Number Of Pulmonary Nodules Research Articles

Sarcoid Nodule or Lung Cancer? A High-Resolution Computed Tomography-Based Retrospective Study of Pulmonary Nodules in Patients with Sarcoidosis.

Background: The objective of this retrospective study was to compare the characteristics of sarcoid nodules and neoplastic nodules using high-resolution computed tomography (HRCT) in sarcoidosis patients. Methods: This is a single-center retrospective study. From 2010 to 2023, among 685 patients affected by pulmonary sarcoidosis, 23 patients developed pulmonary nodules of a suspicious malignant nature. The HRCT characteristics of biopsy-proven malignant (Group A) vs. inflammatory (Group B) nodules were analyzed and compared. Results: A significant difference was observed between the groups in terms of age (p = 0.012). With regard to HRCT features, statistical distinctions were observed in the appearance of the nodule, more frequently spiculated in the case of lung cancer (p < 0.01), in the diameter of the nodule (Group A: 23.5 mm; Group B: 12.18 mm, p < 0.02), in the median nodule density (Group A: 60.0 HU, Group B: -126.7 HU, p < 0.01), and in the number of pulmonary nodules, as a single parenchymal nodule was more frequently observed in the neoplastic patient group (p = 0.043). In Group A, the 18-PET-CT demonstrated hilar/mediastinal lymphadenopathy in 100% of cases; histology following surgery did not report any cases of malignant lymph node involvement. Conclusions: An accurate clinical evaluation and HRCT investigation are crucial for diagnosing lung cancer in patients with sarcoidosis in order to determine who requires surgical resection. The spiculated morphology of the nodule, greater size, the number of pulmonary nodules, and density using HRCT appear to correlate with the malignant nature of the lesion.

Correlation between lung cancer probability and number of pulmonary nodules in baseline computed tomography lung cancer screening: A retrospective study based on the Chinese population.

Screening for lung cancer with LDCT detects a large number of nodules. However, it is unclear whether nodule number influences lung cancer probability. This study aimed to acquire deeply insight into the distribution characteristics of nodule number in the Chinese population and to reveal the association between the nodule number and the probability of lung cancer (LC). 10,167 asymptomatic participants who underwent LDCT LC screening were collected. Noncalcified nodules larger than 4 mm were included. The nodule number per participant was determined. We defined five categories according to the number of nodules (based on nodule type and size): one, two, three, four, and more than four nodules. We stratified the nodules as groups A, B, and C and participants as Amax, Bmax, and Cmax groups, and explored the association between nodule number and the probability of LC on nodule and participant levels. 97 participants were confirmed to have LC. The probabilities of LC were 49/1719, 22/689, 11/327, 6/166, and 9/175 in participants with one, two, three, four, and more than four nodules (p>0.05), respectively. In the Bmax group, the probability of LC was significantly higher in participants with one nodule than those with >4 nodules (p<0.05), and the probability of LC showed a negative linear trend with increasing nodule numbers (p<0.05). Based on the nodule-level analyses, in Group B, LC probability was significantly higher when participants had a solitary nodule than when they had >4 nodules (p<0.05). LC probability does not significantly change with the number of nodules. However, when stratified by the nodule size, the effect of nodule number on LC probability was nodule-size dependent, and greater attention and active follow-up are required for solitary nodules especially SNs/solid component of PSNs measuring 6-15 mm or NSNs measuring 8-15 mm. Assessing the nodule number in conjunction with nodule size in baseline LDCT LC screening is considered beneficial.

Computed tomography findings, associated factors, and management of pulmonary nodules in 54,326 healthy individuals.

To investigate the pulmonary nodules detected by low-dose computed tomography (LDCT), identified factors affecting the size and number of pulmonary nodules (single or multiple), and the pulmonary nodules diagnosed and management as lung cancer in healthy individuals. A retrospective analysis was conducted on 54,326 healthy individuals who received chest LDCT screening. According to the results of screening, the detection rates of pulmonary nodules, grouped according to the size and number of pulmonary nodules (single or multiple), and the patients' gender, age, history of smoking, hypertension, and diabetes were statistically analyzed to determine the correlation between each factor and the characteristics of the nodules. The pulmonary nodules in healthy individuals diagnosed with lung cancer were managed with differently protocols. The detection rate of pulmonary nodules was 38.8% (21,055/54,326). The baseline demographic characteristics of patients with pulmonary nodules were: 58% male and 42% female patients, 25.7% smoking and 74.3% nonsmoking individuals, 40-60 years old accounted for 49%, 54.8% multiple nodules, and 45.2% single nodules, and ≤5-mm size accounted for 80.4%, 6-10 mm for 18.2%, and 11-30 mm for 1.4%. Multiple pulmonary nodules were more common in hypertensive patients. Diabetes is not an independent risk factor for several pulmonary nodules. Of all patients with lung nodules, 26 were diagnosed with lung cancer, accounting for 0.1% of all patients with pulmonary nodules, 0.6% with nodules ≥5 mm, and 2.2% with nodules ≥8 mm, respectively. Twenty-six patients with lung cancer were treated with surgical resection (57.7%), microwave ablation (MWA, 38.5%), and follow-up (3.8%). LDCT was suitable for large-scale pulmonary nodules screening in healthy individuals, which was helpful for the early detection of suspicious lesions in the lung. In addition to surgical resection, MWA is an option for early lung cancer treatment.

