Pulmonary Metastatic Lesions Research Articles

Primary lung adenoid cystic carcinoma: a case report and review of the literature

Adenoid cystic carcinoma (ACC) is a rare low-grade malignant epithelial tumor that usually originates in the salivary glands. It shows a slow progression and metastasizes rarely. A 74-year-old male patient was admitted to our clinic due to pulmonary lesions seen on a chest-X ray coincidentally. The patient, 6 years before admission, was operated on for a peptic ulcer perforation and a right hilar mass lesion, and bibasilar pulmonary nodular lesions were also found on his chest radiograph. A bronchoscopic biopsy revealed ACC and surgical treatment was offered to the patient; however, he refused it. The patient, who had a 130-pack-year smoking history, was asymptomatic on admission to our clinic. Since metastatic pulmonary lesions were present, the patient was diagnosed with stage IV lung cancer and given chemotherapy. Thorax computerized tomography, performed after treatment, revealed no change in the size or number of pulmonary lesions, and the patient has been followed since then and is still asymptomatic. This case of metastatic ACC was reported, after a review of the literature, as being a rare case, as the patient revealed no symptoms from the time of diagnosis until the end of treatment.

Staging of neuroendocrine tumours: comparison of [68Ga]DOTATOC multiphase PET/CT and whole-body MRI

Purpose: In patients with a neuroendocrine tumour (NET), the extent of disease strongly influences the outcome and multidisciplinary therapeutic management. Thus, systematic analysis of the diagnostic performance of the existing staging modalities is necessary. The aim of this study was to compare the diagnostic performance of 2 whole-body imaging modalities, [68Ga]DOTATOC positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging (MRI) in patients with NET with regard to possible impact on treatment decisions. Materials and methods: [68Ga]DOTATOC-PET/CT and whole-body magnetic resonance imaging (wbMRI) were performed on 51 patients (25 females, 26 males, mean age 57 years) with histologically proven NET and suspicion of metastatic spread within a mean interval of 2.4 days (range 0–28 days). PET/CT was performed after intravenous administration of 150 MBq [68Ga]DOTATOC. The CT protocol comprised multiphase contrast-enhanced imaging. The MRI protocol consisted of standard sequences before and after intravenous contrast administration at 1.5 T. Each modality (PET, CT, PET/CT, wbMRI) was evaluated independently by 2 experienced readers. Consensus decision based on correlation of all imaging data, histologic and surgical findings and clinical follow-up was established as the standard of reference. Lesion-based and patient-based analysis was performed. Detection rates and accuracy were compared using the McNemar test. P values <0.05 were considered significant. The impact of whole-body imaging on the treatment decision was evaluated by the interdisciplinary tumour board of our institution. Results: 593 metastatic lesions were detected in 41 of 51 (80%) patients with NET (lung 54, liver 266, bone 131, lymph node 99, other 43). One hundred and twenty PET-negative lesions were detected by CT or MRI. Of all 593 lesions detected, PET identified 381 (64%) true-positive lesions, CT 482 (81%), PET/CT 545 (92%) and wbMRI 540 (91%). Comparison of lesion-based detection rates between PET/CT and wbMRI revealed significantly higher sensitivity of PET/CT for metastatic lymph nodes (100% vs 73%; P < 0.0001) and pulmonary lesions (100% vs 87%; P = 0.0233), whereas wbMRI had significantly higher detection rates for liver (99% vs 92%; P < 0.0001) and bone lesions (96% vs 82%; P < 0.0001). Of all 593 lesions, 22 were found only in PET, 11 only in CT and 47 only in wbMRI. The patient-based overall assessment of the metastatic status of the patient showed comparable sensitivity of PET/CT and MRI with slightly higher accuracy of PET/CT. Patient-based analysis of metastatic organ involvement revealed significantly higher accuracy of PET/CT for bone and lymph node metastases (100% vs 88%; P = 0.0412 and 98% vs 78%; P = 0.0044) and for the overall comparison (99% vs 89%; P < 0.0001). The imaging results influenced the treatment decision in 30 patients (59%) with comparable information from PET/CT and wbMRI in 30 patients, additional relevant information from PET/CT in 16 patients and from wbMRI in 7 patients. Conclusion: PET/CT and wbMRI showed comparable overall lesion-based detection rates for metastatic involvement in NET but significantly differed in organ-based detection rates with superiority of PET/CT for lymph node and pulmonary lesions and of wbMRI for liver and bone metastases. Patient-based analysis revealed superiority of PET/CT for NET staging. Individual treatment strategies benefit from complementary information from PET/CT and MRI.

