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Single-port Complete Thoracoscopic Lobectomy Feasibility

Clinical comparisons of single-port versus three-port complete thoracoscopic lobectomy for lung cancer patients Abstract
Objective: To compare the feasibility and safety of single-port versus three-port complete thoracoscopic lobectomy for lung cancer patients.
Methods: A retrospective study was conducted on 60 lung cancer patients from June 2014 to August 2014 in Department of Thoracic Surgery, Union Hospital, Fujian Medical University. There were 30 patients in single-port complete thoracoscopic lobectomy group (single-port group) and other 30 in three-port complete thoracoscopic lobectomy group (three-port group). Total lymph node harvest, mediastinal lymph node harvest, dissection of mediastinal lymph node groups, operation time, intraoperative blood loss, extubation time, postoperative hospital stay, visual analogue scale (VAS) one day after operation, and the complication rate were thoroughly compared between the two groups.
Results: There were no significant differences in total lymph node harvest, mediastinal lymph node harvest, dissection of mediastinal lymph node groups, intraoperative blood loss, extubation time, postoperative hospital stay, and complication rate between the two groups (p> 0.05). However, the operation time of single-port group (209.0±45.5 min) was significantly longer than that of three-port group (154.5±30.9 min) (p< 0.05). VAS one day after operation in single-port group (3.6±0.7) was significantly lower than that in three-port group (5.5±1.0) (p< 0.05).
Conclusion: For lung cancer patients, the feasibility and safety of single-port complete thoracoscopic lobectomy is similar to three-port complete thoracoscopic lobectomy. Compared with three-port complete thoracoscopic lobectomy, the operation time of single-port complete thoracoscopic lobectomy is longer, but its postoperative pain is gentler. As the experience accumulating, single-port complete thoracoscopic lobectomy should be popularized with its merits of minimal invasiveness.
Keywords: single-port, three-port, lobectomy, lung cancer.
Introduction: Currently, lobectomy is the prior intervention to treat early-stage non-small cell lung cancer (NSCLC) [1]. As a minimally invasive technique, thoracoscopic lobectomy has been widely used in current thoracic department [2]. Although single-port complete thoracoscopic lobectomy has been introduced to treat NSCLC, no literature was available to compare its feasibility and safety with three-port complete thoracoscopic lobectomy. Therefore, we conducted a retrospective comparison study in lung cancer patients enrolled from June 2014 to August 2014 to investigate the feasibility and safety of single-port complete thoracoscopic lobectomy.
1. Methods and materials 1.1 General information
A total of 60 lung cancer patients from June 2014 to August 2014 in Department of Thoracic Surgery, Fujian Medical University Union Hospital were included in this retrospective study. There were 30 patients in single-port complete thoracoscopic lobectomy group (single-port group) and other 30 in three-port complete thoracoscopic lobectomy group (three-port group). All patients underwent associated examination such as thoracic computed tomography (CT), cerebral magnetic resonance imaging (MRI), skeletal emission computed tomography (ECT), and abdominal and cervical color Doppler ultrasound (CDU). Positron emission tomography-CT (PET-CT) might also need to be conducted to exclude metastasis if necessary. Electrocardiogram, cardiac CDU, and pulmonary function test were conducted to assess cardiopulmonary function. The inclusion criteria include: 1) patients with stage I-II (cTNM classification) peripheral lung cancer; 2) no thoracic surgery history; 3) lobectomy can be tolerated by cardiopulmonary function; 4) preoperative complications have been stably controlled.