Effect of propofol on lung metastasis of circulating tumor cells after colorectal cancer surgery

&#x0D; &#x0D; &#x0D; &#x0D; Purpose: To investigate the effect of propofol on lung metastasis of circulating tumor cells (CTCs) after colorectal cancer (CRC) surgery, and the mechanism involved.&#x0D; Methods: Specific-pathogen-free (SPF) male BALB/c mice (n = 30; mean age = 7 ± 1 weeks; mean weight = 19 ± 3 g) were used for this study. To establish mouse model of CRC, 100 μL of CRC (CT26) cells was injected into the caudal vein of each mouse. Three groups of 10 mice were used: control, 5 μL/mL propofol, and 10 μL/mL propofol groups. Changes in pulmonary superficial nodules of mice lungs were determined. Colorectal cancer cell (CT26) proliferation and apoptosis were measured using Ki-67 immunohistochemical staining and in situ terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assays, respectively.&#x0D; Results: The number of pulmonary nodules and proportion of proliferating cells (Ki-67 expression level) were significantly higher in 5 μL/mL propofol-treated mice, relative to control, but markedly lower in 10 μL/mL propofol group than in 5 μL/mL propofol group (p &lt; 0.05). Although apoptotic index increased in 5 μL/mL propofol group, cell apoptosis was comparable among the groups (p &gt; 0.05).&#x0D; Conclusion: These results suggest that propofol promotes pulmonary metastasis of CTCs after CRC surgery via stimulation of CTC proliferation in the lungs. Therefore, caution should be exercised in the use of propofol in colorectal cancer surgery.&#x0D; &#x0D; &#x0D; &#x0D;

The evaluation of non-anesthetic computed tomography for detection of pulmonary parenchyma in feline mammary gland carcinoma: a preliminary study

BackgroundThoracic radiography in awake cats is a common procedure for the evaluation of pulmonary metastasis in feline mammary gland carcinoma (MGC). However, due to poor sensitivity, computed tomography (CT) is progressively taking its place. To perform CT in animals, general anesthesia is normally preferred but can cause lung atelectasis, affecting lung interpretation. Besides, MGC is often found in senile cats that are concurrently affected with other diseases, increasing anesthetic risk. Therefore, this study was aimed at comparing the effect of anesthesia on lung atelectasis observed through CT in clinically healthy cats and comparing the feasibility of non-anesthetic CT with non-anesthetic radiography in the detection of lung lesions in feline MGC. Thoracic CTs from anesthetized, clinically healthy cats and non-anesthetized either clinically healthy cats or MGC-affected cats were reviewed. In clinically healthy cats, motion artifacts and characteristics of lung atelectasis were observed and compared. In MGC-affected cats, motion artifacts were observed and compared to clinically healthy cats, and the number of MGC-affected cats, the number and characteristics of lung lesions were compared between non-anesthetic thoracic CT and radiography.ResultsAnesthesia significantly increased lung CT attenuation (P = 0.0047) and was significantly correlated with lung atelectasis (OR = 15; CI 2.02–111.18; P = 0.0081), particularly of the cranial lung lobe. Nonetheless, significantly higher motion artifacts in the caudal thoracic area were found in non-anesthetized healthy cats (P = 0.0146), but comparable low motion artifacts were observed in anesthetized healthy and MGC-affected cats. Non-anesthetic CT revealed higher numbers of MGC-affected cats and pulmonary nodules with a significantly lower nodular diameter (P = 0.0041) than those observed on radiographs. The smallest nodular diameters detected on radiographs and CT were 2.5 and 1.0 mm, respectively. Furthermore, CT showed additional information such as intra-thoracic lymphadenopathy, that could not be seen on radiographs.ConclusionsDespite the motion artifacts, CT without anesthesia is a sensitive technique as it provides better lung inflation. Furthermore, compared to non-anesthetic radiography, non-anesthetic CT provided more information such as higher number of pulmonary nodules of a smaller size, including more distinct intra-thoracic lesions, such as lymphadenopathy, in MGC-affected cats.