A single-institution study of stereotactic body radiotherapy for patients with unresectable visceral pulmonary or hepatic oligometastases

PurposeThe purpose of this study is to evaluate the feasibility, efficacy and toxicity of SBRT for treatment of unresectable hepatic or lung metastases regardless of their primary tumor site for patients who received prior systemic chemotherapy.Methods and materialsBetween July 2007 and June 2010, 90 patients were treated with the CyberKnife® SBRT system for hepatic or pulmonary metastatic lesions. Medical records were retrospectively reviewed. The endpoints of this study were local control, overall survival (OS), disease-free survival (DFS), local relapse free-survival (LRFS), and treatment toxicity.ResultsA total of 113 liver and 26 lung metastatic lesions in 52 men (58%) and 38 women (42%) were treated. Median follow-up was 17 months. Median age at treatment was 65 years (range, 23–84 years). Primary cancers were 63 GI, three lung, eight breast, four melanoma, three neuro-endocrine tumors, and three sarcomas. Median diameter of the lesions was 28 mm (range, 7–110 mm) for liver and 12.5 mm (range, 5–63.5 mm) for lung. Local control rates at 1 and 2 years were 84.5% and 66.1%, respectively. Two-year overall survival rate was 70% (95% CI: 55–81%). The 1 and 2-year disease-free survival rates were 27% (95% CI: 18–37%) and 10% (95% CI: 4–20%), respectively. Median duration of disease-free survival was 6.7 months (95% CI: 5.1–9.5 months). Observed toxicities included grade 1–3 acute toxicities. One grade 3 and no grade 4 toxicity were reported.ConclusionHigh-dose SBRT for metastatic lesions is both feasible and effective with high local control rates. Overall survival is comparable with other available techniques. Treatment is well tolerated with low toxicity rates. It could represent an interesting treatment option for oligometastatic patients not amenable to surgery, even when patients had been pre-treated with chemotherapy.SummaryStereotactic body radiotherapy (SBRT) has previously been successfully used in the treatment of metastatic lesions. It could be considered as a curative option for oligometastatic patients. This retrospective study involved 90 patients, designed to test potential effectiveness of SBRT in the treatment of oligometastases irrespective of primary. Results suggest SBRT could be an effective treatment extending patients’ life span. This treatment appears to be more effective when used prior to multiple systemic treatment regimens.

97P The Role of Id Proteins in the Induction of Tumor-Initiating Cells During Pulmonary Colonization of Metastatic Breast Cancer

ABSTRACT Breast cancer studies have revealed distinct subpopulations of tumor cells with a high capacity for de novo tumor growth initiation. Tumor-initiating cells (TICs) constitute a small percentage of the bulk tumor and may be responsible for breast cancer relapse in patients. Recently, it has been shown that induction of the epithelial-to-mesenchymal transition (EMT) can trigger reprogramming of cells to a TIC-like phenotype, suggesting a direct relationship between EMT and TIC. Our studies demonstrate that the transcriptional regulator Id1, which has been shown to be important in maintaining the self-renewal and stem cell properties in a variety of normal cell lineages, can induce TIC properties in breast cancer cells independently from EMT. Importantly, factors such as Snail, Twist and TGF-b, which induce EMT and TIC potential, also induce Id expression and we show Id is required for the maintenance of TIC properties. In various mouse models of breast cancer, sporadic Id expression is localized to the invasive edge of the primary tumor, while it is more widely expressed in lung metastatic sites. It has been previously shown that the Id proteins Id1 and Id3 are required for the re-initiation of pulmonary metastatic lesions, which fits well with our discovery of the induction of TICs by Id1 over-expression. But in addition to re-initiation, in order to colonize the metastatic site cells also undergo a mesenchymal-to-epithelial transition (MET). Over-expression of Id1 may also fulfill this need as we show that Id1 over-expression is correlated with a more epithelial phenotype. Furthermore, breast cancer cells that have undergone EMT due to Twist over-expression revert to an epithelial phenotype upon Id1 over-expression while maintaining their TIC properties. As a possible mechanism of Id1 induction, we have observed that TGF-b induces Id1 expression in Snail and Twist over-expressing cells. Therefore we propose that TGF-b up-regulation of Id1 in cells undergoing EMT (i.e. at the primary site) is sufficient to maintain the TIC character of these cells even when factors maintaining an EMT state are no longer present (i.e. during MET at the metastatic site). Disclosure All authors have declared no conflicts of interest.

