Minimally Invasive Esophagectomy

Updated: Aug 11, 2015
  • Author: Michael Scott Halbreiner, MD; Chief Editor: Kurt E Roberts, MD  more...
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The incidence of esophageal cancer has increased over the last several decades, and adenocarcinoma now surpasses the incidence of squamous cell carcinoma. Treatment of esophageal carcinoma has become more aggressive and effective, and the overall morbidity and mortality in those who are surgically treated have declined, approaching 8-11% and 40-50%, respectively. [1, 2]

The history of esophageal disease and its surgical treatment dates back to 2500 BC in ancient civilizations. However, it was not until the 17th century that the first cervical esophagotomy was reported; in the latter part of the 19th century, the first cervical esophagectomy was performed by Johann Nepomuk Czerny. [3]

In 1913, Franz Torek, a German-born surgeon, performed the first thoracic esophagectomy for cancer in the German (now Lenox Hill) Hospital in New York City. Although advised against performing such a procedure, Torek was successful in part because of the recent developments in intratracheal anesthesia and asepsis. [4] Over the next several decades, open surgical esophagectomy developed as an acceptable treatment for benign disease as well as esophageal cancer.

In 1989, interest in laparoscopic surgical techniques was sparked, as the first laparoscopic cholecystectomy was performed. [5] This technique was first adapted into the field of esophageal disease in 1991 with laparoscopic fundoplication, performed by Dallemagne et al. [6] With this, the shift toward minimally invasive esophageal surgery began.

Traditional approaches via open transhiatal or transthoracic (Ivor Lewis) resections were first "hybridized" with minimally invasive techniques, where parts of the procedure were performed in a minimally invasive fashion and other parts via standard incisions. [7] The first esophagectomy performed completely via laparoscopy through a transhiatal approach was in 1995 by DePaul et al [8] In 1999, Watson et al first described a completely minimally invasive Ivor Lewis technique. [9]

See the video below for a discussion on robotic-assisted minimally invasive surgery.

The advantages of robotic-assisted minimally invasive surgery. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Inderpal S. Sarkaria, MD.


Traditionally, esophagectomy has been performed via open transthoracic or transhiatal approaches, with randomized trials showing no significant difference in overall survival or disease-free survival. Furthermore, outcomes in minimally invasive esophagectomy (MIE) compare favorably to the reported series of open esophagectomy. [10]

Minimally invasive approaches to treatment of benign esophageal diseases have been met with widespread acceptance. This includes diseases such as achalasia, paraesophageal hernia, and other complex esophageal disorders. [11, 12, 13, 14] This has not been the case with malignant disease of the esophagus. Currently, no criteria define when a minimally invasive procedure should be performed in oreference to an open procedure. [15]

However, an increasing trend exists for many high-volume institutions to use MIE in treatment of Barrett disease with high-grade dysplasia and in patients with small resectable lesions that have limited nodal involvement (N0-1). This includes T1 (invasion of the lamina propria or submucosa), T2 (invasion of the muscularis propria), and some instances of T3 lesions (invasion of the adventitia). Neoadjuvant chemoradiation is not a contraindication to a minimally invasive approach. [16, 17]


Currently, no standardized contraindications exist regarding the use of MIE. However, T4 lesions (invasion of surrounding tissues) are generally not amenable to any form of surgical resection. Extensive nodal disease and metastatic disease are also advanced stages that may require an open surgical approach or even endoscopic stenting for palliation instead of an attempt at MIE. [17] Furthermore, any patient with a lesion that bridges the esophagogastric junction may not be considered a candidate for this approach unless the gastric margin can be cleared and an esophagogastrectomy can be done either via open approach or minimally invasively.

