Surgical approach to pulmonary metastases from breast cancer

Abstract: 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.     

Effects of systemic and regional chemotherapy after hepatic resection for colorectal metastases

Background: Although the survival benefit of hepatic resection for colorectal metastasis has been established, some controversy remains regarding the significance of adjuvant chemotherapy after hepatic resection. Methods: One hundred thirty-two consecutive patients who had liver resection for colorectal metastasis at our hospital between 1980 and 1997 were studied. After curative hepatic resection, 37 patients underwent systemic chemotherapy, administered orally or intraportally. Forty patients had no adjuvant chemotherapy. The chemotherapeutic agents used for oral administration were uracil and Tegafur or Tegafur alone. Mitomycin C (MMC) or 5-FU was used for IV chemotherapy. Combinations of 5-FU/leucovorin or MMC/5-FU (doxorubicin) were used for regional chemotherapy. Univariate and multivariate analyses were applied to test the significance of adjuvant chemotherapy for patient survival or disease-free survival. Results: Overall 5-year survival was 42.2% (95% CL: 31.2%, 53.2%). Among the possible prognostic factors studied, univariate analysis showed a significant difference in survival based on the number of tumors and lymph node metastases in the hepatic hilum. There was a significant difference in disease-free survival based on adjuvant chemotherapy and lymph node metastasis. The multivariate analysis for patient survival selected four prognostic factors (P<.05), including adjuvant chemotherapy, lymph node metastasis, disease-free interval, and tumor size. The multivariate analysis for disease-free survival selected adjuvant chemotherapy, lymph node metastasis, and disease-free interval as significant factors. The most common recurrence site was remnant liver, regardless of adjuvant chemotherapy. Conclusions: Adjuvant chemotherapy significantly improved survival and disease-free survival after hepatic resection for colorectal metastases. It did not decrease recurrence rate in the remnant liver.Presented at the 51st Annual Cancer Symposium of The Society of Surgical Oncology, San Diego, California, March 26–28, 1998.     

A new approach for performing a one-stage operation through the mediastinum to resect bilateral lung metastases: Report of a case

We describe herein a new operative technique for reaching the opposite lung from the thoracotomy site through the mediastinum. This procedure was successfully performed on a 76-year-old woman with bilateral lung metastases whose case is presented. After resection of the right lower lobe which contained two metastases, the anterior mediastinum was opened, and contralateral metastasis located in the lingular segment was resected using a neodymium:yttrium-aluminum-garnet (Nd:YAG) laser. A chest drainage tube was inserted through the mediastinal window. This transmediastinal approach seems to be a feasible technique for preserving the respiratory function of the chest wall in patients with imbalanced bilateral metastases.     

In-vivo evaluation of a novel bipolar radiofrequency device for interstitial thermotherapy of liver tumors during normal and interrupted hepatic perfusion

BACKGROUND: Only monopolar systems have thus far been available for radiofrequency ablation of liver tumors, whose application is restricted because of the incalculable energy flow, reduction of electrical tissue conduction, and limited lesion size. The aim of this study was to evaluate a novel internally cooled bipolar radiofrequency application device under in vivo conditions and to compare the effect of this system on lesion size when combined with hepatic arterial microembolization or complete hepatic blood flow occlusion. MATERIALS AND METHODS: In a porcine liver model, RFA (60 W, 12 min) was performed with either normal (n = 12), partially interrupted (arterial microembolization via a hepatic artery catheter n = 12) or completely interrupted hepatic perfusion (Pringle's maneuver, n = 12). RFA parameters (impedance, power output, temperature, applied energy) were determined continuously during therapy. RFA lesions were macroscopically assessed after liver dissection. RESULTS: Bipolar RFA induced clinical relevant ellipsoid thermal lesions without complications. Hepatic inflow occlusion led to a 4.3-fold increase in lesion volume after arterial microembolization and a 5.8-fold increase after complete interruption (7.4 cm(3)versus 31.9 cm(3)versus 42.6 cm(3), P < 0.01). CONCLUSIONS: The novel bipolar RFA device is a safe and effective alternative to monopolar RFA-systems. Interrupting hepatic perfusion significantly increases lesion volumes in bipolar RFA. This beneficial effect can also be achieved in the percutaneous application mode by RFA combined with arterial microembolization via a hepatic artery catheter.     

