Feasibility of Radical Gastrointestinal Tumor Resection with Simultaneous off-Pump Coronary Artery bypass Surgery for Patients with Severe Heart Problems: A Retrospective Cohort Study from A Single Institutional Database

Background: Clinical treatment of gastrointestinal neoplasms in patients with severe coronary stenosis is dicult, and it remains controversial to perform staged or simultaneous surgeries. The purpose of this study was to retrospectively analyze the feasibility and indications for simultaneous gastrointestinal tumor resection and off-pump coronary artery bypass (OPCAB) graft surgery. Methods: Data collected from a total of ve patients, including three patients with gastric cancer and two patients with colorectal cancer, who underwent simultaneous radical cancer resection and OPCAB between September 2010 and October 2019, were retrospectively analyzed. Among these patients, one had an incomplete colonic obstruction. All patients had severe coronary stenosis, and one experienced acute heart failure before surgery. OPCAB was performed rst, followed by the radical cancer resection. Results: All ve patients were discharged from hospital without perioperative death, major cardiovascular events or anastomotic leakage. The mean postoperative hospital stay was 9.4 days. One patient experienced slight gastrointestinal bleeding after surgery, which improved with conservative treatment. After a mean follow-up of 39 months, two patients with gastric cancer died from tumor metastasis at 28 months and 37 months, while the remaining three patients did not have tumor recurrence or metastasis. None of the patients experienced myocardial ischemia. Conclusion: It is safe and feasible to perform simultaneous OPCAB and gastrointestinal surgeries on the premise of strictly controlling the indications for patients with gastrointestinal tumors complicated with severe coronary artery stenosis.


Background
Gastric cancer and colorectal malignancies, two major cancers that threaten human life, rank sixth and second in terms of global incidence of cancer, respectively, and gastric cancer ranks second in terms of mortality 1 . Cardiovascular disease is the most common risk factor that complicates the radical resection of gastrointestinal tumors in elderly patients 2 . In recent years, with the development of the economy and improvement in health care within China, the average life span has been signi cantly extended 3 . At the same time, the incidence of cardiovascular diseases has also increased signi cantly 4 . The number of patients with ischemic heart disease, especially those with multiple coronary arteries severely affected by stenosis, has gradually increased 5 . As such, the number of patients with gastrointestinal tumors complicated by multivessel coronary artery disease is also trending upwards.
Studies have con rmed that the incidence of perioperative myocardial ischemia is approximately 40% for non-cardiac surgery in cardiovascular patients/high-risk patients, which is nine times higher than low-risk patients, and postoperative negative cardiac events are signi cantly increased 6 . Patients with coronary heart disease, especially those with multiple vessels affected, who only undergo peripheral vascular, chest and abdominal surgery without coronary revascularization, have an increased risk of myocardial infarction and cardiac death 7 . Coronary revascularization can help reduce the risk of heart attack and death in these highrisk patients 8 . Therefore, for patients with gastrointestinal cancer complicated by severe coronary artery stenosis, it has become a di cult surgical problem to achieve complete radical resection of the tumor while reducing the risk, as much as possible, of perioperative myocardial infarction and death. This study retrospectively analyzed the data of ve patients who underwent concurrent off-pump coronary artery bypass (OPCAB) and radical resection of a gastrointestinal tumor between September 2010 and October 2019, in order to provide additional insight regarding the treatment of these patients. We present the following article/case in accordance with the TREND reporting checklist.

Patients
A total of ve patients underwent OPCAB and radical resection of a gastrointestinal tumor in Huashan Hospital, a liated with Fudan University, between September 2010 and October 2019 ( Table 1). All ve patients were male and the average age was 61.8 years. Three patients with gastric cancer were admitted to hospital due to discomfort in the upper abdomen after eating, among which two patients had accompanying unstable angina pectoris and one patient had severe left heart failure. There were two patients with colon cancer. One of these patients was admitted to hospital due to unstable angina pectoris; preoperative examination revealed low hemoglobin, and colonoscopy revealed a colonic tumor at the hepatic exure. The second patient with colon cancer was admitted due to incomplete intestinal obstruction and unstable angina pectoris. All ve patients underwent preoperative evaluations, including clinical history, physical examination, routine blood examination of liver and kidney function, gastroenteroscopy, abdominal and chest computed tomography (CT) scans, and others. All patients were pathologically diagnosed with adenocarcinoma prior to surgery.  (Table 2), which con rmed severe coronary heart disease including three-vessel, left main, and main-like disease, all requiring coronary artery bypass grafting (CABG). Coronary angiography of Case 5 was shown in Fig. 1.Transthoracic echocardiography indicated that the left ventricular ejection fraction (LVEF) was 56.8% (45-65%) on average. According to the preoperative NSQIP-MICA score, the risk of perioperative myocardial infarction and cardiac arrest was extremely high. Surgical procedures and follow up.