Development and clinical application of deep learning model for lung nodules screening on CT images

Lung cancer screening based on low-dose CT (LDCT) has now been widely applied because of its effectiveness and ease of performance. Radiologists who evaluate a large LDCT screening images face enormous challenges, including mechanical repetition and boring work, the easy omission of small nodules, lack of consistent criteria, etc. It requires an efficient method for helping radiologists improve nodule detection accuracy with efficiency and cost-effectiveness. Many novel deep neural network-based systems have demonstrated the potential for use in the proposed technique to detect lung nodules. However, the effectiveness of clinical practice has not been fully recognized or proven. Therefore, the aim of this study to develop and assess a deep learning (DL) algorithm in identifying pulmonary nodules (PNs) on LDCT and investigate the prevalence of the PNs in China. Radiologists and algorithm performance were assessed using the FROC score, ROC-AUC, and average time consumption. Agreement between the reference standard and the DL algorithm in detecting positive nodules was assessed per-study by Bland–Altman analysis. The Lung Nodule Analysis (LUNA) public database was used as the external test. The prevalence of NCPNs was investigated as well as other detailed information regarding the number of pulmonary nodules, their location, and characteristics, as interpreted by two radiologists.

P229 Primary cardiac angiosarcoma of the right atrium: a rare entity presenting with an atrial arrhythmia

Abstract Introduction Primary cardiac tumors are rare entities and 75% are benign. Angiosarcoma is the most common malignant primary cardiac tumor. We report the case of cardiac angiosarcoma presenting with an atrial arrhythmia. Clinical case A 39-year-old female patient with no past medical history presented to the emergency department with heart palpitations and atypical chest pain. Electrocardiogram on admission showed atrial flutter with a heart rate of 153 beats per minute. Laboratory analysis were performed showing elevated D-dimer levels (2210 ug/L). A thoracic CT scan was performed, which ruled out pulmonary embolism, but showed multiple pulmonary nodules and a right atrial (RA) mass measuring 48 mm that could correspond to a thrombus or neoplasia. The patient was admitted in the Cardiology ICU of our hospital and was started on beta-blocker and amiodarone with conversion to sinus rhythm. Additional exams were performed: - Transthoracic echocardiogram (TTE) revealed an heterogenous 32,6 x 17,7 mm mass in the lateral wall of the RA with an adherent mobile mass near the tricuspid valve with 28 mm diameter (possible adherent thrombus). - Cardiac magnetic resonance imaging confirmed a RA tumor with invasion of the atrial free wall and compression of the superior vena cava. Due to the unclear etiology of the RA mass, ultrasound-guided intracardiac biopsy was performed. Pathological examination revealed spindle cell proliferation, consistent with the diagnosis of angiosarcoma. Immunohistochemical staining was positive for Vimentin, CD34 and CD31, with 70% Ki67 expression. Later on, the patient developed melena with significant drop of hemoglobin levels, requiring daily red blood cell transfusions and anticoagulation had to be stopped. The patient was transferred to the Internal Medicine ward and thoracic-abdomen-pelvis staging computed tomography (CT) scan showed a significant increase in the number of pulmonary nodules, bilateral ovarian masses, 4 hepatic nodules and ileum metastization. During hospitalization, the patient developed right leg deep venous thrombosis and thoracic CT scan revealed bilateral pulmonary embolism. After improvement of the clinical status, palliative chemotherapy was started and the patient was discharged, maintaining regular outpatient follow-up in the Oncology Department for 1 month. Cardiac angiosarcoma generally presents in a late stage of the disease with metastatic involvement. When surgical treatment is not possible, despite agressive chemotherapy, the prognosis remains poor. Abstract P229 Figure. Echocardiogram: right atrium mass

Management of Older Patients With Metastatic Renal Cell Carcinoma Receiving Sunitinib: A Hypothetical, Illustrative Case Scenario

CASE STUDY Tom, a 75-year-old white male, was recently diagnosed with metastatic renal cell carcinoma (RCC; Tom's case is not an actual clinical case but has been developed by the authors as an exemplar). Two years prior, he had undergone a left partial (laparoscopic) nephrectomy for clear cell RCC. At that time, he had a stage 3 disease (the tumor extended into perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota's fascia [Cancer.net, 2016]), and regularly (every 3-6 months) scheduled surveillance imaging did not show metastatic disease. Recent imaging with a computed tomography (CT) of the chest/abdomen/pelvis revealed small bilateral pulmonary nodules that did not have the radiographic appearance of a primary lung tumor, but rather that of metastatic disease. Therefore, a decision was made to repeat CT scans in a shorter interval (in 6 weeks) to assess growth kinetics. Subsequent CT scan showed an increase in size and number of pulmonary nodules, so the decision was made to begin systemic treatment. At the time of Tom's metastatic evaluation, his Eastern Cooperative Oncology Group performance status was 0 as he was asymptomatic and fully active (Table 1). He was classified as favorable risk according to Heng criteria (Table 2). Tom is married and lives with his wife. He is independent in his self-care but also relies on his wife for health-care decision-making. He does not drink alcohol and is a former smoker with a history of 30 pack-years. Tom's medical history includes hypertension that is adequately controlled with lisinopril (20 mg/day), coronary artery disease (on daily aspirin 81 mg) with left ventricular ejection fraction (LVEF) of > 50%, which is within the normal range (50%-75%), benign prostatic hyperplasia for which he is treated with finasteride, and hyperlipidemia that is treated with atorvastatin.