The role of the new Ca2+ antagonist, CV159, in hepatic I/R injury-the evaluation of hepatic organ reducing activity using in vivo and ex vivo EPR

We investigated the organ-reducing ability of 1,2-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine-dicarboxylic acid methyl 6-(5-phenyl-3-pyrazolyloxy) hexyl ester (CV159) that exhibits selective blocking of Ca(2+)/calmodulin and inhibition of Ca(2+) overloading in living organisms (Sprague Dawley rats) using an in vivo and an ex vivo electron paramagnetic imaging technique. Decay rates in CV159-treated rats were significantly higher than those in untreated rats and were almost equal to those in the sham group. Both cytosol and mitochondrial superoxide scavenging activity in CV159-treated rats were significantly higher than those in untreated rats, and cytosol superoxide scavenging activity only was slightly higher than that in the sham group. Faint staining for anti-superoxide dismutase antibody was markedly observed in necrotic lesions in the liver of control group. Alanine aminotransferase level in CV-treated rats were significantly decreased as compared with the levels in untreated rats. Electron microscopy showed a decreased number of damaged mitochondria, whereas mitochondrial damage was significantly reduced in CV-treated animals. We conclude that CV159 retains the organ-reducing activity against radicals in hepatic I/R injury that is mediated by the inhibition of Ca(2+) overloading.     

Attenuated Salmonella typhimurium prevents the establishment of unresectable hepatic metastases and improves survival in a murine model

Purpose

The authors investigated the utility of attenuated Salmonella typhimurium for preventing the establishment of hepatic metastases in a murine model.

Methods

A single, oral 10⁸ cfu dose of attenuated S typhimurium was given 8 days before the establishment of a model of unresectable hepatic metastases. Animals were assessed for hepatic tumor number and volume, hepatic lymphocyte population analysis, and survival.

Results

Pretreatment with Salmonella provided a 10-fold reduction in hepatic tumor burden compared with saline-treated controls. The antitumor effect is associated with markedly elevated natural killer (NK), CD8+ and CD4+ hepatic lymphocytes. Pretreatment with Salmonella provided a 90-day survival rate of 30%, whereas control animals were dead by 30 days. All long-term survivors were devoid of hepatic tumor.

Conclusions

Attenuated S typhimurium effectively prevents the establishment of hepatic metastases in a murine model, providing a clear survival benefit. Thus, it may represent a novel form of in vivo immunotherapy for the prevention of hepatic metastases for patients with locally advanced colorectal cancer.     

Protamine sulfate reduces the susceptibility of thermally injured mice to Pseudomonas aeruginosa infection

BACKGROUND: In this study, we investigated the ability of protamine sulfate, at sub-bactericidal dosing, to interfere with the in vivo virulence of Pseudomonas aeruginosa (PAO1) during burn wound infection. MATERIALS AND METHODS: The study was conducted using the murine model of thermal injury. Preliminary experiments determined a protocol for administration of protamine sulfate that had no in vivo bactericidal effects. Based on this, the effect of local injection of protamine sulfate on the in vivo virulence of PAO1 was assessed using these parameters: (1) the percent mortality among PAO1-infected, thermally injured mice; (2) the local proliferation and spread of PAO1 within the infected burned tissue; (3) the systemic spread of PAO1 within thermally injured/infected mice; and (4) the local cytokine response elicited by PAO1 thermally injured/infected mice. RESULTS: Injection of protamine sulfate into the thermally injured tissue of PAO1-infected/thermally injured mice significantly decreased the percent mortality and inhibited the systemic dissemination of PAO1 microorganisms to the liver and spleen. It had no effect, however, on the ability of the bacteria to proliferate and spread within the thermally injured tissue. It also was determined that protamine sulfate was ineffective at preventing mouse death at the dose administered if injected intramuscularly instead of directly into burned tissue. Protamine sulfate reduced the expression of the proinflammatory cytokines IL-6 and LIF in the injured/infected tissue. Heparan sulfate given in conjunction with protamine sulfate returned mortality levels to those of untreated mice. CONCLUSIONS: Our results suggest that: (1) local injection of sub-bactericidal doses of protamine sulfate reduces the virulence of P. aeruginosa; (2) this effect is due to interference with the systemic rather than local spread of P. aeruginosa; and (3) local application of protamine sulfate may have potential as supportive therapy for prevention of systemic P. aeruginosa infection in severely burned patients.     