1.2 Anesthesia and surgical procedure
Double-lumen endobronchial tubes (DLT) were used for intubation for the two groups, and the healthy lung received ventilation. All patients underwent thoracoscopic lobectomy under general anesthesia. For single-port group, a 3.5-4.5cm incision was made from the 4th intercostal space to the 5th intercostal space along the anterior axillary line. The patients underwent thoracoscopic lobectomy with video assistance. For three-port group, a 1.5cm observation port was made on the cross point of midaxillary line and the 7th intercostal space, and a 2-4cm operation port was made on the cross point of anterior axillary line and the 4th/5th intercostal space. A 1.5-2.5cm operation-aided port was made on the cross point of the 7th intercostal space and infrascapular line. For peripheral lung cancer, pulmonary wedge resection was conducted to remove the focus. Once the resection samples were confirmed as malignant tumor by fast frozen pathology, the following standard lobectomy and mediastinal lymphadenectomy would be employed. For central lung cancer, standard lobectomy was conducted. Once the resection samples were confirmed as malignant tumor by fast frozen pathology, the following mediastinal lymphadenectomy would be employed. Electrocautery and ultrasonic scalpel were used to distract the vessels and bronchus. Suture clamps were used to fix great vessels such as pulmonary veins, pulmonary artery and so on. Hemolock, titanium clip, electrocautery, ultrasonic scalpel and silk ligation were used to handle small vessels. No definite order was made to conduct the lobectomy, which mostly depended on the development of interlobar fissure. Specimen bag was used to extract the removals preventing from contaminating the cuts, and analgesia pumps were used for the two groups. Indications for removing the drain included: 24h drainage flow was less than 100mL; postoperative lung recruitment was favorable without pleural effusion.
1.3 Observation parameters
The observation parameters included: 1) parameters during perioperative period: operation time, intraoperative blood loss, postoperative drainage flow, postoperative thoracic cavity drainage time, visual analogue scale (VAS) one day after operation, postoperative hospital stay, death rate during perioperative period, complications during perioperative period. 2) parameters related to tumor resection: total lymph node harvest, node-positive number, node-positive rate, N1 lymph nodes, N2 lymph nodes, N2 lymph node rate, and N2 lymph node groups.
1.4 Statistical methods
Statistical software SPSS 16.0 was conducted to analyze the data. Quantitative data was showed as x–±s, and independent t-test was used to test the group comparisons. Enumeration data was presented as rate, and ?ï¼’ test was used to test group comparisons. Statistical significance was set as P< 0.05.
2. Results 2.1 Clinical characteristics
There were no significant differences in sex, age, tumor location, postoperative pathological type, tumor invasion, visceral pleura invasion, and tumor classification, respectively (P> 0.05) (Table 1). In addition, there were no significant differences in total lymph node harvest, positive lymph node number, total mediastinal lymph node harvest, and dissection of mediastinal lymph node groups (P> 0.05) (Table 2).
Table 1. Comparisons of pathological information between single-port group and three-port group.
Single-port group (n=30)
Three-port group (n=30)
P value
Gender
0.183
Male
9
11
Female
21
19
Age (year)*
25-77(61)
45-70(58)
0.583
Tumor location
0.096
Left upper lobe
8
4
Left inferior lobe
5
3
Right upper lobe
8
9
Right middle lobe
3
4
Right inferior lobe
6
10
Tumor type
0.341
Adenocarcinoma
25
22
Squamous carcinoma
2
6
Others
3
2
Tumor invasion
0.583
Carcinoma in situ
2
0
Micro invasion
5
6
Invasion
23
24
Visceral pleura invasion
0.799
No
22
21
Yes
8
9
TNM classification
0.989
Stage 0
1
1
Stage Ia
14
10
Stage Ib
6
10
Stage IIa
2
3
Stage IIb
3
2
Stage IIIa
4
4
*age:extreme value (median).
Table 2. Comparisons of lymph node harvest between single-port and three-port group.
Single-port group (n=30)
Three-port group (n=30)
P value
Total lymph node harvest
23.6±11.2
25.4±7.3
0.737
Positive lymph nodes
1.5±3.1
1.9±4.9
0.971
Total mediastinal lymph node harvest
16.2±9.2
17.2±6.5
0.731
Dissection of mediastinal lymph node groups
4.4±1.0
4.4±0.8
0.637
2.2 Perioperative information
All operations were under the video-assistance of total thoracoscopic lobectomy without other assisted endoscope incision. There were no deaths during preoperative period. However, there were a total of five cases with complications, two cases (1 case of arrhythmia; 1 case of systemic infections) in single-port group (6.7%), and another three cases (1 case of arrhythmia; 1 case of air leakage; 1 case of chylothorax) in three-port group (10.0%). There was no significant difference in complications between the two groups (P>0.05). Additionally, no significant differences in intraoperative blood loss, postoperative extubation time and postoperative hospital stay were observed (P>0.05). However, operation time in single-port group (209.0±45.5 min) was longer than that in three-port group (154.5±30.9min) (P< 0.05). VAS one day after operation in single-port group (3.6±0.7) was lower than that in three-port group (5.5±1.0) (P< 0.05). The summary information was included in Table 3.