Biopsy: CT-guided fine needle aspiration is best? radiologist perspective

Availability of computed tomography (CT) and advances in lung screening techniques allowed the identification of growing number of pulmonary nodules. The ability to differentiate between benign and malignant lesions is a challenge. Cytological or tissue sampling of suspected nodules by percutaneous guided imaging, has increasingly been placed as an effective and safe alternative. Analysed cases of fine needle aspiration biopsy (FNAB) and core biopsy performed at the Intervention Center of our institution. As well, review of literature to compare indications, limitations and complications of techniques. FNAB is often used in a number of situations. Thyroid, breast nodules, and suspicious lymph nodes are examples. Percutaneous CT-guided FNAB is widely accepted as an accurate and safe procedure for pulmonary nodules. Core biopsy has gained space, with higher accuracy, low false negative indices, high positivity and similar complication. Interventionist practice is the first option in the diagnostic approach of suspected pulmonary nodules. Both strategies have a minimal morbi-mortality rate if compared to conventional surgical biopsy.

Clinical validation of a blood-based classifier for diagnostic evaluation of asymptomatic individuals with pulmonary nodules

BackgroundThe number of pulmonary nodules detected in the US is expected to increase substantially following recent recommendations for nationwide CT-based lung cancer screening. Given the low specificity of CT screening, non-invasive adjuvant methods are needed to differentiate cancerous lesions from benign nodules to help avoid unnecessary invasive procedures in the asymptomatic population. We have constructed a serum-based multi-biomarker panel and assessed its clinical accuracy in a retrospective analysis of samples collected from participants with suspicious radiographic findings in the Prostate, Lung, Chest and Ovarian (PLCO) cancer screening trial.MethodsStarting with a set of 9 candidate biomarkers, we identified 8 that exhibited limited pre-analytical variability with increasing clotting time, a key pre-analytical variable associated with the collection of serum. These 8 biomarkers were evaluated in a training study consisting of 95 stage I NSCLC patients and 186 smoker controls where a 5-biomarker pulmonary nodule classifier (PNC) was selected. The clinical accuracy of the PNC was determined in a blinded study of asymptomatic individuals comprising 119 confirmed malignant nodule cases and 119 benign nodule controls selected from the PLCO screening trial.ResultsA PNC comprising 5 biomarkers: CEA, CYFRA 21-1, OPN, SCC, and TFPI, was selected in the training study. In an independent validation study, the PNC resolved lung cancer cases from benign nodule controls with an AUC of 0.653 (p < 0.0001). CEA and CYFRA 21-1, two of the markers included in the PNC, also accurately distinguished malignant lesions from benign controls.ConclusionsA 5-biomarker blood test has been developed for the diagnostic evaluation of asymptomatic individuals with solitary pulmonary nodules.

P1.03-057 Assessment of Lung Cancer Risk- Regional Respiratory Disease Screening Report in Jilin, China

Both morbidity and mortality of lung cancer ranks first in China. According to the “2012 cancer registration report of China“, Northeast China is a high prevalence area of lung cancer, so early diagnosis of lung cancer is particularly important. Based on this, we made the regional survey in Changchun city. (1) To investigate the incidence of pulmonary nodules and lung cancer in Changchun city. (2)To provide the foundation of large data study on early screening of lung cancer and disease control. Carry out the investigation of the people over 50 years of age in 10 communities in Changchun of Jilin Province (A total of 1461 people), including questionnaire, pulmonary function tests and low-dose spiral CT examination. The disease assessment and patient management are based on “Diagnosis and treatment of pulmonary nodules in Chinese expert consensus.” The percentage of lung disease in the investigated population was 25.67%, and the constitution of the lung disease included: 30.67% of the lung nodules, 37.07% of chronic obstructive pulmonary disease, 18.67% of inflammation, 5.6% of the lung, 2.13% of pulmonary interstitial fibrosis, 2.13% of pleural effusion and 3.73% of other lung diseases. The number of pulmonary nodules was 115, accounting for 7.87% of the total number of screening, 89 cases of solitary nodules, 26 cases of multiple nodules. A total of 4 patients with lung cancer were confirmed by pathology, including 2 cases of adenocarcinoma, 1 case of squamous cell carcinoma and 1 case of mucinous carcinoma of the lung. All of the cancer cases were solitary nodules, and accounted for 3.48% of the total samples. Among them, 3 patients are male with a history of smoking, and 1 is female without any history of smoking. According to the nodule size, the diameters of nodule in 3 cases are greater than 8mm and 1 case is less than 4mm. According to the quality of nodules, 3 cases are solid and mixed nodules, and 1 case is ground-glass opacity. (1) Smoking is a risk factor for lung cancer. (2) Solid and mixed character nodules in pulmonary nodules and larger diameter nodules are more likely to develop into cancer, so they should be strengthened management. (3) Low-dose spiral CT is helpful for early diagnosis of lung cancer.