Oncologic aspects of the decision-making process for surgical approach for colorectal liver metastases progressing during chemotherapy

Colorectal cancer represents the third most diagnosed malignancy in the world. The liver is the main site of metastatic disease, affected in 30% of patients with newly diagnosed disease. Complete resection is considered the only potentially curative treatment for colorectal liver metastasis (CRLM), with a 5-year survival rate ranging from 35% to 58%. However, up to 80% of patients have initially unresectable disease, due to extrahepatic disease or bilobar multiple liver nodules. The availability of increasingly effective systemic chemotherapy has contributed to converting patients with initially unresectable liver metastases to resectable disease, improving long-term outcomes, and accessing tumor biology. In recent years, response to preoperative systemic chemotherapy before liver resection has been established as a major prognostic factor. Some studies have demonstrated that patients with regression of hepatic metastases while on chemotherapy have improved outcomes when compared to patients with stabilization or progression of the disease. Even if disease progression during chemotherapy represents an independent negative prognostic factor, some patients may still benefit from surgery, given the role of this modality as the main treatment with curative intent for patients with CRLM. In selected cases, based on size, the number of lesions, and tumor markers, surgery may be offered despite the less favorable prognosis and as an option for non-chemo responders.     

Noninvasive visualization of tumor growth in a human colorectal liver metastases xenograft model using bioluminescence in vivo imaging

Background

Bioluminescence imaging (BLI) is an ideal tool for noninvasive, quantitative monitoring of tumor progression/regression in animal models. The effectiveness of different treatment strategies is displayed by an altered intensity of bioluminescence, demonstrating a change of the tumor burden. The aim of this study was to establish a reliable, reproducible colorectal hepatic metastases cancer animal model.

Methods

Cells of the human colon carcinoma cell line HCT-116 Luc^pos expressing the firefly luciferase enzyme gene were used. HCT-116 Luc^pos cells (2.5 × 10⁶) were injected through the portal vein into the liver of immunoincompetent nude mice. BLI was used to analyze intrahepatic tumor burden and growth kinetic.

Results

HCT-116 Luc^pos cells demonstrated a progressive and reproducible growth in the liver after intraportal injection. Four days after injection, the animals were analyzed for tumor growth by BLI, and mice without or too low bioluminescence signals were excluded (between 10% and 20% animals). HCT-116 Luc^pos intrahepatic tumors responded successfully to different dosages (5 and 10 mg/kg) of 5-fluorouracil.

Conclusions

BLI is an important tool with many potential advantages for investigators. The measurement of intrahepatic tumor growth by imaging luciferase activity noninvasively provides valuable information on tumor burden and effectiveness of therapy. Thus, the presented intrahepatic metastases model based on the growth of HCT-116 Luc^pos cells is suitable for in vivo testing of different cancer therapy strategies.     