Table 3. Comparisons of perioperative outcomes between single-port and three-port group
Single-port group (n=30)
Three-port group (n=30)
P value
Operation time (min)
209.0±45.5
154.5±30.9
0.000
Intraoperative blood loss (ml)
90.6±49.3
79.5±45.2
0.840
Postoperative extubation time (d)
4.0±1.5
5.4±3.7
0.256
Postoperative VAS
3.6±0.7
5.5±1.0
0.000
Postoperative hospital stay (d)
6.9±4.0
8.5±11.8
0.441
Postoperative complications
2
3
0.799
Arrhythmia
1
1
Systemic complications
1
0
Air leakage
0
1
Chylothorax
0
1
3. Discussions Single-port thoracoscopic technique was first reported to diagnose and treat non-complicated pleura-related disease in 2003[7]. In 2004, it was used in pulmonary wedge resection by Rocco et al.[8]. Seven years later, single-port thoracoscopic technique was reported to conduct lobectomy and lymphadenectomy by Gonzalez et al[9]. Since then, it was applied gradually in segment resection of lung [10], total pneumonectomy [11], bronchial sleeve resection [12] and angioplasty of pulmonary arteries [13]. However, most available literature focused on the feasibility and safety of single-port thoracoscopic lobectomy, and no studies compared it with three-port thoracoscopic lobectomy. The presented study retrospectively investigated the differences of clinical outcomes between single-port thoracoscopic lobectomy and three-port thoracoscopic lobectomy for lung cancer. Jiang et al. [14] compared 160 cases of thoracoscopic lobectomy and 247 cases of conventional open surgery and found no significant differences in perioperative death (0.6% vs. 2.8%) and complication rate (9.4% vs. 11.7%) (P>0.05). It is indicated that thoracoscopic lobectomy was technically safe to treat NSCLC. Similarly in our study, the complication rates were 6.7% and 10.0% for single-port group and three-port group, respectively. However, there were no deaths during perioperative period in our study. Therefore, our study indicated that single-port lobectomy was at least technically safe compared with three-port group.
The vital factor for radical resection of lung cancer by single-port thoracoscopic lobectomy was the dissection of lymph nodes. Jiang et al. [14] found no significant differences in dissection of lymph node groups (2.4±1.5 vs. 2.6±1.6) and lymph node harvest (9.8±6.2 vs. 9.9±5.9) between thoracoscopic lobectomy group and conventional open surgery group (P> 0.05). Similarly, Zhang et al.[15] found no significant differences in lymph node harvests (14.6±7.5 vs. 15.2±4.5) between video-assisted thoracoscopic surgery group and video-assisted micro thoracoscopy group. That was to say, the lymph node dissection by thoracoscopic lobectomy was at least equivalent to that by open surgery. In the presented study, there were no significant differences in total lymph node harvest (23.6±11.2 vs.25.4±7.3), mediastinal lymph node harvest (16.2±9.2 vs. 17.2±6.5), dissection of mediastinal lymph node groups (4.4±1.0 vs. 4.4±0.8) between the single-port group and three-port group. These results suggested that the lymph node harvest was at least equivalent to the previous studies. In other words, the dissection of lymph nodes by single-port thoracoscopic lobectomy was feasible in respect of radical removal of tumors. However, the long-term outcomes need further follow-up to confirm in the future.