Oncolytic Virus and Anti–4-1BB Combination Therapy Elicits Strong Antitumor Immunity against Established Cancer

Oncolytic virotherapy using vaccinia virus (Vv) has shown some encouraging antitumor responses in mouse models and patients, but the breadth of efficacy in clinical trials has been somewhat limited. Given that antitumor effects have correlated with increased host immune responses, we hypothesized that improved therapeutic outcomes may be achieved by using oncolytic virus (OV) in combination with a potent immune agonist reagent. In this study, we carried out a preclinical evaluation of a genetically engineered strain of oncolytic vaccinia virus (Vvdd) for its capacity to induce antitumor responses when combined with an agonist antibody (Ab) specific for the costimulatory molecule 4-1BB (CD137). In immune-competent syngeneic mouse models of cancer, this combination therapy significantly reduced the growth of established subcutaneous tumors relative to either treatment alone. Importantly, the development of pulmonary metastatic lesions was also reduced. Tumor growth inhibition was associated with increased numbers of CD11b(+) and CD11c(+) myeloid cells in the tumor draining lymph nodes, greater infiltration of CD8(+) effector T and natural killer (NK) cells, and a more sustained presence of neutrophils at the tumor site. Depletion of T or NK cells or neutrophils reduced efficacy, confirming their contribution to an effective therapeutic response. We further extended this conclusion through results from IFNγ-deficient mice. In summary, our findings offered a proof-of-concept for a combinatorial approach to enhance the antitumor efficacy of an OV, suggesting a strategy to improve their use as an immunotherapeutic treatment for cancer.

What Would You Do? Challenges in Knee Surgery

18F-5-fluoro-N-(2-(Diethylamino)ethyl)picolinamide (18F-5-FPN) is a new positron-emission tomography (PET) radiopharmaceutical with potential for the detection of lymph node (LN) and pulmonary metastatic lesions of melanoma. We compared its performance with that of 18F–deoxyglucose (18F–FDG).Cervical LN and lung melanoma metastasis models were established in C57BL/6 mice. Primary tumors were created by injection of melanoma cells into the pinna, and the resulting cervical LN metastases were evaluated. Lung metastases were created by intravenous injection of melanoma cells. The mice underwent 18F–FDG and 18F-5-FPN positron emission tomography (PET) imaging. A biodistribution study was conducted after imaging. Histopathologic evaluation of the tumors was also performed.LN metastases with a diameter < 1 cm were more visible on 18F-5-FPN PET imaging than 18F–FDG imaging. Quantitative analysis showed that the uptake of 18F-5-FPN was significantly higher than that of 18F–FDG, with values of 13.29 ± 3.80% ID/g and 7.24 ± 1.95% ID/g (n = 5, P < 0.05), respectively. LN-to-muscle ratios were 21.23 ± 6.02 and 4.50 ± 2.11 (n = 5, P < 0.01) for 18F-5-FPN and 18F–FDG, respectively. Biodistribution results were similar, with high uptake of 18F-5-FPN in the LN. 18F-5-FPN imaging manifested the pulmonary lesions clearly, while the 18F–FDG imaging showed no uptake in lesions <2 mm. The related uptakes of 18F-5-FPN and 18F–FDG were 3.12 ± 1.17% ID/g and 1.48 ± 0.15% ID/g, respectively (n = 5, P < 0.05), with lung metastasis-to-muscle ratios of 8.16 ± 3.12 and 1.28 ± 0.18 (n = 5, P < 0.01), respectively. H&E and Prussian blue staining displayed pluri nucleated or mega nucleus cells and dark brown granules in the metastatic tissues, characteristic of melanoma.18F-5-FPN targeted small metastatic lesions with a higher target-to-normal ratio of uptake than those of 18F–FDG, which suggests its ability to detect metastatic lesions earlier than 18F–FDG. Further studies with a wide range of melanoma cell lines should be needed to confirm the similar performance.