Prognostic factors and survival after complete resection of pulmonary metastases from colorectal carcinoma: experiences in 167 patients

OBJECTIVE: Surgical resection is an important form of treatment for pulmonary metastases from colorectal carcinoma. We analyzed the clinical course, outcome, and prognostic factors after surgery. METHODS: Between 1985 and 2000, 167 patients (103 men, 64 women) underwent complete pulmonary resection of metastatic colorectal carcinoma. Only patients who met the criteria for potentially curative operation, in particular, control of the primary tumor, ability to resect all metastatic disease, and no other extrapulmonary metastases, were included. RESULTS: The overall 5-year survival was 32.4%. A significantly longer survival was observed in multivariate analysis in patients without lymph node involvement compared with patients with pulmonary or mediastinal lymph node metastases or both. The number of pulmonary metastases significantly influenced survival. In patients with a solitary metastasis, we observed a 5-year survival of 45%, whereas the rate was 19.8% in patients with more than a single metastasis. In multivariate analysis, we also found the prethoracotomy carcinoembryonic antigen serum level to be an independent significant prognostic factor for survival. In patients with a serum carcinoembryonic antigen level exceeding 5 ng/mL and in patients with a serum carcinoembryonic antigen level in the normal range, the 5-year survivals were 22.7% and 48.3%, respectively. CONCLUSIONS: We conclude that pulmonary resection of metastatic colorectal carcinoma is safe and results in long-term survival. Thoracic lymph node metastases, serum carcinoembryonic antigen level before metastasectomy, and the number of pulmonary metastases were identified as prognosis-related criteria for surgery.     

MF-tricyclic inhibits growth of experimental abdominal aortic aneurysms

BACKGROUND: Experimental abdominal aortic aneurysm (AAA) development can be pharmacologically suppressed by inhibiting matrix metalloproteinase-9 (MMP-9). Cyclooxygenase-2 (COX-2) inhibitors are potent anti-inflammatory agents that have been demonstrated to inhibit experimental aneurysm development. We hypothesized that treatment with MF-tricyclic, a selective COX-2 inhibitor, incorporated into rodent chow would inhibit aneurysm development in a rat AAA model. METHODS: Twelve male Sprague Dawley rats underwent induction of experimental AAA using intra-aortic porcine elastase infusion. Six rats received control feed, and six received MF-tricyclic rodent chow for a period of 14 days. Aortic diameters were measured pre- and postinfusion as well as at harvest. Aortic tissue samples were evaluated by real-time polymerase chain reaction (RT-PCR) for MMP-9, by immunohistochemistry for elastin. RESULTS: Elastase infusion produced AAA in all untreated rats. At 14 days MF-tricyclic-treated rats had significantly reduced aortic diameter (1.9 +/- 0.1 mm versus 2.4 +/- 0.0 mm, P = 0.00001). Percent increase in aortic diameter was also significantly less in animals receiving MF-tricyclic (65.7 +/- 8.5% versus 132.3 +/- 7.3%, P = 0.0001). RT-PCR demonstrated a decrease in the mean expression of MMP-9 in the treated animals (0.414 ng of RNA versus 1.114 ng of RNA) (P = 0.07). Sections stained for elastin demonstrated preserved elastin integrity in MF-tricyclic treated aortas. CONCLUSIONS: COX-2 inhibition helps to retard the growth of experimental AAAs possibly through inhibition of MMP-9. Experimentally treated animals demonstrated smaller aortic diameters and lower levels of tissue MMP-9 when compared to untreated animals. Selective COX-2 inhibition may offer an additional method to pharmacologically inhibit AAAs.     

3He-MRI-based vs. conventional determination of lung volumes in patients after unilateral lung transplantation: a new approach to regional spirometry