The incision of single-port thoracoscopic lobectomy was located at the cross point of anterior axillary line and the 4th/5th intercostal spaces, which, unlike conventional three-port thoracoscopy, did not have observation port or assisted-operation port. The 4th/5th intercostal spaces were wider with less muscle and less bleeding, which might have little impact on the postoperative recover with less pain. After comparing 20 cases of three-port thoracoscopic lobectomy and 10 cases of single-port thoracoscopic lobectomy in treating interstitial lung disease, Chen et al.[16] found that postoperative one-day VAS in single-port group (4.95±0.39) was significantly lower than that in three-port group (4.5±0.7) (P=0.03). Similarly in our study, postoperative one-day VAS in single-port group (3.6±0.7) was significantly lower than that in three-port group (5.5±1.0) (P< 0.05)
In the presented study, the operation time (209.0±45.5 min) in single-port group was significantly lower than that in three-port group (154.5±30.9 min). The reasons included 1) all the operating instruments and thoracoscopy went through the single port, which might interfere each other, especially when the focus was near the dorsal cavity and diaphragm. 2) single-port thoracoscopic lobectomy had a strict skill requirement of qualified camera assistant. The camera assistant was supposed to know how to cooperate with the operator, how to allocate the location within the incision, and how to keep the camera stable. Our operation team launched the single-port-thoracoscopic lobectomy since May 2014, and we believed that the operation time would be shortened as we optimized our technique gradually.
In summary, the feasibility and safety of single-port thoracoscopic lobectomy were similar to three-port thoracoscopic lobectomy for lung cancer patients. With the development of instruments, the optimization of surgical procedure, and the accumulation of surgical experience, the operation time would likely be shortened gradually. Therefore, single-port complete thoracoscopic lobectomy was supposed to be popularized with its merits of minimal invasiveness.

MCP-1: Origins and Uses for Inflammatory Treatment

Introduction Chemokines are able to attract and activate leukocyte subsets in exclusion to other subsets (1) and monocyte chemoattractant protein 1 (MCP-1) is an inflammatory chemokine that targets monocytes, T lymphocytes and cells that express the C-C chemokine receptor (2) including myocytes (3). MCP-1 (also known as CCL2) was the third chemokine to be purified to homogeneity, after platelet factor 4 and interleukin 8 (4). It was discovered by a number of groups at similar times. One group was investigating factors involved in atherosclerosis (5), whilst another was assessing the properties of monocytes (6). The full structure was cloned by Yoshimura and colleagues (7).
In addition to its effects on leukocytes MCP-1 has profound effects on the innate and adaptive immune responses, due to it’s responsibility for monocyte recruitment (4).
This account outlines the origins and functions of MCP-1 before going on to discuss its relevance to inflammatory processes, including some of the research into methods of minimising the damage caused by inflammatory diseases by targeting either MCP-1 or its receptor.
Structure and origins of MCP-1 MCP-1 is a 76 amino acid protein and a member of the C-C family of chemokines (8), initially cloned by 3 separate groups in the late 1980s (1). Chemokines are chemotactic cytokines that are structurally related small proteins that have a role in leukocyte migration and activation (9). The C-C family are those in which 2 cysteine residues are adjacent, as opposed to the C-x-C family, in which they are separated by an amino acid (1). MCP-1 forms dimers at physiological concentrations (10) and it attracts monocytes in vitro at subnanomolar concentrations (11). Chemokines recruit cells by binding to their G-protein coupled receptors, but it isn’t a simple case of 1 receptor = 1 ligand (12) as different chemokines are able to act on multiple receptors, as well as individual receptors being activated by different ligands.
MCP-1 can be synthesised by mesangial and tubular epithelial cells (13) as well as the monocytes and other leukocytes. The synthesis of MCP-1 by mesangial cells has been shown to occur in response to glomerular injury and the factors involved in that process, such as interleukin-1, TNFα and low-density lipoprotein (13). In addition high glucose levels are also known to induce MCP-1, which has a relevance when discussing the role of MCP-1 in diseases such as diabetes (see below).
MCP-1 regulation MCPs attract cells through the activation of their CCR2 receptor, expressed on the cell surface of monocytes (14). CCR2 can be expressed by non leukocytes including neurons, suggesting that it has a role in activities in addition to inflammation (4). CCR2 is expressed by virtually all monocytes but also around 15% of CD4 T cells in the circulation (15). This is important when considering the involvement of MCP-1 in the adaptive and innate immune response. CCR2 is a member of the g protein coupled 7 transmembrane receptor superfamily expressed on most monocytes (9). The crucial role of the CCR2 receptor is evidenced by the fact that genetically deficient mice have reduced tissue recruitment of monocytes (14). Likewise mice lacking MCP-1 itself show similar deficits.