All patients were given lipid-lowering drugs and beta-blocker prior to the operation. Except for case 2, the patients were discontinued from clopidogrel and aspirin seven to eight days before surgery, and low molecular weight heparin (4100 U, q12h) was injected subcutaneously for bridging. During the bridging process, severe angina or chest tightness did not occur in any case, nor did gastrointestinal bleeding occur.
Case 2 had severe coronary artery stenosis before surgery and presented with left heart failure, while antiplatelet drugs, cardiotonic diuretics and other drugs did not improve the patient's condition. After implantation of an intra-aortic balloon pump (IABP), the blood ow was stable enough to perform an emergency OPCAB and radical resection of the gastric cancer.
All the patients were operated on by the same group of cardiac and gastrointestinal surgeons. OPCAB was performed rst, followed by radical cancer resection of the gastrointestinal tumors. After conventional anesthesia, a median incision was made into the chest to harvest the internal mammary artery, the great saphenous vein, and the left radial artery as graft vessels. Heparin (1 mg/kg) was administered intravenously before the graft was disengaged. The proximal end of the graft was sutured to the aorta using 5 − 0 prolene, and the distal end was sutured to the coronary artery using 7 − 0 prolene. After completion of the grafting, protamine sulfate (1.5x the amount of heparin) was administered for heparin neutralization. After rigorous maintenance of hemostasis and placement of a thoracic drainage tube, the chest was closed. The abdomen was then disinfected again, and a midabdominal incision was made approximately 5 cm from the lower edge of the chest incision to perform the radical resection of the gastrointestinal tumor. All patients underwent an R0 resection and standard lymph node dissection. Negative pressure drainage was established, and gastric cancer patients were tted with a nasal nutrition tube (Table 3). Following the operations, patients were placed in the intensive care unit for monitoring. The IABP was removed shortly after the operation, and the tracheal intubation was removed at the appropriate time.
Patients with gastric cancer received enteral nutrient solution, aspirin, clopidogrel, beta-blockers, and lipidlowering drugs through the nasal feeding tube beginning from the rst day after surgery. Patients with colorectal cancer received intravenous nutrition and low molecular weight heparin (4100 U, q12h) was injected subcutaneously from the rst postoperative day. After eating, the patients were given the above drugs orally. The drainage tube was removed when the pleural mediastinal drainage was less than 200 mL/day. After con rming that there were no gastrointestinal stulas, the abdominal drainage tube and enteral feeding tube were removed and the patients were discharged. The patients were prescribed additional medication and were followed up regularly (Table 4).  Antiplatelet drugs were stopped, and conservative treatment was provided. The patient improved after four days. During the discontinuation of antiplatelet drugs, the patient did not experience any cardiovascular symptoms such as chest tightness or shortness of breath. Two patients (case 2 and 3) developed atrial brillation after surgery, which improved with medication. Case 5 underwent colostomy surgery two months after the combined operation.
The average follow-up was 39 months (5-115 months). Two patients with gastric cancer died at 28 months and 37 months due to tumor metastasis, and there was no chest tightness or shortness of breath during this period. The remaining patients were alive without cardiovascular events or tumor progression at the end of the follow-up period (Table 5).

Discussion
For patients with gastrointestinal malignancies and severe coronary stenosis, the choice between staged or simultaneous surgeries is still controversial. Staged radical resection of the tumor following CABG has been the traditional approach in the past 9, 10 . However, it has been reported that a second non-cardiac surgery within 30 days has a higher risk of death and cardiovascular complications. In general, it is recommended that the subsequent operation be performed six to 12 weeks after grafting 11 . In addition, the general nutritional status of gastrointestinal tumor patients was lower, and the recovery time after CABG was longer.
