Min P. Kim

Human lung cancer cells grown in an ex vivo 3D lung model produce matrix metalloproteinases not produced in 2D culture.

We compared the growth of human lung cancer cells in an ex vivo three-dimensional (3D) lung model and 2D culture to determine which better mimics lung cancer growth in patients. A549 cells were grown in an ex vivo 3D lung model and in 2D culture for 15 days. We measured the size and formation of tumor nodules and counted the cells after 15 days. We also stained the tissue/cells for Ki-67, and Caspase-3. We measured matrix metalloproteinase (MMP) levels in the conditioned media and in blood plasma from patients with adenocarcinoma of the lung. Organized tumor nodules with intact vascular space formed in the ex vivo 3D lung model but not in 2D culture. Proliferation and apoptosis were greater in the ex vivo 3D lung model compared to the 2D culture. After 15 days, there were significantly more cells in the 2D culture than the 3D model. MMP-1, MMP-9, and MMP-10 production were significantly greater in the ex vivo 3D lung model. There was no production of MMP-9 in the 2D culture. The patient samples contained MMP-1, MMP-2, MMP-9, and MMP-10. The human lung cancer cells grown on ex vivo 3D model form perfusable nodules that grow over time. It also produced MMPs that were not produced in 2D culture but seen in human lung cancer patients. The ex vivo 3D lung model may more closely mimic the biology of human lung cancer development than the 2D culture.

Human Lung Cancer Cells Grown on Acellular Rat Lung Matrix Create Perfusable Tumor Nodules

BACKGROUND Extracellular matrix allows lung cancer to form its shape and grow. Recent studies on organ reengineering for orthotopic transplantation have provided a new avenue for isolating purified native matrix to use for growing cells. Whether human lung cancer cells grown in a decellularized rat lung matrix would create perfusable human lung cancer nodules was tested. METHODS Rat lungs were harvested and native cells were removed using sodium dodecyl sulfate and Triton X-100 in a decellularization chamber to create a decellularized rat lung matrix. Human A549, H460, or H1299 lung cancer cells were placed into the decellularized rat lung matrix and grown in a customized bioreactor with perfusion of oxygenated media for 7 to 14 days. RESULTS Decellularized rat lung matrix showed preservation of matrix architecture devoid of all rat cells. All three human lung cancer cell lines grown in the bioreactor developed tumor nodules with intact vasculature. Moreover, the lung cancer cells developed a pattern of growth similar to the original human lung cancer. CONCLUSIONS Overall, this study shows that human lung cancer cells form perfusable tumor nodules in a customized bioreactor on a decellularized rat lung matrix created by a customized decellularization chamber. The lung cancer cells grown in the matrix had features similar to the original human lung cancer. This ex vivo model can be used potentially to gain a deeper understanding of the biologic processes involved in human lung cancer.

Esophageal salvage with removable covered self-expanding metal stents in the setting of intrathoracic esophageal leakage

BACKGROUND Intrathoracic contamination from esophageal perforation, staple line dehiscence, or trauma can be a preterminal event. In our institution, covered self-expanding metal stents have been used aggressively in the management of esophageal leak, but their use remains controversial. The primary objective of this study was to evaluate the efficacy of esophageal salvage using stents to assist in the management of intrathoracic esophageal leakage. METHODS Over 38 months, 63 patients with esophageal or gastric leaks were evaluated for stenting as primary treatment and identified using a prospective database. RESULTS Fifty-six patients were managed with endoscopic stenting as primary therapy and 30 of those patients required a thoracic intervention after stenting. Seven of these patients required esophageal diversion after stent failure. Thirty-day mortality was 10% in the patients with intrathoracic contamination. CONCLUSIONS We suggest that the use of covered self-expanding metal stents in patients with intrathoracic leak after esophageal perforation is safe and offers esophageal salvage in 77% regardless of time of presentation.

Contemporary Surgical Management of Cardiac Paragangliomas

BACKGROUND Cardiac paragangliomas are an extremely rare subset of chromaffin cell tumors that develop from neural crest cells. METHODS Between March 2004 and October 2010, 7 male patients from our two institutions who underwent surgical resection of cardiac paraganglioma were retrospectively reviewed. RESULTS In 5 patients, paragangliomas originated from the roof of the left atrium, and in 2 patients, they originated from the aortic root. Hospital mortality was 14%. CONCLUSIONS Complete surgical resection remains the mainstay of therapy and can be curative, but carries a significant risk of intraoperative bleeding and usually requires cardiopulmonary bypass and often complex resection techniques, including cardiac autotransplantation.

Circulating tumor cells from 4D model have less integrin beta 4 expression.

BACKGROUND Currently, there is no in vitro or ex vivo model that can isolate circulating tumor cells (CTCs). Recently, we developed a four-dimensional (4D) lung cancer model that allows for the isolation of CTCs. We postulated that these cells have different properties than parental (2D) cells. MATERIALS AND METHODS We obtained CTCs by growing A549, H1299, 393P, and 344SQ cell lines on the 4D lung model. The CTCs were functionally characterized in vitro and gene expression of the cell adhesion molecules was compared with respective 2D cells. Integrin beta 4 (ITGB4) was further investigated by stably transfecting the A549 and H1299 cells. RESULTS We found that all cell lines produced CTCs, and that CTCs from the 4D model were less adherent to the plastic and have a slower growth rate than respective 2D cells (P < 0.01). Most of the cell adhesion molecules were downregulated (P < 0.05) in CTCs, and ITGB4 was the common molecule, significantly more underexpressed in CTCs from all cell lines than their respective 2D cells. The modulation of ITGB4 led to a differential function of 2D cells. CONCLUSIONS CTCs from the 4D model have different transcriptional, translational, and in vitro characteristics than the same cells grown on a petri dish, and these CTCs from the 4D model have the properties of CTCs that are responsible for metastasis.