At physiological concentrations all free MCP-1 is monomeric and it is thought that it is this form of MCP-1, rather than the tetrameric form, that activates CCR2 (4). However there is currently debate about that, as other researchers believe that the dimmers are physiologically active (10).
Protein kinase C (PKC) activation is able to induce MCP-1 expression and macrophage recruitment (13). This forms another potential target for pharmacological intervention in disease processes, as altering the PKC activity can also influence MCP-1 expression, as described below.
MCP-1 in disease processes Whilst ordinarily MCP-1 has a physiological action, the presence of inflammation gives rise to its up-regulation, and possibly pathological consequences. The normal physiological role of MCP-1 does involve the recruitment of monocytes, which are involved in cardiac repair and protection processes (16). Of particular interest is the fact that MCP-1 is chemotactic for endothelial cells and can induce those cells to sprout, as well as encouraging the growth of collateral vessels through ischaemic tissue (16). Thus chemokines, whilst potentially damaging to cardiac tissue, are also important in early cardiac repair. CCR2 knockout mice had a reduced amount of cardiac fibrosis following myocardial infarct, indicating that, as macrophage infiltration had been reduced, myocardial ischaemia-reperfusion injury was also reduced (3).
MCP-1 has been found to be up-regulated in a number of disease processes, including pancreatitis, where it is believed to contribute to the pathogenesis of mononuclear infiltration (2). MCP-1 is produced in pathological settings that are characterised by monocyte-rich infiltrates, including tuberculosis and atherosclerosis (1). Inflammatory diseases are often characterised by MCP-1 expression, such that rheumatoid arthritis inflamed synovium has an up-regulated MCP-1 expression and anti-arthritic drugs act to reduce the levels (9). Irritable bowel disease involves inflammatory chemokines in the mucosa. The mere presence of MCP-1 is believed to be responsible for the invasion of blood monocytes and granulocytes in the inflamed tissue (17). This was evidenced by the fact that blockade of the effect of MCP-1 via a neutralising antibody abrogated the recruitment of monocytes and that mRNA is upregulated, as is the protein itself. MCP-1 mRNA and protein has been shown to be strongly expressed in epithelial and endothelial cells from patients with idiopathic pulmonary fibrosis (IPF), a chronic fibrosing interstitial pneumonia with a median life expectancy of 3-4 years (10).
Chronic pancreatitis is characterised by the inflammatory infiltration of pancreatic tissue, as well as fibrosis and atrophy of the acinar cells (8). Figure 2 below gives a summary of the chemokines and disease process for pancreatitis. In particular it should be noted that MCP-1 was induced by injured acinar and ductal cells and damaged tissue as well as the expected monocytes and macrophages (8).
MCP-1 is involved in atherosclerosis as the early stages of the disease involve the infiltration of circulating monocytes to the arterial subendothelium (4). In human atherosclerosis it has been found that MCP-1 is synthesised primarily by endothelial cells but also subendothelial macrophages and foam cells (1). Atherosclerosis develops from the migration of monocytes through the vascular walls, whereupon they are changed to lipid-laden foam cells (18). The expression of MCP-1 is directly related to the extent of atherosclerosis and macrophage infiltration, such that it is considered a biochemical marker of early atherosclerosis. Mature atherosclerotic plaques also produce MCP-1 from subendothelial macrophages. Indeed all elements of the arterial wall are capable of synthesising MCP-1 (4). MCP-1 deficient mice could be fed a high cholesterol diet and not develop atherosclerosis, in conjunction with a decreased number of macrophages being present in the arterial wall (4).
The involvement of MCP-1 in diabetes mellitus has also been indicated, whereby the serum concentrations of MCP-1 were shown to be significantly higher in diabetes mellitus patients, when compared to healthy controls (18). Likewise the expression of CCR2 on monocytes was also significantly increased, indicating that monocyte accumulation in diabetic vascular disease is a result of over production of MCP-1 and an up-regulation of CCR2 leading to monocytes extravasation.