Metastatic Patterns of Myxoid/Round Cell Liposarcoma: A Review of a 25-Year Experience

Myxoid/round cell liposarcoma (MRCL), unlike other soft tissue sarcomas, has been associated with unusual pattern of metastasis to extrapulmonary sites. In an attempt to elucidate the clinical features of MRCL with metastatic lesions, 58 cases, from the medical database of Keio University Hospital were used for the evaluation. 47 patients (81%) had no metastases, whereas 11 patients (11%) had metastases during their clinical course. Among the 11 patients with metastatic lesions, 8 patients (73%) had extrapulmonary metastases and 3 patients (27%) had pulmonary metastases. Patients were further divided into three groups; without metastasis, with extrapulmonary metastasis, and with pulmonary metastasis. When the metastatic patterns were stratified according to tumor size, there was statistical significance between the three groups (P = 0.028). The 8 cases with extrapulmonary metastases were all larger than 10 cm. Similarly, histological grading had a significant impact on metastatic patterns (P = 0.027). 3 cases with pulmonary metastatic lesions were all diagnosed as high grade. In conclusion, large size and low histological grade were significantly associated with extrapulmonary metastasis.

Uncommon Pulmonary Metastases and Metastasectomy: A Review

Background: The development of pulmonary metastases is a critical step in oncology management as it is a major determinant of survival for patients with cancer. Primaries that commonly metastasize to the lung arise from breast, head/neck, and the gastrointestinal tract. The aim of this study was to review the pathobiogenesis of pulmonary metastases and the evolution of curative pulmonary metastasectomy as reported in the literature in addition to analyzing in detail uncommon pulmonary metastatic lesions received over a period of 14 years. Design: The indexed uncommon pulmonary metastases were reviewed and analyzed in detail. A 14-year (1996-2010) computer-based review using the Laboratory-Information-System was conducted in our laboratory. Results were categorized based on age, sex, and primary sites of origin with special emphasis to study unusual pulmonary metastases. Results: 230 cases of pulmonary metastases were retrieved on review. 129 females (56%) and 101 males (44%) ranging in age from 19 months to 91 years (median 65 years) were identified with their primary sites of origin being: breast (28.3%), gastrointestinal tract (27.8%), kidney (8.7%), and melanoma (7.0%). Three uncommon diagnoses were identified and studied in detail: 1) an index case of metastatic benign pleomorphic adenoma, case series of 2) endometrial stromal sarcoma and 3) osteosarcoma. Conclusion: Due to the poor prognosis of metastatic lung cancer, early recognition with accurate diagnosis is an important step for optimal patient management. In this context, pathologic awareness of uncommon metastases remains a challenging task. Pulmonary metastasectomy is a curative option for an increasing number of patients due to recent advances in chemotherapy that achieve locoregional control of the primary tumours. With this increased number of pulmonary metastasectomy, recognition of not only ‘common’ pulmonary malignancies but also more rare entities becomes central to best practices in surgical pathology.

Primary Adrenal Leiomyosarcoma: Case Report and Review of Literature

Primary adrenal leiomyosarcomas are rare and usually symptomatic at presentation. The presentation of a large adrenal mass should raise suspicion of adrenal leiomyosarcoma as a differential diagnosis. To our knowledge, primary adrenal leiomyosarcoma has been reported in 20 cases in the English literature. Here we describe a case of primary adrenal leiomyosarcoma in a 76-year-old Caucasian female. The patient complained of right upper quadrant abdominal pain for 2 months. Contrast-enhanced magnetic resonance imaging showed a heterogeneous 10.5 cm adrenal mass with a suspected inferior vena cava tumor thrombus without lymph node enlargement or distant metastasis. The patient underwent a right adrenalectomy, partial resection of the inferior vena cava and reconstruction of the inferior vena cava with a pericardial patch. Histopathologic examination was consistent with leiomyosarcoma. At 3 months postoperatively, a follow-up computed tomography scan of the chest, abdomen and pelvis without intravenous contrast was done that showed multiple bilateral pulmonary metastatic lesions, bilateral hilar and mediastinal lymphadenopathy, liver metastasis, a new mass at the head of the pancreas, and a new mass at the lower pole of the right kidney. The patient was deemed to be unfit for systemic chemotherapy, and was referred to the hospice service for palliative care. The patient died 4 months after surgery.