As with other laparoscopic procedures, patients with extensive adhesions and scar tissue over the abdomen or chest wall, particularly in areas where the thoracoscope or laparoscope would be placed, are a higher-risk group for treatment with MIE. Older patients and those with comorbid conditions are not candidates for surgery, because of the high morbidity with either an MIE or a standard procedure, but they may benefit more from nonsurgical therapy. [18]


Minimally invasive techniques for esophageal resection have been reported to have acceptably reduced procedure-related morbidity without compromising disease-free survival rates. [10]

Luketich et al have an extensive reported experience; their initial series of 222 patients has grown to more than 1000. [19] In the initial series, mortality was 1.4% versus 5.5% for an open approach. [18, 20, 21] Furthermore, the survival curve at 19-month follow-up was comparable in the two groups. [18]  In their 2012 report of 1011 patients who underwent MIE via either a modified McKeown minimally invasive approach or an MIE Ivor Lewis approach, the authors cited a 0.9% mortality for the MIE Ivor Lewis approach. [19]

In another analysis of 41 elderly patients over the age of 75 years who underwent minimally invasive esophagectomy, no operative deaths occurred, with a survival of 81% at 20 month follow-up. [22] These findings suggest that MIE can be safely performed in selected patients and even those considered high-risk that might not otherwise be considered for an open surgery.

Other outcome improvements seen with minimally invasive esophagectomy include decreased ICU and hospital length of stay, decreased blood loss, and operating times. In particular, Luketich et al reported a median ICU stay of 1 day and a total length of hospital stay of 7 days, compared with the average hospital stay of 16.6 days in the open approach. Operating room times in the same study averaged 306 minutes, whereas the average for an open procedure is 336 minutes. [18, 20] Similar results can be seen in multiple other series as compared to open procedures (see the table below).

Outcomes based on procedure type. Outcomes based on procedure type.

Complications and outcomes are significantly influenced by the volume of patients, because a large learning curve exists. High-volume centers tend to have more experience and, therefore, better outcomes than smaller-volume hospitals.

Wang et al carried out a propensity score-matched comparison of MIE and open esophagectomy with respect to outcomes, quality of life, and survival in patients with squamous cell carcinoma. [23]  They found that MIE was associated with a shorter operating time (191 ± 47 minutes vs 211 ± 44 minutes), reduced blood loss (135 ± 74 mL vs 163 ± 84 mL), a similar lymph node harvest (24.1 ± 6.2 vs 24.3 ± 6.0), a shorter postoperative hospital stay (11 days vs 12 days), a lower rate of major complications (30.4% vs 36.9%), a lower rate of readmission to the intensive care unit (ICU; 5.6% vs 9.7%), and comparable perioperative mortality.

van der Sluis et al assessed the long-term oncologic results of robot-assisted minimally invasive thoracolaparoscopic esophagectomy (RAMIE) with two-field lymphadenectomy in 108 patients with potentially resectable esophageal cancer. [24] They found RAMIE to be oncologically effective and capable of providing good local control with a low percentage of local recurrence at long-term follow-up.

In a prospective phase II study (coordinated by the Eastern Cooperative Oncology Group) aimed at assessing the feasibility of MIE in a multi-institutional setting, Luketich et al reported the following results [25] :

  • The 30-day mortality in eligible patients who underwent MIE was 2.1%
  • The median ICU stay was 2 days
  • The median hospital stay was 9 days
  • Adverse events classified as grade 3 or higher included anastomotic leakage (8.6%), acute respiratory distress syndrome (ARDS; 5.7%), pneumonitis (3.8%), and atrial fibrillation (2.9%)
  • The estimated 3-year overall survival (median follow-up, 35.8 months) was 58.4%
  • Locoregional recurrence occurred in only 7 patients (6.7%)

Periprocedural Care

Patient preparation


The implications involving anesthesia when performing minimally invasive esophagectomy (MIE) include longer operating times, possible prone positioning, and longer duration of single-lung ventilation (SLV) with thoracoscopic approaches. The use of protective ventilation is often implemented with SLV, whereby smaller tidal volumes (5 mL/kg) and a positive end-expiratory pressure (PEEP) of 5 cm H2O are used.

Although no evidence exists regarding the benefit of protective ventilation during MIE, it seems appropriate to use given the increased time on ventilation and the benefits in decreasing the inflammatory response and improving lung function postoperatively that have been demonstrated in the open transthoracic approach. [26]

The risk of tracheal aspiration is increased in patients undergoing a thoracotomy. It is particularly influenced by the presence of esophageal cancer, which affects normal lower esophageal sphincter function. For this reason, prophylactic gastroesophageal reflux management, rapid-sequence intubation, and securing the airway with a cuffed endotracheal tube, which have been shown to reduce pulmonary aspiration, are standard procedures in this patient population. [27] Repeated low-grade nasogastric and oropharynx suctioning before and after extubation further minimizes the risk of aspiration.