MCP-1 is also involved in diseases characterised by disruption of the blood brain barrier leading to vascular permeability and leukocyte infiltration, including stroke, multiple sclerosis and Alzheimer’s disease (19). MCP-1 knockout mice have been shown to have reduced levels of inflammatory cytokines as well as reduced ischaemia and leukocyte infiltration (20). During CNS inflammation MCP-1 is expressed in perivascular space as well as brain parenchyma (19). Further it has been shown that MCP-1 is actually directly responsible for increasing blood brain barrier permeability, achieving this by altering the tight junction complex (19). MCP-1 also acts indirectly by recruiting monocytes into the brain parenchyma, which will also act to increase blood brain barrier permeability.
It is worth noting that, in a rather contrary way, MCP-1 is actually reduced in multiple sclerosis cerebrospinal fluid, and it is suggested that this is due to it being consumed by CCR2 migrating cells (15). MCP-1 is therefore produced by reactive astrocytes during inflammation, has a role in leukocyte accumulation in multiple sclerosis lesions and is then consumed by the CCR2 cells as they enter the lesion (15).
Pharmacological targets of MCP-1 The inflammatory aspects of pancreatitis are mediated in the main part by monocytes and macrophages (8), so any factors that increase their recruitment would be suitable targets for the treatment of chronic pancreatitis. Gene therapy has been used in the treatment of pancreatitis, whereby an amino terminal deletion of MCP-1 causes a mutated form that acts as a potent dominant negative MCP-1 agonist (mMCP-1) (8). When this mMCP-1 was used in a rat model of pancreatitis there was significantly less pancreatic inflammation than when an empty plasmid was used. This can be seen in figure 3 below, where B is a rat which shows signs of inflammatory pancreatitis, and C is a rat treated with mMCP-1 and shows much less inflammation. The authors conclusions were that mMCP-1 gene transfer resulted in the suppression of monocyte and macrophage recruitment and activation (8).
The 7ND (amino terminal deletion) model of MCP-1 forms heterodimers with wild type MCP-1 and prevents wild type MCP-1 from binding to CCR2 receptors (10). 7ND gene transfer was found to greatly reduce the pathological effects in a mouse model of IPF (bleomycin induced pneumopathy). Specifically it acted to attenuate DNA damage, apoptosis and pulmonary fibrosis if given 7 days after the initial insult. The authors concluded therefore that MCP-1 has its principal role in IPF during the late phases of lung injury and fibrogenesis and has a much lesser role in the early inflammatory stages (10).
The use of LY333531, a protein kinase C inhibitor, has been shown to reduce the expression of MCP-1 in the kidney (13), indicating that PKC is necessary for the synthesis and expression of MCP-1, and anti-inflammatory effects can be mediated by it’s blockade. This has much potential for future therapy as it wouldn’t affect the other ligands binding to CCR2, thus shouldn’t have as great an impact on physiological activity.
Conclusion MCP-1 is a potent chemokine that has a crucial role in the recruitment and activation of monocytes in the inflammatory and immune responses. Unfortunately it has been strongly implicated in a number of pathological conditions characterised by inflammation including atherosclerosis, rheumatoid arthritis and diabetes mellitus. Therefore pharmacological targets aim to reduce its overall expression or reduce the activation of its CCR2 receptor. Unfortunately it is not possible to simply block CCR2 as it has too many necessary physiological roles. Early CCR2 antagonists suffered from poor binding, poor functional activity and off-target activities (9) which diminished the enthusiasm for the development of a pharmacological therapy targeting CCR2. However research does continue and there is little argument that over expression of MCP-1 does have a significant role in inflammatory disease. The task ahead is to investigate why and try to alter the hyperactivity in a way that reduces pathological symptoms at the same time as retained physiological activity.
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Footnotes
[a] Key Triangle: N-terminus of mature MCP-1. Dashed line: potential N-linked glycosylation site. Solid line: oligonucleotide probe sequence. Dotted line: polyadenylation signal
[b] Key CCR-2, C-C chemokine receptor; α-SMA, α smooth muscle actin; TGF-β, transforming growth factor β; PDGF, platelet derived growth factor; IL-1β, interleukin 1β; IL-6, interleukin 6.

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