Palliative radiation therapy for pulmonary metastases from hepatocellular carcinoma

Although the lung is the most common site of extrahepatic metastases from hepatocellular carcinoma (HCC), the optimal treatment for such metastases has'nt been established. External beam radiotherapy (EBRT) is becoming a useful local control therapy for lung cancer. To evaluated the efficacy of EBRT treatment for such metastases, we retrospectively studied 13 patients (11 men and 2 women; mean age, 52.6 years) with symptomatic pulmonary metastases from HCC who had been treated with EBRT in our institution. The palliative radiation dose delivered to the lung lesions ranged from 47 to 60 Gy (median 50) in conventional fractions, while the intrahepatic lesions were treated with surgery or transarterial chemoembolization, and/or EBRT. Follow-up period from radiotherapy ranged from 3.7 to 49.1 months (median, 16.7). Among the 13 patients, 23 out of a total of 31 pulmonary metastatic lesions received EBRT. In 12/13(92.3%) patients, significant symptoms were completely or partially relieved. An objective response was observed in 10/13(76.9%) of the subjects by computed tomography imaging. The median progression-free survival for all patients was 13.4 months. The 2-year survival rate from pulmonary metastasis was 70.7%. Adverse effects were mild and consisted of bone marrow suppression in three patients and pleural effusion in one patient (all CTCAE Grade II). In conclusion, EBRT with ≤60 Gy appears to be a good palliative therapy with reasonable safety for patients with pulmonary metastases from HCC. However, large-scale randomized clinical trials will be necessary to confirm the therapeutic role of this method.

Surgical Approach to Pulmonary Metastases from Breast Cancer

One of the main characteristics of breast cancer is its capability to disseminate. Solitary pulmonary metastases from breast cancer occur rarely (0.4%). The aim of this study is to check whether or not the outcome following the surgical treatment of pulmonary metastases in patients with breast cancer is in accordance with the data in the literature and based on it to identify prognostic factors. We have reviewed retrospectively data for 33 patients who underwent 43 curative resections of breast cancer pulmonary metastases between 1997 and 2002 at our department. Potential prognostic factors affecting survival, namely survival after lung metastasectomy, assessed were disease-free interval (DFI), the number and location of lung metastases, the diameter in mm of metastases and the extent of pulmonary resection. The median survival for 33 patients with pulmonary breast cancer metastatic lesions after metastasectomy was 73.2 months. Mean 5-year survival was 54.5%. There was a statistically significant difference in survival time with better prognosis for patients with DFI > 36 months (p = 0.0007), complete metastasectomy (p = 0.0153), unilateral pulmonary metastases (p=0.0267) and for patients who underwent multiple operations (p = 0.0211). In multivariate analysis there was significant influence for long-term prognosis for patients with DFI > 36 months (p = 0.0446) and for complete resection of the metastases (p = 0.0275). Analysis of the survival rates for patients with solitary pulmonary metastasis, with different size of tumors and after different types of pulmonary resection showed no significant differences. It was concluded that resection of lung metastases from breast cancer may offer a significant survival benefit for selected patients. The identified prognostic factor for survival after metastasectomy is DFI longer than 36 months and complete resection of the metastases. In our group of patients, DFI longer than 36 months, unilateral pulmonary metastases and number of operations significantly influenced survival. Also, the results showed that lung metastasectomy by conventional surgery is a safe procedure with low perioperative morbidity and mortality rate.

Microwave Ablation Therapy: Clinical Utility in Treatment of Pulmonary Metastases

To prospectively evaluate the safety and efficacy of microwave ablation therapy of unresectable pulmonary metastases. All patients provided informed consent for this prospective institutional review board-approved study. Eighty patients (30 men, 50 women; mean age, 59.7 years ± 6.4; range, 48-68 years) underwent computed tomography-guided percutaneous microwave ablation of pulmonary metastatic lesions in 130 sessions. The tumors represented metastases from colorectal carcinoma, breast carcinoma, hepatocellular carcinoma, renal cell carcinoma, and bronchogenic carcinoma; there was no evidence of extrapulmonary metastasis for any tumor. Logistic regression analysis was used for evaluation of the statistical significance of factors affecting the end result of microwave ablation therapy. The Kaplan-Meier method was used for estimation of survival rates. Complete, successful ablation was achieved in 95 (73.1%) of 130 lesions. Successful tumor ablation was significantly more frequent for lesions with a maximal axial diameter of 3 cm or smaller (90 of 110) than for lesions greater than 3 cm in maximal axial diameter (five of 20) (P < .0001) and for peripheral lesions (80 [80%] of 100) than for centrally located lesions (15 [50%] of 30) (P = .002). The histopathologic type of the metastasis did not significantly correlate with the ablation result (P > .3). The 12- and 24-month survival rates were 91.3% and 75%, respectively. There was no intraprocedural death, and the overall 60-day mortality rate after ablation was 0%. Higher survival rates were observed in patients with tumor-free states after successful ablation than in patients with failed ablation (P = .001). The incidence of pneumothorax was 8.5% (11 of 130). An intercostal chest tube was applied in one (0.8%) of the 11 sessions. Pulmonary hemorrhage developed in eight (6.2%) of 130 sessions. Microwave ablation therapy may be safely and effectively used as a therapeutic tool for treatment of pulmonary metastases. The efficacy of the treatment is primarily determined by preablation tumor size and location in relation to the hilum.