Early extubation, provided it can be done safely, has been shown to decrease length of stay in both the intensive care unit (ICU) and the hospital. It contributes to improved outcomes and had no significant difference compared to late extubation in terms of in-hospital mortality. [28, 29]

Thoracic epidural anesthesia (TEA) has clear benefits in perioperative pain relief, facilitating faster extubation and earlier mobilization, thereby reducing respiratory complications and length of stay. TEA for more than 48 hours was shown to reduce the incidence of reintubation and pneumonia as well as ICU and hospital stay compared to no epidural or a TEA for less than 48 hours. [30]


The minimally invasive approaches to esophageal resection are the laparoscopic and thoracoscopic Ivor Lewis (transthoracic) esophagectomy, the laparoscopic transhiatal esophagectomy, and thoracoscopic esophageal mobilization with then laparoscopic transhiatal resection. All procedures typically begin with the patient in a supine position so that esophagogastroscopy can be performed to assess precise location and extension of the tumor. Suitability of the stomach as a conduit may also be assessed. [7, 31]

Thoracoscopic mobilization is performed either in the left lateral decubitus or prone position; the patient is then turned supine for gastric pull through and cervical anastomosis. For an Ivor Lewis procedure, the laparoscopic mobilization is performed first, and then the patient is turned and the procedure is completed in the chest with the anastomosis. The standard transhiatal resection can be performed with only laparoscopy and a cervical incision. [32]

See the video below for a discussion of room setup and port placement.

Room setup and port placement. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Inderpal S. Sarkaria, MD.


Robotic-assisted esophagectomy

The videos below demonstrate the procedure for a robotic-assisted esophagectomy.

Robotic-assisted esophagectomy: Part 1. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Inderpal S. Sarkaria, MD.
Robotic-assisted esophagectomy: Part 2. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Inderpal S. Sarkaria, MD.
Robotic-assisted esophagectomy: Part 3. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Inderpal S. Sarkaria, MD.
Robotic-assisted esophagectomy: Part 4. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Inderpal S. Sarkaria, MD.
Robotic-assisted esophagectomy: Part 5. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Inderpal S. Sarkaria, MD.
Robotic-assisted esophagectomy: Part 6. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Inderpal S. Sarkaria, MD.
Robotic-assisted esophagectomy: Part 7. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Inderpal S. Sarkaria, MD.

Transthoracic esophagectomy with cervical anastomosis

After endoscopy to visualize the extent of disease and suitability of the gastric conduit, the patient is intubated with a double-lumen endotracheal tube and placed in a left lateral decubitus or prone position. Four thoracoscopic trocars are introduced into the right thorax. Three 10-mm ports and one 5-mm port are placed. One 5-mm port is used for retraction and is placed just anterior to the tip of the scapula. The first 10-mm port placed in the seventh or eighth intercostal space anterior to the midaxillary line is for the camera.

The second 10-mm port is positioned at the anterior axillary line in the fourth intercostal space. This is typically used to place the lung retractor. The final 10-mm port, which is used mainly for dissection and coagulation, is placed at the eighth or ninth intercostal space at the posterior axillary line. A fifth 5-mm port can be placed anteriorly at the sixth intercostal space as needed for suction and assistance with the intrathoracic anastomosis (see the image below). [31, 32]

Thoracoscopic port sites for the transthoracic app Thoracoscopic port sites for the transthoracic approach.

The first step after setting up accurate port placement and visualization is to place a suture (0-Surgiteck Endostitch) through the central tendon portion of the diaphragm. This suture is then brought out anteriorly and inferiorly through the thorax at the level of insertion of the diaphragm to facilitate retraction and exposure of the distal esophagus and gastroesophageal junction.