BACKGROUND: To use 3Helium (3He)-MRI in patients with unilateral lung grafts to assess the contributions of graft and native lung to total ventilated lung volume, and second to compare conventional measurements of intrapulmonary gas volume (spirometry, body plethysmography) with image-based volumetry of ventilated lung parenchyma visualized by hyperpolarized 3He-MRI. METHODS: With Ethics Committee approval, five patients with single lung transplantation (SLTX) for idiopathic pulmonary fibrosis (IPF) underwent both conventional pulmonary function testing (PFT) and 3He-MRI of the lung. Intrapulmonary gas volume (GV) during the inspiratory breathhold for 3He-MRI was calculated from measured functional residual capacity (corrected for supine position) and inspired tidal volume. Image-based global and regional lung volumetries (LV) were performed in three-dimensionally reconstructed 3He-MR images (corrected for the fraction of tissue and blood). RESULTS: Transplanted lungs were characterized by a homogeneous distribution of signal intensity, whereas the native lungs of the patients suffering from IPF displayed an inhomogeneous signal distribution pattern with numerous round or wedge-shaped ventilation defects. Total ventilated lung volume determined by 3He-MRI correlated well with PFT-based measurements, but with a systematic overestimation of the 3He-based lung volumetry of approximately 20%. Functioning lung grafts contributed 66+/-6% and their corresponding native IPF lungs 34+/-6% to total ventilated volume (P<0.05; mean+/-SD). CONCLUSION: 3Helium-MRI of the lung offers a novel approach to regional determination of ventilated lung volume, including its blood and tissue compartments. The advantage of this technique over computed tomography or ventilation scintigraphy is the lack of radiation exposure, and hence its repeatability. Follow up of SLTX patients with this new technique may allow the monitoring of functional and structural developments of grafted lungs with better sensitivity and specificity than PFT.     

Attenuated Salmonella typhimurium with interleukin 2 gene prevents the establishment of pulmonary metastases in a model of osteosarcoma

Purpose

The current management of osteosarcoma (OS) entails an aggressive preoperative and postoperative chemotherapeutic regimen with limb salvage surgery. Despite these efforts, relapse-free survival is less than 60% in patients with classic OS, whereas most patients relapse with pulmonary metastases. In these studies, we sought to prevent the establishment of pulmonary metastases from OS with a single oral dose of SalpIL2.

Methods

Mice were administered attenuated Salmonella typhimurium with (SalpIL2) and without a gene for human interleukin 2 (Sal-NG) 7 days before challenge with 2 × 10⁵ OS cells via tail vein. Three weeks after injection, mice were harvested for splenic lymphocytes and tumor enumeration.

Results

Prophylaxis with attenuated SalpIL2 significantly reduces pulmonary metastases in number and volume (P < .0001 and P < .0001) with respect to saline controls. Furthermore, splenic natural killer cell populations were increased 396% with SalpIL2 (P < .0007) and 426% with Sal-NG (P < .0003) compared to nontreated groups.

Conclusions

Host natural killer response is greatly amplified and maybe partially responsible for the effective immune response against the formation of pulmonary metastases. A single oral dose of SalpIL2 may be a novel form of adjuvant therapy for patients after early detection of primary OS.     

Dual-color imaging of nascent blood vessels vascularizing pancreatic cancer in an orthotopic model demonstrates antiangiogenesis efficacy of gemcitabine

BACKGROUND: The stem cell marker nestin recently has been shown to be expressed in nascent blood vessels in nestin-driven green fluorescent protein (ND-GFP) transgenic nude mice. MATERIALS AND METHODS: In the present study, we visualized by dual-color fluorescence imaging tumor angiogenesis in the ND-GFP transgenic nude mice after orthotopic transplantation of the MIA PaCa-2 human pancreatic cancer line expressing red fluorescent protein. Mice were treated with gemcitabine at 150 mg/kg/dose on days 3, 6, 10, and 13 after tumor implantation. At day 14, mice were sacrificed and mean nascent blood vessel density and tumor volume were calculated and compared to control mice. RESULTS: Nestin was highly expressed in proliferating endothelial cells and nascent blood vessels in the growing tumor. Results of immunohistochemical staining showed that CD31 co-localized in ND-GFP-expressing nascent blood vessels. The density of nascent blood vessels in the tumor was readily quantitated. Gemcitabine significantly decreased the mean nascent blood vessel density in the tumor as well as decreased tumor volume. CONCLUSION: The dual-color model of the ND-GFP nude mouse orthotopically implanted with RFP-expressing pancreatic tumor cells enabled the simultaneous visualization and quantitation of tumor angiogenesis and tumor volume. These results demonstrated for the first time that gemcitabine is an inhibitor of angiogenesis as well as tumor growth in pancreatic cancer. The results have important implications for the clinical application of gemcitabine in this disease.