Preliminary study of whole-body diffusion-weighted imaging in detecting pulmonary metastatic lesions from clear cell renal cell carcinoma: comparison with CT

Whole-body diffusion-weighted imaging (DWI) has been widely used in detecting malignant metastases, including pulmonary metastases. To evaluate the possible utility of whole-body DWI in detecting pulmonary metastases of patients with clear cell renal cell carcinoma (ccRCC) and compare the exact differences between MR and CT in detecting pulmonary lesions. Whole-body DWI and chest CT examinations were performed on nine consecutive patients (8 men and 1 woman) with histologically confirmed ccRCC and possible metastatic lesions before chemotherapy. CT and MR demonstrated pulmonary metastases in seven patients and no metastatic lesions in two patients. The numbers of pulmonary metastases detected on CT, DWI-only, T1WI-only and DWI in combination with T1WI were 83, 35, 34 and 39, respectively. Metastases with a diameter above 1.0 cm could all be detected by DWI and a diameter above 0.7 cm could all be detected by DWI in combination with T1WI. Significant differences were obtained both for correlationship between diameter and detection rates of DWI and T1WI by using Spearman rank correlation analysis. Although MR cannot be considered a replacement for CT in pulmonary metastases from ccRCC, whole-body DWI, with the combination of T1 dual echo, might be helpful for the evaluation of tumor response to chemotherapy in the follow-up of patients when the diameter of the pulmonary metastases is over 1.0 cm.

Resection of lung metastases from hepatocellular carcinoma after living donor liver transplantation: Report of two cases

Hepatocellular carcinoma (HCC) recurrence after liver transplantation is associated with a poor prognosis; nonetheless, we report two cases of long-term survival after resection of pulmonary metastatic lesions following living donor liver transplantation (LDLT). The intervals between LDLT and pulmonary resection for the metastatic lesion were 24 months and 30 months, respectively. Regular checking of tumor markers and prompt workup for early detection may contribute to the resectability of such metastatic lesions. These cases suggest that resection of a solitary metastatic lesion in the lung from HCC after liver transplantation may be a feasible treatment for selected patients.

A Prospective Study to Determine the Incidence of Non-Imaged Malignant Pulmonary Nodules in Patients Who Undergo Metastasectomy by Thoracotomy With Lung Palpation

To prospectively assess the incidence of non-imaged malignant nodules in patients who undergo thoracotomy for metastasectomy with bimanual lung palpation. This is a prospective cohort study of patients who underwent open metastasectomy by thoracotomy. All patients had metastatic lung lesions, underwent 64-slice helical computed tomographic (CT) scan with intravenous contrast using 5-mm collimated cuts, and most had integrated PET (positron emission tomography)-CT. Unsuspected malignant pulmonary nodules that were palpated and removed, and that were not imaged preoperatively, were recorded. From January 2006 to March 2010, 152 patients underwent metastasectomy by rib-sparing, nerve-sparing thoracotomy by 1 surgeon. Fifty-one (34%) patients had 57 pulmonary nodules that were not imaged preoperatively and 32 of the 57 (56%) nodules were malignant. Thirty patients had non-imaged malignant nodules that were palpated and removed. There were 15 malignant nodules that were in different lobes than the imaged nodules. The 3 most commonly missed malignant nodules occurred in patients with colorectal cancer, renal cell, and sarcoma. Metastasectomy by thoracotomy, which affords bimanual palpation of the entire lung, discovers ipsilateral non-imaged malignant pulmonary metastases in 1 of 5 patients who had at least 1 imaged metastatic pulmonary lesion. This is true despite preoperative, fine cut chest CT scan with contrast, and integrated 18F-fluorodeoxyglucose-PET-CT scanning. The clinical significance of these non-imaged, resected malignant nodules is unknown, nor is the added morbidity of resecting benign nodules.