BLOCKADE OF EPIDERMAL GROWTH FACTOR RECEPTOR, CYCLOXYGENASE-2 (COX-2) AND MAMMALIAN TARGET OF RAPAMYCIN (M-TOR) IN ANIMAL MODEL OF LUNG CANCER

To explore the effectiveness and possible toxicity of the use of epidermal growth factor receptor inhibitor (EGFR Inhibitor), Celecoxib (COX2 inhibitor) and Sirolimus (m-TOR inhibitor) as single agents and drug combinations for the treatment of lung cancer in an experimental model. Lung cancer was induced in Balb-C mice by intraperitoneal injection urethane. Mice were treated with water (control) , Erlotinib (E) (50 mg/kg), Celecoxib (X) (50 mg/kg), Sirolimus (R) (2 mg/kg) given alone and in the following doublet and triplet combinations in the same dosages for 7 days. The number of pulmonary nodules in the combined treatment was significantly inhibited compared with control (p=0.010); E (p=0.028), EX (p=0.010), ERX (p=0.040) showed a smaller number of statistically significant nodules. Regarding coat changes we observe statistically significant differences among groups (p&lt;0.001) where ERX and ER had a higher occurrence of this change. There was a higher incidence of skin rashes in groups: E (p&lt;0.001), ER (p&lt;0.0001), and ERX (p&lt;0.001). Regarding weight we identify weight loss in the ERX (p=0.025). The combination of EGFR inhibitor, COX-2 inhibitor and m-TOR inhibitor had anti-tumor activity in experimental lung cancer. The combination of Celecoxib treatment with Erlotinib is a suggestion for decrease of dermatological events in patients. The combination of EGFR inhibitor and Sirolimus does not decrease the number of lung nodules and potentiates adverse events.

Abstract 3844: A novel liposomal Clodronate depletes tumor-associated macrophages in primary and metastatic melanoma: anti-angiogenic and anti-tumor effects

Abstract The depletion of tumor-associated macrophages (TAMs), involved in different stages of cancer development and progression, is an appealing strategy in cancer therapy. We developed novel Clodronate-containing liposomes (Clo-Lipo-DOTAP) presenting good physicochemical properties (size distribution, polidispersity index and Z-potential). In vitro, Clo-Lipo-DOTAP inhibited proliferation, reduced viability and induced apoptosis of a macrophage-like cell line in a dose- and time-dependent manner. In proof of functionality experiments, Clo-Lipo-DOTAP depleted macrophages in a genetic mouse model of chronic hepatitis and hepatocellular carcinoma leading to a significant reduction of F4/80-positive cells in the liver and spleen of treated mice compared to PBS-treated controls. The number of granulocytes, B and T lymphocytes was not affected. In B16/F10 subcutaneous melanoma-bearing mice, Clo-Lipo-DOTAP significantly reduced the volume of primary tumors (P &amp;lt; 0.001). Within the tumors, the expression F4/80 and α-SMA was significantly lowered. Plasma levels of IL-10, Mo KC, TNF-α, VEGF and PDGF-bb were statistically decreased. In B16/F10 lung metastatic melanoma model, treatment with Clo-Lipo-DOTAP significantly reduced the number of pulmonary nodules (P &amp;lt; 0.05). F4/80-positive cells and microvessel density were statistically decreased. In conclusion, the depletion of TAMs in primary and metastatic melanoma presents anti-tumor efficacy via inhibition of angiogenesis and modulation of inflammation related cytokines. Citation Format: Chiara Brignole, Patrizia Perri, Francesca Piaggio, Fabio Pastorino, Daniela Di Paolo, Laura Emionite, Antonio Daga, Vangelis Kondylis, Manolis Pasparakis, Domenico Ribatti, Mirco Ponzoni. A novel liposomal Clodronate depletes tumor-associated macrophages in primary and metastatic melanoma: anti-angiogenic and anti-tumor effects. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3844.

Antitumor and antimetastasis effects of macerating solutions from an injectable chitosan-based hydrogel on hepatocarcinoma.

