unresectable PC.

Toxicity of copper and cadmium in combinations to Duckweed analyzed by the biotic ligand model.

The biotic ligand model (BLM) of acute toxicity to aquatic organisms is based on the concept that metals binding onto biotic ligand may cause toxic effect on the organism. The BLM can take into incorporation between metal speciation and the protective effects of competing cations account. The demonstrated BLM can provide a good estimation of the amount of single metal effect under various conditions such as pH, coexistence of other non toxic cations. However, toxic metals are often found as mixture in nature. This study estimated combined toxicity of Cu and Cd examined by growth inhibition of Duckweed (Lemna paucicostata) by using single toxicity data as toxic unit (TU) derived by three types of model, BLM and two conventional models, free ion activity model (FIAM), and total metal concentration model. According to our results, single toxicity data derived by the BLM can estimate combined toxicity described as a function of TU. Particularly under the high level of heavy metals stress, BLM clearly predicted toxicity of heavy metals compared with other two models. According to numeric correlation (R(2), root mean square error), the order is BLM (R=0.83, RMSE=13.5)> total metal concentration model (R=0.41, RMSE=24.9)> FIAM (R=0.36, RMSE=26.1).

Prediction of genotoxicity of various environmental pollutants by artificial neural network simulation.

In order to evaluate human carcinogenic risks, genotoxicity data such as animal cancer bioassay are often not available. In this study, to assess the relevance of indicator of carcinogenic risks, we used the "molecular diversity approach" to estimate the genotoxicity based upon Salmonella genotoxicity test using the umu test and systemic toxicity data of the 82 environmental chemicals predicted by neural network simulation. The 82 environmental chemicals were randomly selected for this study according to the production and usage in Japan. Even in this challenging trial for QSTR (Quantitative Structure Toxicity Relationship) study, approaches using artificial neural networks can account for about 94% of the variation in the genotoxicity results derived by the umu-test.

Development of new toxicity identification evaluation by assessing toxicity reduction on adsorption and ion-exchange treatments.

A new toxicity identification evaluation method for water exhibiting toxicity has been suggested by evaluating toxicity reduction resulting from adsorption and ion-exchange treatments. Adsorption using various adsorbents such as activated carbon, chitosan and zeolite, and ion-exchange using cationic and anionic ion-exchange resins were performed. In addition, toxicity was evaluated by a cell survival test using human liver cancer origin cells (HepG2), and the dose response data was applied to treatment characteristics. The amount of toxicity adsorbed by the various adsorbents was defined based on adsorption isotherm. Parameters of the toxicity adsorption isotherm provided information that allowed us to identify the toxicity-controlling chemicals in environmental water containing various chemicals. The method is promising for water quality management because it can be used to identify toxicity-controlling chemicals among various environmental pollutants.

Estimation of cytotoxicity to HEP-G2 cells of 255 environmental pollutants and water using QSAR (Quantitative Structure-Activity Relationship).

Although bioassays are considered to be a rational method for environmental management, the procedure is generally too complicated to be applied to daily water quality management. In this study, the feasibility of using for application of a conventional QSAR (Quantitative Structure-Activity Relationship) method was examined to estimate the cytotoxicity of various pollutants found in environmental water. logP, pKa, and molecular weight were chosen as the physico/chemical properties of the pollutants, and defined equations for estimating cytotoxicity based on multiple linear regression analysis between these properties and in vitro cytotoxicity data from our previous results. As a result, a method for estimating cytotoxicity of environmental pollutants that had a certain probability (R>0.8) for the 255 chemicals was successfully developed. Considerably high reliability was shown in the leave-one-out prediction of multi-regression analysis. In addition, the cytotoxicity of environmental water samples was estimated based on multi-regression analysis, using as our samples leachates from 25 landfill sites in Japan. The method developed in this study estimated quantitatively the cytotoxicity of the environmental water from chemical analysis data without conducting a cytotoxicity test.