Functional characterization of IGFBP5 in the inhibition of osteosarcoma tumorgenicity.

10038 Background: Osteosarcoma (OS) is the most common primary malignancy of bone. At presentation, the majority of patients have metastatic disease. Therefore, there is a clinical need to identify molecular markers that provide insight into the pathogenesis OS. The goal of this investigation is to functionally characterize the novel marker, IGFBP5, in osteosarcoma tumor progression. Methods: We created adenoviral constructs expressing the unique domains of IGFBP5 (N-term, C-term, linker), full length IGFBP5, and siIGFBP5. We conducted in vitro and in vivo assays on adenovirally infected OS cell lines MG63, MG63.2, and 143B. Western blot and immunohistochemical (IHC) staining were used to assay the apoptotic marker Caspase 3. Cell migration and invasion were measured using Wound Healing and Matrigel assays. Osteoblastic differentiation was measured using alkaline phosphastase activity and IHC staining for the late osteogenic markers osteocalcin and osteopontin. Finally, clinical patient samples were stained for IGFBP5 expression in patient matched primary tumors and metastatic pulmonary lesions. Results: IGFBP5 inhibited in vitro cell proliferation, migration and invasion of OS cells. Additionally, IGFBP5 overexpression promoted apoptosis and osteogenic differentiation. Analysis of the three functional domains indicated that the N-terminal domain was primarily responsible for inhibiting cell proliferation and inducing apoptosis, while the C-terminal domain inhibited cell migration and invasiveness. In an orthotopic animal model, overexpression of IGFBP5 inhibited OS tumor growth and lung metastasis, while siRNA-mediated knockdown of IGFBP5 promoted OS tumor growth and lung metastasis. IHC staining of clinical OS samples confirmed that primary OS tumors expressed significantly lower levels of IGFBP5 than their corresponding pulmonary metastases. Conclusions: These results suggest that IGFBP5 is a novel marker in OS pathogenesis, and the loss of IGFBP5 function may contribute to more metastatic phenotypes in OS. Furthermore, while the N-terminal domain of IGFB5 is responsible for inhibition of cell proliferation, the C-terminal domain is responsible for inhibiting cell invasion and migration.

Abstract 2422: Epithelial interleukin-4 receptor promotes metastasis of mammary tumor cells

Abstract Interleukin-4 (IL4) is known primarily for its immune system functions where it can stimulate lymphocytes and promote macrophage activation. Various cancer cells, including breast, are now known to express functionally active IL4 receptors, which appear to play a role in cell survival. We believe that blocking IL4 signaling specifically in epithelial cells will attenuate metastasis because of reduced cell survival in secondary sites. To test this hypothesis, we have generated multiple clones of two murine mammary tumor cell lines that show efficient knockdown of an essential component of the IL4 receptor, IL4-receptor [IL4R] alpha. Initial characterization of knockdown and control clones showed a significantly slower growth rate in vitro as assessed both by metabolic (MTT) assays and direct cell counting. Flow cytometric analysis using either annexin V staining or sub G1 measurement showed that clones lacking IL4Ralpha had 2-fold higher basal levels of apoptosis. To test effects in vivo, we have performed experimental and spontaneous metastasis assays using clones of the 4T1 cell line. Both pulmonary and hepatic metastatic lesions were significantly decreased [2.4-fold lower] in mice injected with IL4Ralpha knockdown clones compared to controls. There was however no significant effect on the primary mammary tumors. Together these results suggest that IL4 signaling in epithelial tumor cells is pro-metastatic, and blocking it may be a useful therapeutic approach for preventing metastatic spread. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2422. doi:10.1158/1538-7445.AM2011-2422