In our previous studies, injectable chitosan-based hydrogel (CH) was prepared and its application in surgery removal of tumor was studied. In this study, the antitumor and antimetastasis effects of the macerating solutions from CH were investigated. Our in vitro results showed that macerating solutions from CH significantly increased the proliferation of human normal liver L02 cells. In contrast, macerating solutions from CH showed significant inhibitory effects on the growth of human hepatoma Bel-7402 cells. In a mouse H22 tumor model, intraperitoneal injection of macerating solutions from CH decreased tumor growth and prevented tumor diffusion. Tumor weight was decreased dramatically in mice treated with macerating solutions from CH. The thymus index and spleen index were significantly increased by treatment with macerating solutions from CH. Administration of macerating solutions from CH also remarkably increased serum levels of TNF-α, IL-2, IFN-γ, and decreased serum VEGF content as compared with the control group treated with saline. The antimetastasis studies showed that the number of pulmonary nodules, pulmonary metastases index, and lymph nodes index were significantly decreased in experimental groups treated with macerating solutions from CH. This study provided more supporting data for the potential clinical application of CH after surgical removal of tumor.

Do Mesenchymal Stromal Cells Influence Microscopic Residual or Metastatic Osteosarcoma in a Murine Model?

Mesenchymal stromal cells (MSCs) have been shown in rodent models to promote primary and pulmonary metastatic sarcoma growth when injected in the presence of gross tumor. In theory, this would limit their use in a clinical setting after limb salvage treatment for osteosarcoma. Although concerning, these models do not translate to the clinical setting wherein MSCs could be used after primary tumor resection to aid in bone healing and incorporation of tumor endoprostheses. If we can determine whether the use of MSCs in this setting is safe, it might improve our ability to augment bone healing in patients undergoing limb salvage. The purpose of this study was to determine (1) whether MSCs promote pulmonary metastatic disease progression in a murine osteosarcoma model; and/or (2) whether they affect local disease recurrence in the presence of microscopic residual osteosarcoma. An orthotopic model of luciferase-expressing osteosarcoma was developed. At 10 days, resection of the primary tumor was performed. One hundred fourteen female C3H mice were inoculated with DLM8-luc osteosarcoma in the proximal tibia. Ninety-four mice developed orthotopic osteosarcoma with luciferase expression. Mice with bioluminescent evidence of a primary tumor received either a microscopically "clean" amputation at a time when residual microscopic metastatic disease was present in the lungs (pulmonary metastasis group; n = 65) or a "dirty" amputation (local recurrence group; n = 29). Mice were randomized to receive intravenous MSCs, MSCs at the surgical site, or no MSCs. Mice were monitored for development and progression of pulmonary metastasis and local recurrence by bioluminescence imaging and daily measurements at the surgical site. The number of pulmonary nodules, time to first evidence of metastasis, and size of recurrent tumor were compared using Kruskal-Wallis, analysis of variance, Welch's, t-tests, or Mann-Whitney tests as appropriate for the specific data sets with p < 0.05 considered significant. Mice receiving intravenous MSCs had a faster time to first detection of pulmonary metastasis (2.93 ± 1.90 days) compared with mice with local injection of MSCs (6.94 ± 6.78 days) or no MSCs (5.93 ± 4.55 days) (p = 0.022). MSC treatment did not influence whether mice developed local recurrence (p = 0.749) or size of recurrent tumors (p = 0.221). MSCs delivered to the surgical site did not promote local recurrence or size of recurrent tumors, but intravenous injection of MSCs did hasten onset of detection of pulmonary metastatic disease. Although local administration of MSCs into a surgical site does not appear to promote either pulmonary metastatic disease or local recurrence, large variation within groups and small numbers diminished statistical power such that a Type II error cannot be ruled out. If MSCs are to be used to augment bone healing in the postlimb salvage setting in patients with osteosarcoma, it will be important to understand their influence, if any, on pulmonary micrometastsis or residual microscopic local disease. Although murine models do not completely recapitulate the clinical scenario, these results suggest that intravenous delivery of MSCs may promote micrometastatic pulmonary disease. Local administration into a surgical wound, even in the presence of residual microscopic disease, may be safe, at least in this murine model, but further investigation is warranted before considering the use of MSCs for clinical use in patients with osteosarcoma.

Tacrolimus promotes hepatocellular carcinoma and enhances CXCR4/SDF-1α expression in vivo