At this point, division of the inferior pulmonary ligament as performed. Achieving dissection onto the pericardium is important, with retraction of the inferior pulmonary vein, to ensure medial exposure and to mobilize the subcarinal lymph nodes and surrounding tissue, as this will be removed with the specimen. Further dissection is carried out through the mediastinal pleura along the hilum to the level of the azygos vein. Once the azygos vein has been dissected circumferentially, it is divided using an endoscopic stapler. [7, 31, 32]

The next step is to mobilize the esophagus. This is started by dissecting the lateral pleura overlying the esophagus from the azygos vein down to the gastroesophageal junction, focusing on avoiding injury to the thoracic duct or aorta. By avoiding injury to the thoracic duct, the need for ligation of the duct is obviated. All periesophageal nodes and fat are included with the specimen. A Penrose drain is helpful in completely mobilizing the esophagus, allowing retrieval during neck dissection (see the image below).

Mobilization of the thoracic esophagus using a Pen Mobilization of the thoracic esophagus using a Penrose drain.

To prevent traction injury to the recurrent laryngeal nerves, the vagal trunks should be divided at the level of the azygos vein. Furthermore, aortoesophageal attachments are thoroughly dissected, clipped, and divided. Next, the lung is inflated, and the tracheal, bronchial, and parenchymal injuries are assessed. Under thorascopic visualization, a 28-French chest tube is placed through the 10-mm camera port. The remaining ports are then removed, and port sites are closed using polyglactin sutures. Using bupivacaine, regional anesthesia is given to the intercostal areas around the port sites. [18, 33]

The next portion of the procedure is the abdominal laparoscopy. The patient is placed in the supine position and steep reverse Trendelenburg. At this time, the double-lumen endotracheal tube can be replaced with a single-lumen tube. Five ports are needed during this part of the procedure. A 10-mm port is first placed under direct vision in the epigastrium between the xiphoid and umbilicus just to the right of midline. CO2 insufflation is provided via this port.

Once adequate pneumoperitoneum is obtained, a 10-mm camera can be placed and, under laparoscopic visualization, the additional ports can be placed. A 5-mm port is placed just to the left of the midline at the same level as the 10-mm port. The 10-mm camera can be removed, and a 5-mm, 30o camera is placed through the 5-mm port. Additional 5-mm ports are inserted at the right and left subcostal margins. The final 5-mm port is placed at the right flank to allow liver retraction (see the image below). [18, 31, 32, 33]

Abdominal port sites for the laparoscopy. Abdominal port sites for the laparoscopy.

At this point, the liver retractor is placed to elevate the left lobe of the liver to allow adequate visualization of the hiatus. The gastrohepatic ligament is divided, and the now exposed right and left crura are dissected until the gastroesophageal junction is freed. Avoiding dividing the phrenoesophageal ligament this early is important so that pneumoperitoneum is maintained. The gastrocolic ligament is identified and, using ultrasonic coagulation shears, is divided lateral to the right gastroepiploic arcade.

After this, the short gastric arteries are divided along the greater curvature to allow mobilization of the stomach. Once dissection has reached the left crus, posterior gastroesophageal attachments and gastrocolic omentum are divided, preserving the right gastroepiploic arcade. The stomach is retracted superiorly to expose the left gastric and celiac vessels. Nodal tissue in this region is dissected out and collected with the specimen. The left gastric artery and vein are then isolated and divided with clips and ties or a vascular stapler.

The next step, after the stomach has been mobilized, is to perform a pyloroplasty. To minimize traumatic injury, the stomach must be handled with care. The pyloroplasty is usually performed in the Heinecke-Mikulicz fashion. A suture is placed superiorly and inferiorly on the pylorus to allow retraction. The ultrasonic shears or cautery is then used to create an opening in the pylorus. The opening is subsequently closed with sutures in a transverse interrupted fashion. To allow the pylorus to reach the right crus and obtain adequate mobilization of the gastric tube, the retrogastric and duodenal attachments are dissected as needed (see the image below). [18, 33]

Pyloroplasty during laparoscopy. Pyloroplasty during laparoscopy.

The gastric tube construction is then carried out as the next step. Creating a gastric tube with a diameter no smaller than 4-5 cm is important. Anything narrower increases the risk of gastric tip necrosis and neck leaks. To create the gastric tube, a vascular-loaded endoscopic gastrointestinal anastomosis (GIA) stapler is first fired across the lesser-curvature vessels toward the incisura, preserving the right gastric vessels. This step determines the diameter of the gastric tube and is based on the angle of the staple line.