Complete Resection of Pulmonary Metastatic Melanoma

BackgroundThe prognosis of melanoma metastasized to other organs is very poor. There have been many studies on metastatic melanoma in Western society, but there have been few studies done in Korea because of the small number of cases.Materials and MethodsA retrospective review of 7 patients who underwent complete resection of pulmonary metastases from melanoma from January 2005 to December 2009 was performed. When the primary lesion was controlled or simultaneously controllable and no other metastatic lesion was found, pulmonary resections were performed. We analyzed the clinical prognoses after the initial melanoma diagnosis.ResultsOf the seven patients, one was male and six were female. The mean age was 58.2 years (range 45~71). Six patients had a single pulmonary lesion and one patient had three lesions confined to the same lobe. The mean disease-free interval was 43.5 months (0~146 months). Before pulmonary resection, 4 patients had received systemic therapy. After pulmonary resection, 6 patients received systemic therapy. Complete resection was confirmed histologically. The metastasectomy was performed by wedge resection (6 patients) or lobectomy (1 patient). There were no mortalities or complications. After pulmonary resection, 1 patient had recurrent multiple lesions in the lung and 4 patients had metastases to other organs. The organs were the liver, brain, pleura, and lymph nodes. The mean observation time was 31.6 months and 3 patients died during observation. The mean survival was 27.7 months (14~60 months) and the 1-year and 3-year survival rates were 100% and 42%, respectively.ConclusionWhen patients were selected carefully, the complete resection of pulmonary metastatic lesions was considered a major therapeutic tool.

103P NEPHROBLASTOMA (WILMS TUMOR) IN AN ADULT PRESENTING WITH LUNG METASTASES

Introduction: Wilms tumor (nephroblastoma) represents 20% of malignant tumors in childhood. Less than 3% of diagnosed cases are found in adults and 10% of those are diagnosed in stage IV with multiple metastases (contralateral kidney, liver etc). Lung metastases is uncommon (<10%). Purpose: Reporting a clinical case of an adult patient diagnosed with Wilms tumor (stage IV) presenting with multiple lung metastases. Material and Methods:We retrospectively studied patient’s medical records and thoroughly reviewed the disease course, clinical, laboratory and imaging investigations and patient outcome. Results: A 39 year-old female patient was admitted to hospital due to a progressively worsening exertional dyspnea and bilateral gluteal pain for the past 3 months. The patient presented with hypoxia. Chest X ray revealed multiple bilateral nodular lesions that were confirmed by Chest Computed Tomography (CT) as metastatic lesions. Abdominal CT scan showed a solid and partially cystic mass (7.7 cm diameter) in left upper renal lobe causing compression to surrounding structures and an epidural lumbar mass (L1-L2) that was diagnosed as metastases by spinal MRI. The patient underwent a nephrectomy. Histological examination revealed nephroblastoma Grade IV. The patient received palliative radiotherapy in the lumbar spine (28Gy) and chemotherapy (2 sessions of Adriamycin, Vincristine, Actinomycin-D: Protocol SIOP Willms Tumor final Version 2002) with a good response. Three months later disease progression was observed and 8 new chemotherapy sessions followed (Isofosfamide, carboplatin, etoposide, and Bevasizumab). Additionally 3 new sessions with Farmoroumpicine, Cyclophosphamide, Vincristine and Etoposide were performed that stabilized evolution and reduced pulmonary lesions’ size. Conclusions: Nephroblastoma in adults and multiple metastatic pulmonary lesions are both uncommon. In symptomatic patients, chemotherapy combined with stereotactic radiation therapy are both suggested after nephrectomy. Radiation therapy is advised in the surgical field (when surgical borders and lymph nodes are positive) and metastasectomy by means of modern radiotherapeutic methods (IMRT-IGRT, Cyberknife). Disclosure: All authors have declared no conflicts of interest.

Preoperative chest computerized tomography in patients with locally advanced mid or lower rectal cancer: Its role in staging and impact on treatment strategy

Pulmonary metastasis is frequent in rectal cancer. Some guidelines recommend chest computerized tomography (CT) for preoperative workup in rectal cancer patients, which have no solid evidence to support this recommendation. This study was designed to evaluate the role of chest CT on preoperative staging in rectal cancer patients and to assess the impact on treatment strategy. Data were prospectively collected from 103 clinically T3/T4 mid or lower rectal cancer patients who had chest X-ray (CXR) and CT to evaluate lung metastasis. The chest images were classified into four groups: metastasis, indeterminate, benign, and negative. Patients showing indeterminate lesions had follow-up CTs at 3- to 6-month intervals. Nine patients (8.7%) had pulmonary metastases detected on CT. CXR did not reveal any pulmonary metastatic lesions in four of the nine patients. Of these four, treatment was changed in three patients because of these findings. Forty (38.8%) patients had indeterminate nodules on chest CT. Of these, 37 patients had follow-up CTs and four patients (10.8%) showed interval changes that were confirmed as pulmonary metastasis. It seems reasonable to perform chest CT for preoperative staging in patients with T3/T4 mid or lower rectal cancer.