The aim of our study was to elucidate the effect of tacrolimus (FK506) and of C-X-C chemokine receptor type 4 (CXCR4), which is a receptor specific to the stromal cell-derived factor-1α (SDF-1α), on growth and metastasis of hepatocellular carcinoma (HCC). Following treatment with different concentrations of FK506, AMD3100 or normal saline (NS), the proliferation of Morris rat hepatoma 3924A (MH3924A) cells was measured by the MTT assay, the expression of CXCR4 was analyzed with immunohistochemistry, and the morphological changes and the invasiveness of cells were studied with a transwell assay and under a scanning electron microscope, respectively. In addition, August Copenhagen Irish rat models implanted with tumor were used to examine the pathological changes and invasiveness of tumor in vivo, the expression of CXCR4 in tumor tissues and the expression of SDF-1α in the adjacent tissues to the HCC ones, using immunohistochemistry. In vitro, FK506 (100–1,000 μg/l) significantly promoted the proliferation of MH3924A cells (P<0.01), and increased the expression of CXCR4 in MH3924A cells, albeit with no significance (P>0.05). By contrast, AMD3100 had no effect on the proliferation of MH3924A cells, but significantly reduced the expression of CXCR4 (P<0.05). The invasiveness of MH3924A cells was significantly (P<0.01) enhanced following treatment with FK506, SDF-1α, FK506 + AMD3100, FK506 + SDF-1α or FK506 + AMD3100 + SDF-1α. In vivo, tumor weight (P=0.041), lymph node metastasis (P=0.002), the number of pulmonary nodules (P=0.012), the expression of CXCR4 in tumor tissues (P=0.048) and that of SDF-1α in adjacent tissues (P=0.026) were significantly different between the FK506-treated and the NS group. Our results suggest that FK506 promotes the proliferation of MH3924A cells and the expression of CXCR4 and SDF-1α in vivo. Therefore, inhibiting the formation of the CXCR4/SDF-1α complex may partly reduce the promoting effect of FK506 on HCC.

Pulmonary Extranodal Marginal Zone Lymphoma Of MALT Type Associated With Pulmonary Amyloidosis - Two Case Reports

Background Light chain (AL) amyloidosis is typically a systemic disease resulting from the malignant production and deposition of immunoglobulin light chain fragments in various tissues. Pulmonary AL amyloidosis is uncommon but can be seen concomitantly with non-Hodgkin lymphoma (NHL) as one of two distinct syndromes. In the more common presentation, a NHL, typically lymphoplasmacytic lymphoma or extranodal marginal zone lymphoma, produces a measurable serum/urine M-protein or light chain resulting in a systemic AL amyloidosis. There have also been sporadic reports of a less common, nodular form of pulmonary AL amyloidosis due to peritumoral amyloid deposition in patients with pulmonary extranodal marginal zone lymphoma of MALT type. This latter association is probably under-recognized. Here we present two cases from our institution with important diagnostic and therapeutic implications. Case 1 A 60 year old male was found to have bilateral pulmonary nodules. A percutaneous biopsy of the largest lesion in the left perihilar region revealed a MALT lymphoma. He was treated with eight cycles of R-CVP with a partial response. Significant residual disease led to further treatment with radioimmunotherapy using ibritumomab tiuxetan but without additional radiographic improvement. Due to concerns about the persistence of multiple pulmonary nodules, the original diagnostic biopsy was stained with Congo red to reveal amyloid deposition. No measurable monoclonal protein was present in the serum or urine. He has been observed now for an additional 4 years without evidence of progression. This patient has pulmonary amyloidosis in a nodular pattern in conjunction with a pulmonary MALT lymphoma. Pathologic review has shown the individual pulmonary nodules to be composed of both lymphoma and amyloid. The decrease in the size of the nodules with initial chemotherapy indicates a response to therapy, likely of the lymphoma component. The lack of response to typically effective additional therapy and the stability of the nodules over an extended period of time lead us to conclude that the residual nodules are likely to be primarily composed of amyloid. The initial lack of recognition of the amyloid component was disadvantageous and made determination of treatment response difficult. Case 2 A 37 year old male with HIV was found to have multiple pulmonary nodules. Pulmonary wedge resection revealed an extranodal marginal zone lymphoma of MALT type and amyloidosis that was confirmed as AL type by laser dissection and mass spectroscopy. Initial PET/CT demonstrated widespread FDG-avid lymphadenopathy and non-FDG-avid pulmonary nodules. There was no other evidence of systemic amyloidosis. The patient has been treated with three cycles of bendamustine and rituximab. Restaging PET/CT has shown a decrease in FDG-avid lymphadenopathy but no significant improvement in the size or number of pulmonary nodules. His chemotherapy is being continued. This patient has pulmonary AL amyloidosis in association with a stage IV extranodal marginal zone lymphoma. At first glance, the patient appears to have had a discordant response to initial treatment. However, the diagnosis of amyloidosis allows us to determine that his lymphoma has responded to therapy and the lack of response seen in the lungs is likely due to the presence of persistent amyloid. If the diagnosis of pulmonary amyloidosis was not made or known, this may have been mistakenly considered as refractory disease resulting in an unnecessary change in therapy. Conclusion The association between pulmonary amyloidosis and extranodal marginal zone lymphoma of MALT type may be more prevalent than previously recognized. All cases of pulmonary MALT lymphoma should be carefully examined for evidence of amyloid deposition. If proven, imaging studies, serum/urine electrophoresis and serum free light chain studies and organ assessments will help to determine whether the amyloid is a nodular form due to local deposition of light chain fragments or a systemic amyloidosis secondary to NHL. The former has a better prognosis than its systemic counterpart since the amyloidosis is typically localized to the lungs, has a more indolent course and is unlikely to involve other organs. As the above cases highlight, assessment of lymphoma response is greatly complicated by the concurrent presence of amyloid and PET/CT may be particularly useful in this scenario. Disclosures: No relevant conflicts of interest to declare.