Subsequent stapling should be done along a line parallel to the greater-curvature vessels and arcade to maintain a consistent width in the gastric tube and to avoid gastric tube spiraling. The resected portion is attached to the gastric tube with two endosutures placed from the tip of the fundus to the lesser curvature of the specimen minimizing the bulk as this is passed through the hiatus and out the neck incision and avoiding twisting. [18, 31, 32, 33]

A feeding jejunostomy is then placed. This may require an additional 10-mm port in the right lower quadrant. With an Endostitch, a proximal jejunal limb, determined by first identifying the ligament of Treitz and tracing about 40 cm back, is attached to the left lateral anterior abdominal wall. A 5-French needle catheter is then placed percutaneously into the jejunum (Compact Biosystems, Minneapolis, MN) under laparoscopic visualization. A guide wire is placed through the needle, which is then followed by a jejunal catheter to a distance of about 20 cm.

The feeding tube is then additionally tacked to about 3-4 cm of distance to the anterior abdominal wall for further support. To assess adequate placement, 10 mL of air or water are instilled through the tube. The last part of the abdominal operation is to now divide the phrenoesophageal ligament to facilitate passage of the conduit through the hiatus. [18, 33]

The final stage of the operation is the neck anastomosis. To start, a 4-cm to 6-cm horizontal neck incision is made above the sternal notch along the cervical crease to expose the cervical esophagus. Platysmal flaps are developed, the omohyoid is divided, and dissection is carried down to the prevertebral fascia. The cervical esophagus is then carefully dissected and retracted medially. With dissection carried down inferiorly, an open communication to the thoracic inlet should now exist. The Penrose drain from the thoracic procedure should then be brought up through the outlet to complete dissection. The specimen can then be slowly delivered through the neck incision with the gastric conduit. An assistant should visualize the passage of the conduit through the hiatus laparoscopically to ensure adequate and safe delivery.

Once delivered through the neck, the two sutures holding the gastric tube to the specimen are divided and the specimen is removed. The proximal esophagus is mobilized by dividing 1-2 cm below the cricopharyngeal muscle, and then a purse-string suture is placed using an auto-purse-string device (US Surgical, Norwalk, CT). After the viability of the gastric conduit is ensured, an end-to-end anastomosis (EEA) is performed with a 25-mm EEA stapler; the anvil is placed in the cervical esophagus and the purse-string tied tightly around it while a small gastrotomy is created in the proximal gastric tube. Once the anastomosis is complete, a nasogastric tube is placed under direct vision, and the gastrotomy is closed with an endoscopic GIA stapler.

The last step of the operation is to return to the abdominal cavity and apply gentle traction to the antral area until the cervical anastomosis returns into the neck incision. This also allows removal of the redundant gastric tube in the mediastinum. To prevent proximal herniation of the gastric tube, tacks are applied to attach the gastric tube to the hiatus. Typically, three sutures are placed. One is placed from the greater curvature to the left crus. Another is placed from the lesser curvature to the right crus. The final tack attaches the central edge of the hiatus to the anterior gastric tube. The cervical anastomosis is irrigated, hemostasis is maintained, and closure of all port sites and the cervical incision is performed. [18, 33]

Laparoscopic transhiatal esophagectomy

The laparoscopic transhiatal esophagectomy begins with the patient supine in the reverse Trendelenburg position, withthe right thorax raised by 30º in case there is need for an emergency thoracotomy. Typically, the surgeon stands between the patient's legs. As with the transthoracic approach, five ports are used. Placement of the first port is along the midline about 5 cm above the umbilicus using a 12-mm port.

Pneumoperitoneum is established and a 30º scope inserted. The remaining ports can now be placed under laparoscopic visualization to avoid intra-abdominal injury. A 5-mm port is inserted at the subxiphoid for liver retraction. Two more 12-mm ports are placed, one on the right midclavicular line (grasping) and the other on the left midclavicular line (dissection). The final 5-mm port is inserted at the left paraumbilical side for additional retraction. [34, 35]

To start, the left lobe of the liver is retracted, and the lesser omentum is incised and entered. Surrounding lymph nodes and fatty tissue are cleared to adequately visualize the celiac axis and origin of the common hepatic artery and splenic artery. The left gastric artery and vein are dissected and ligated and divided. Then, the left and right crura are dissected, starting at the anterior arcuate ligament. After this, the posterior mediastinum can be entered to continue dissection. Care must be taken to avoid violating the pleura.