Circulating tumor cells from a 4-dimensional lung cancer model are resistant to cisplatin

OBJECTIVE To determine the effect of cisplatin on circulatory tumor cells (CTC) and tumor nodules in a four-dimensional (4D) lung cancer model. METHODS CTCs from the 4D model seeded with H1299, A549, or H460 and respective cells that were grown under two-dimensional conditions in a Petri dish were treated with 50 μM cisplatin for 24 and 48 hours and cell viability was determined. The lung nodules in the 4D model were then treated with different continuous or intermittent doses of cisplatin and the nodule size, the number of CTCs, and the level of matrix metalloproteinase (MMP) were determined. RESULTS Cisplatin led to a significant decrease in the viability of tumor cells grown under 2D conditions (P < .01) but not in CTCs from the 4D model after both 24 hours and 48 hours. Cisplatin led to regression of tumor nodules with both the continuous and intermittent treatments. Moreover, there was a significantly higher number of CTCs per tumor area (P < .05) and MMP-2 production per tumor area (P = .007) for all human lung cancer cell lines grown in the 4D model when treated with cisplatin. CONCLUSIONS The 4D lung cancer model allows for the isolation of CTCs that are resistant to cisplatin treatment. The model may allow us to better understand the biology of cisplatin resistance.

The “Texas Two-Step” procedure

From the Division of Thoracic Surgery, Department of Surgery,Weill Cornell Medical College, and the Houston Methodist DeBakey Heart and Vascular Center, Department of Cardiovascular Surgery, Houston Methodist Hospital, Houston, Tex. Disclosures: Authors have nothing to disclose with regard to commercial support. Received for publication June 6, 2017; revisions received July 31, 2017; accepted for publication Aug 24, 2017; available ahead of print Sept 28, 2017. Address for reprints: Michael J. Reardon, MD, Houston Methodist Hospital, 6550 Fannin St, Smith Tower, Suite 1401, Houston, TX 77030 (E-mail: mreardon@houstonmethodist.org). J Thorac Cardiovasc Surg 2018;155:285-7 0022-5223/

Limitations of 18F-2-deoxy-d-glucose positron emission tomography in N1 detection in patients with pathologic stage II-N1 and implications for management

36.00 Copyright 2017 by The American Association for Thoracic Surgery https://doi.org/10.1016/j.jtcvs.2017.08.117 Inflammatory pseudotumor requiring cardiac reconstruction and staged pneumonectomy.

Treatment of Sternoclavicular Joint Osteomyelitis with Debridement and Delayed Resection with Muscle Flap Coverage Improves Outcomes

BACKGROUND The definitive use of 18F-2-deoxy-d-glucose positron emission tomography (FDG-PET) to detect nodal metastasis in patients with early-stage non-small cell lung cancer (NSCLC) being evaluated for local nonsurgical management, such as stereotactic body radiation therapy and minimally invasive percutaneous ablative therapies, underscores the importance of diagnosing N1 disease by FDG-PET. The purpose of this study was to evaluate FDG-PET in the detection of N1 disease and to determine if FDG-PET-positive N1 disease predicts poor survival in patients with pathologic stage II-N1 NSCLC. METHODS We reviewed all patients who underwent surgical resection for lung cancer at MD Anderson Cancer Center from 2000 to 2011 who had pathologic stage T1 to T2 and N1 disease and a preoperative FDG-PET. We compared the clinicopathologic characteristics and survival of patients who had PET-positive N1 and PET-negative N1 disease. RESULTS A total of 104 patients met the inclusion criteria. The pathologic stage in 87 patients was IIA (T1a N1, T1b N1 or T2a N1) and in 17 patients was IIB (T2b N1). Only 25 of 104 patients (24%) had PET-positive N1 disease. There was no clinical or pathologic difference between the patients who had PET-positive N1 and PET-negative N1 disease. No significant difference was found in the survival rates between patients from the PET-positive N1 and the PET-negative N1 groups (p = 0.9). CONCLUSIONS FDG-PET has poor sensitivity in detecting N1 disease, and N1-positive disease on FDG-PET does not have an effect on survival. FDG-PET should not be used alone to determine management in patients with early-stage non-small cell lung cancer being evaluated for local nonsurgical management.

Clinical outcomes following self-expanding metal stent placement for esophageal salvage

The objective of this study was to evaluate the efficacy of various treatment options for sternoclavicular joint osteomyelitis. We evaluated patients with a diagnosis of sternoclavicular joint osteomyelitis, treated at our hospital from 2002 to 2012. Four treatment options were compared. Three out of twelve patients were successfully cured with antibiotics alone (25%). Debridement with or without negative pressure therapy was successful for one of three patients (33%). Simultaneous debridement, bone resection, and muscle flap coverage of the acquired defect successfully treated one of two patients (50%). Debridement with delayed bone resection and muscle flap coverage was successful in five of five patients (100%). Osteomyelitis of the sternoclavicular joint is a rare disease that has become more prevalent in recent years and can be associated with increasing use of long-term indwelling catheters. Initial debridement with delayed bone resection and pectoralis major muscle flap coverage can effectively treat sternoclavicular joint osteomyelitis.