Neutrophil elastase in the development of nephrogenic systemic fibrosis (NSF)-like skin lesion in renal failure mouse model.

Although neutrophil elastase (NE) may play a role in lung fibrosis and liver fibrosis, NE involvement in the development of nephrogenic systemic fibrosis has been unclear. We investigated the involvement of NE in the development of nephrogenic systemic fibrosis-like skin lesions post-injections of linear gadolinium-based contrast agents in renal failure mouse models. Renal failure mouse models were randomly divided into three groups: control group (saline), gadodiamide group, and gadopentetate group. Each solution was intravenously administered three times per week for three weeks. The mice were observed daily for skin lesions. Quantification of skin lesions, infiltrating inflammatory cells, and profibrotic cytokines in the affected skin was performed by immunostaining and reverse-transcription polymerase chain reaction (RT-PCR). Blood samples were collected from the facial vein to quantify NE enzymatic activity. The 158Gd concentrations in each sample were quantified using inductively coupled plasma mass spectrometry (ICP-MS). In the gadodiamide group, the mRNA expression of fibrotic markers was increased in the skin lesions compared to the control group. In the gadopentetate group, only collagen 1α and TGF-ß mRNA expression were higher than in the control group. The expression of CD3+, CD68+, NE cells and the NE activity in the blood serum were significantly higher in the gadodiamide and gadopentetate groups compared to the control group. Gadolinium concentration in the skin of the gadodiamide group was significantly higher than the gadopentetate group, while almost no traces of gadolinium were found in the control group. Although gadopentetate and gadodiamide affected the fibrotic markers in the skin differently, NE may be involved in the development of fibrosis linked to the GBCAs injections in renal failure mouse models.

Early detection of progressive disease using thyroglobulin doubling-time in metastatic differentiated thyroid carcinoma treated with radioactive iodine.

OBJECTIVE: Detectable serum thyroglobulin (Tg) in patients with differentiated thyroid carcinoma (DTC) after total thyroidectomy indicates progression of the disease. Thyroglobulin doubling-time (TgDT) is a powerful prognostic predictor in patients with DTC. We aimed to evaluate the value of the dynamic TgDT for early detection of progressive disease (PD) in the patients of metastatic DTC with I radioactive iodine (RAI) therapy. METHODS: We retrospectively evaluated 21 patients undergoing RAI therapy with metastatic DTC. Patients were defined as PD or non-PD according to Response Evaluation Criteria in Solid Tumors 1.1. TgDT was calculated by Excel-based software using Tg values measured during routine follow-up. Whole data (WDT), initial four data (IDT) and recent four data (RDT) of TgDT after total thyroidectomy were calculated and compared. RESULTS: Among the 21 patients (10 men; median age, 62 years old; range, 33-80), 11 patients were classified into PD and 10 were into non-PD. The initial Tg after total thyroidectomy showed a significant difference between PD and non-PD patients (P = 0.013). Short WDT, IDT and RDT (less than one year) showed a high correlation with PD (P < 0.05). RDT showed the highest predictive value for PD (P < 0.001). All the 11 PD patients showed RDT less than one year before PD (median follow-up, 157 days; range, 88-252). CONCLUSIONS: RDT is a powerful PD predictor in patients with metastatic DTC. Dynamic monitoring of RDT should be applied for the early detection of PD in clinic.

Immuno-PET imaging for non-invasive assessment of cetuximab accumulation in non-small cell lung cancer.

BACKGROUNDS: Overexpression of epidermal growth factor receptor (EGFR) has been established as a valid therapeutic target of non-small cell lung cancer (NSCLC). However, the clinical benefit of cetuximab as an EGFR-targeting drug is still controversial, partially due to the lack of effective means to identify suitable patients. This study aimed to investigate the potential of radiolabeled cetuximab as a non-invasive tool to predict cetuximab accumulation in NSCLC tumor xenografts with varying EGFR expression levels. METHODS: The NSCLC tumors in model mice were subjected to in vivo biodistribution study and positron emission tomography (PET) imaging 48 h after injection of either 111In- or 64Cu-labeled cetuximab. The EGFR expression levels of NSCLC tumors were determined by ex vivo immunoblotting. RESULTS: We found that tumors with high EGFR expression had significantly higher [111In]In-DOTA-cetuximab accumulation than tumors with moderate to low EGFR expression (P < 0.05). Strong correlations were found between [111In]In-DOTA-cetuximab tumor uptake and EGFR expression level (r = 0.893), and between [64Cu]Cu-DOTA-cetuximab tumor uptake with EGFR expression level (r = 0.915). PET imaging with [64Cu]Cu-DOTA-cetuximab allowed clear visualization of tumors. CONCLUSION: Our findings suggest that this immuno-PET imaging can be clinically translated as a tool to predict cetuximab accumulation in NSCLC cancer patients prior to cetuximab therapy.

Activatable fluorescence detection of epidermal growth factor receptor positive mediastinal lymph nodes in murine lung cancer model.