Next, the gastrocolic ligament is opened between the stomach and the transverse colon at the origin of the right gastroepiploic artery. Dissection is carried out toward the gastrosplenic ligament, and the short gastric vessels are divided. The fundus is further released by dissection from the superior splenic pole and division of the pancreaticogastric attachments and the posterior vagus nerve.

Dissection is then performed between the posterior stomach up to the first part of the duodenum (see the image below). Gastric tubulization is performed with an endoscopic GIA stapler as described previously along the greater curvature. With a cotton tape, one end is sutured to the tubule apex and the other to the lesser curvature to facilitate pull-through.

Mobilization of the stomach. Mobilization of the stomach.

Attention is returned to the hiatus, where the distal esophagus is further mobilized circumferentially while the fundus is gently retracted caudally. Included in this step should be division of the phrenoesophageal ligament with mediastinal lymph node dissection up to the level of the carina, again with a large degree of caution to avoid violating the pleura. At this time, a pyloroplasty can be performed as previously described.

In the next stage of this procedure, a cervicotomy is performed along the anterior sternocleidomastoid, and the esophagus is isolated. With mild traction placed on the proximal cervical esophagus, blunt dissection is used to free the cervical esophagus to the thoracic inlet. At this point, the esophagus and gastric tubule can be pulled through the cervicotomy and an end-to-end esophagogastric anastomosis is performed as described previously (see the image below). Finally, a nasogastric tube is inserted, a jejunal feeding tube can be placed, and all incisions are closed as described before. [34, 35, 36]

Completed reconstruction with the gastric conduit. Completed reconstruction with the gastric conduit.

A variation in this technique is the use of mediastinoscopy to further free the intrathoracic esophagus from its attachments and obtain a more adequate lymph node dissection. Another technique aides in better esophageal dissection by passing a vein stripper through a cervical esophagotomy down through the esophagus to the staple line and out a small gastrotomy. An anvil is then attached, and the vein stripper is slowly retracted. As the esophagus gets “inverted,” from the retraction, it allows better dissection along the esophageal tract (see the image below).

Dissection of the esophagus using the inversion te Dissection of the esophagus using the inversion technique.

Once the esophagus is completely inverted and out through the neck incision, the specimen can be divided. A 26-French chest tube is attached to a silk suture that is brought up through the inversion in the posterior mediastinum. The other end of the chest tube is sutured to the gastric conduit, and after proper orientation, the chest tube and the gastric tube are pulled up through the mediastinum to reach the cervical esophagus. [37, 38]

Luketich et al have begun to use a minimally invasive Ivor Lewis (transthoracic) approach in which the anastomosis is being performed within the thoracic cavity. It has been shown that with the experience of this group, morbidity and mortality are similar to those of procedures done with a cervical anastomosis. Furthermore, Luketich has shown that they have eliminated the risk of recurrent laryngeal nerve injury and minimized pharyngeal and oropharyngeal swallowing dysfunction by using a thoracic anastomosis. [39]


Morbidity and mortality from open esophagectomy are significant, ranging from 35% to 50% in reported studies. The most common complication is an anastomotic leak, with rates ranging from 8% to 12%. [18, 40, 41, 42] This is comparable to the open procedure anastomotic leak rate of 9.1% [20] . Luketich et al reported a high narrow gastric tube leak rate of 25.9% in their series; however, they also reported that there was a high incidence in a particular group that had gastric tube diameters smaller than 4 cm. [18]

Other complications vary in incidence across studies but include vocal cord palsy (3.6-14%), chylothorax (1.7-9%), gastric tip necrosis (0.8-3.2%) and tracheal tear (0.4-1%). Cardiopulmonary complications most commonly included atrial fibrillation (11.7%), pneumonia (2-21.4%) and pleural effusion (7.7%). Wound dehiscence rarely occurred in about 0-3.7%, and venous thromboembolism was seen in 0.7-1.4%. [18, 40, 41, 42]