Effect of resveratrol on the metastasis of 4T1 mouse breast cancer cellsin vitroandin vivo

We investigated the effects of resveratrol on metastasis in in vitro and in vivo systems. 4T1 cells were cultured in the presence of various concentrations (0-30 µmol/L) of resveratrol. For experimental metastasis, BALB/c mice were injected intravenously with 4T1 cells in the tail vein, and were orally administered various concentrations (0, 100, or 200 mg/kg Body weight) of resveratrol for 21 days. After resveratrol treatment, cell adhesion, wound migration, invasion, and MMP-9 activity were significantly decreased in a dose-dependent manner in 4T1 cells (P < 0.05). The numbers of pulmonary nodules were significantly decreased in mice fed the resveratrol (P < 0.05). The plasma MMP-9 activity was decreased in response to treatment with resveratrol in mice (P < 0.05). We conclude that resveratrol inhibits cancer metastasis both in vitro and in vivo, and this inhibition is likely due to the decrease in MMP-9 activity caused by resveratrol.

Red Ginseng Extract Reduced Metastasis of Colon Cancer Cells In Vitro and In Vivo

This study investigated the effect of red ginseng extract on metastasis of colon cancer cells in vitro and in vivo. Wound healing migration, cell motility, invasion, and activity, protein expression, and mRNA expression of matrix metalloproteinases (MMPs) were examined in SW480 human colon cancer cells. SW480 cells were cultured with or without 100 μg/L PMA in the absence or presence of various concentrations (100, 200, or 300 μg/mL) of red ginseng extract. Red ginseng extract treatment caused significant suppression of cell motility and invasion (p<0.05) in SW480 cells. Red ginseng extract inhibited MMP-2 and MMP-9 activity and their protein and mRNA expression in a dose-dependent manner (p<0.05) in SW480 cells. For experimental metastasis, BALB/c mice were injected intravenously with CT-26 mouse colon cancer cells in the tail vein, and were orally administered various concentrations (0, 75, 150, or 300 mg/kg body weight) of red ginseng extract for 3 weeks. Numbers of pulmonary nodules were significantly decreased in mice that were fed red ginseng extract (p<0.05). Plasma MMP-2 and MMP-9 activity significantly decreased in response to treatment with red ginseng extract in mice (p<0.05). These data suggest that red ginseng extract may be useful for prevention of cancer invasion and metastasis through inhibition of MMP-2 and MMP-9 pathways.

In vivo UVA irradiation of mouse is more efficient in promoting pulmonary melanoma metastasis than in vitro

BackgroundWe have previously shown in vitro that UVA increases the adhesiveness of mouse B16-F1 melanoma cells to endothelium.We have also shown in vivo that UVA exposure of C57BL/6 mice, i.v. injected with B16-F1 cells, increases formation of pulmonary colonies of melanoma. The aim of the present animal study was to confirm the previously observed in vivo UVA effect and to determine whether in vitro UVA-exposure of melanoma cells, prior the i.v. injection, will have an enhancing effect on the pulmonary colonization capacity of melanoma cells. As a second aim, UVA-derived immunosuppression was determined.MethodsMice were i.v. injected with B16-F1 cells into the tail vein and then immediately exposed to UVA. Alternatively, to study the effect of UVA-induced adhesiveness on the colonization capacity of B16-F1 melanoma, cells were in vitro exposed prior to i.v. injection. Fourteen days after injection, lungs were collected and the number of pulmonary nodules was determined under dissecting microscope. The UVA-derived immunosuppression was measured by standard contact hypersensitivity assay.Results and DiscussionObtained results have confirmed that mice, i.v. injected with B16-F1 cells and thereafter exposed to UVA, developed 4-times more of melanoma colonies in lungs as compared with the UVA non-exposed group (p < 0.01). The in vitro exposure of melanoma cells prior to their injection into mice, led only to induction of 1.5-times more of pulmonary tumor nodules, being however a statistically non-significant change. The obtained results postulate that the UVA-induced changes in the adhesive properties of melanoma cells do not alone account for the 4-fold increase in the pulmonary tumor formation. Instead, it suggests that some systemic effect in a mouse might be responsible for the increased metastasis formation. Indeed, UVA was found to induce moderate systemic immunosuppression, which effect might contribute to the UVA-induced melanoma metastasis in mice lungs.