It is important to detect mediastinal lymph node metastases in patients with lung cancer to improve outcomes, and it is possible that activatable fluorescence imaging with indocyanine green (ICG) can help visualize metastatic lymph nodes. Therefore, we investigated the feasibility of applying this method to mediastinal lymph node metastases in an epidermal growth factor receptor (EGFR)-positive squamous cell carcinoma of the lung. Tumors were formed by injecting H226 (EGFR-positive) and H520 (EGFR-negative) cell lines directly in the lung parenchyma of five mice each. When computed tomography revealed tumors exceeding 8 mm at their longest or atelectasis that occupied more than half of lateral lung fields, a panitumumab (Pan)-ICG conjugate was injected in the tail vein (50 µg/100 µL). The mice were then sacrificed 48 hours after injection and their chests were opened for fluorescent imaging acquisition. Lymph node metastases with the five highest fluorescent signal intensities per mouse were chosen for statistical analysis of the average signal ratios against the liver. Regarding the quenching capacity, the Pan-ICG conjugate had almost no fluorescence in phosphate-buffered saline, but there was an approximate 61.8-fold increase in vitro after treatment with 1% sodium dodecyl sulfate. Both the fluorescent microscopy and the flow cytometry showed specific binding between the conjugate and H226, but almost no specific binding with H520. The EGFR-positive mediastinal lymph node metastases showed significantly higher average fluorescence signal ratios than the EGFR-negative ones (n = 25 per group) 48 hours after conjugate administration (70.1% ± 4.5% vs. 13.3% ± 1.8%; p < 0.05). Thus, activatable fluorescence imaging using the Pan-ICG conjugate detected EGFR-positive mediastinal lymph node metastases with high specificity.

Determining patient selection tool and response predictor for outpatient 30 mCi radioiodine ablation dose in non-metastatic differentiated thyroid carcinoma: a Japanese perspective.

The lack of isolation ward throughout Japan has long been limiting the 131I radioactive iodine (RAI) ablation for differentiated thyroid cancer (DTC) cases. The 30 mCi RAI ablation was only recently permitted for outpatient basis. However, no patient selection tool nor response predictor has been proposed. This study evaluated factors to find response predictor and determinant for the suitable patients. The retrospective study reviewed 47 eligible non-metastatic papillary DTC patients whose had first 30 mCi RAI ablation after total thyroidectomy. Age, gender, clinical stage, risk category, and pre-ablation serum thyroglobulin (Tg) level were among covariates analyzed to determine the patient selection factors; while the thyroid bed uptake on initial whole body scan (WBS) was later also included in determining RAI ablation response. Thirteen (28%) patients had a low risk (T1-2) while 23 (49%) and 11 (23%) had an intermediate (T3) or high risk (T4), respectively. Twenty-five patients were responders, and 22 were non-responders. All factors were similar between responders and non-responders except pre-ablation serum Tg level (p < 0.001). In multivariate analysis, pre-ablation serum Tg level was the only significant factor for both patient selection (odd ratio (OR) = 1.52, 95% confidence interval (CI) = 1.13-2.06) and response predictor (OR = 1.48; 95% CI = 1.12-1.95). With the cut-off of 5.4 ng/mL, pre-ablation serum Tg level predicts RAI ablation response with 92% specificity and 73% sensitivity. Pre-ablation serum Tg level may help patient selection and predict the response to outpatient 30 mCi RAI ablation among post total thyroidectomy non-metastatic DTC patients.

Diagnostic value of 18F-fluorodeoxyglucose uptake parameters to differentiate rheumatoid arthritis from other types of arthritis.

We aimed evaluate F-fluorodeoxyglucose uptake at major joints for differentiating patients with rheumatoid arthritis (RA) from those with non-RA arthritis using F-fluorodeoxyglucose (FDG)-positron emission tomography (PET).Eighteen patients with RA (13 women; age, 66.8 ±â€Š13.2 years) and 17 patients with non-RA (6 women; age, 50.8 ±â€Š12.5 years) were included. Twelve joints of each patient were examined: shoulder, elbow, wrist, hip, knee, and ankle on both sides. A visual scoring (VS) system was used; quantitative parameters such as maximum standardized uptake value (SUVmax), metabolic active volume (MAV), and total lesion glycolysis (TLG) were evaluated. Total score and value of each parameter were compared between the RA and non-RA groups.Total VS score (mean, 37.7 ±â€Š9.0 vs 21.9 ±â€Š7.2; P < .0001) and SUVmax (mean, 28.1 ±â€Š8.5 vs 17.9 ±â€Š5.8; P < .001) were significantly higher in the RA group than in the non-RA group. A significant between-group difference was also observed with respect to total MAV (608.3 ±â€Š370.7 vs 176.5 ±â€Š217.8; P < .001) and total TLG (1139.3 ±â€Š759.1 vs 289.5 ±â€Š395.4; P < .001). Receiver operating characteristic curve analysis revealed that total VS had the highest area under curve (.92), with sensitivity and specificity of 88.9% and 76.4%, respectively.Quantitative PET parameters could differentiate RA from non-RA. Total VS score, however, appears to be the best convenient qualitative tool for diagnosing RA.