Takahashi and colleagues reported that the second operation was delayed in three of nine patients who received staged surgery due to slow recovery following CABG, with an average interval of seven weeks 12 .
Importantly, the tumor may progress while patients are awaiting radical surgery. Additionally, heparinization during CABG and postoperative antiplatelet therapy may lead to gastrointestinal malignancy bleeding, which could be life-threatening. Therefore, to avoid the above shortcomings of staged surgeries, concurrent surgeries may be a better option. In addition, the concurrent surgeries can also reduce the immunosuppression caused by twice the anesthesia, reduce the long-term recurrence rate of the tumor caused by blood transfusions 13 , reduce the pain experienced by patients, and it has health and economic bene ts.
More than 20 patients with gastric cancer and 10 patients with bowel cancer have received simultaneous CABG and radical gastrointestinal tumor resection [14][15][16] . There were no perioperative deaths, and no occurrences of postoperative myocardial infarction or heart failure. A total of ve patients at our center were discharged smoothly without adverse events. There were no perioperative deaths, and no serious cardiovascular events or anastomosis stulas following the concurrent surgeries. The management of patients with severe coronary stenosis who present with acute heart failure may be a more di cult challenge for cardiac surgeons. Most scholars believe that left heart failure that requires large doses of cardiotonic drugs or mechanical circulatory support is a contraindication to simultaneous surgery, and these patients should be operated on in stages 14 . Among our patients, OPCAB was urgently performed on case 2 because of acute left heart failure. After OPCAB, the patient had stable hemodynamics and no obvious bleeding tendencies, so he immediately underwent radical resection of gastric cancer. This is the rst case of heart failure that underwent simultaneous CABG and radical tumor resection, which has provided a potential solution for the treatment of such patients.
In addition to the condition of the heart, the surgery required for the abdominal tumor is also an important factor in considering whether to perform the operations at the same time. Tsuji et al. reported that CABG and total gastrectomy at the same time have a higher risk of mediastinal infection, and proposed that CABG and total gastrectomy should be performed in stages, with the total gastrectomy being performed three to six weeks after CABG 10 . Takahashi suggested that patients with severe coronary heart disease undergoing resection of high-risk tumors, such as esophageal cancer and pancreatic cancer, should also undergo staged surgeries 14 . In addition, Komokata and colleagues published a report on an 83-year-old patient with chronic obstructive pulmonary disease (COPD) who underwent simultaneous aortic valve replacement and radical gastric cancer surgery, and died of respiratory failure following the operation, suggesting that advanced age and COPD are high risk factors for poor outcomes in simultaneous surgeries 15 .
CABG and percutaneous coronary intervention (PCI) are both strategies of coronary revascularization, but making a choice between the two is still controversial. The SYNTAX trail showed that CABG had a mortality bene t over PCI in patients with multi-vessel disease, particularly in those with diabetes and higher coronary complexity 19 . For patients with coronary heart disease undergoing non-cardiac surgery, it is recommended to implant bare stents instead of drug-eluting stents, because this can shorten the time interval between subsequent operations 20 . The ideal interval to perform non-cardiac surgery after implantation of bare stents is three months, when the principle negative events (death, myocardial infarction, stent thrombosis and revascularization) are lowest 21 . Therefore, CABG may be a more reasonable choice for revascularization compared to PCI for patients with multi-vessel disease undergoing surgery for gastrointestinal cancer. After multidisciplinary discussions between cardiologists and cardiac surgeons, we nally decided to adopt CABG as the strategy of coronary revascularization. The use of arterial grafts is bene cial to the long-term prognosis of CABG, especially the internal mammary artery. The internal mammary artery was anastomosed to the anterior descending branch. The radial artery is the second choice, and its long-term patency is better than vein usage 25 , but inferior to the internal mammary artery 26 . However, it takes longer to obtain arterial grafts than venous grafts. We recommend that it is necessary to combine the prognosis of patient and the state of the surgery to decide which type of graft to use. If the long-term prognosis is poor, a venous graft may be a more appropriate choice. If the tumor stage is early and the life expectancy is long, total arterial grafts should be used as far as possible. The preoperative tumor staging of case 2 indicated that the gastric cancer stage was late and the patient with acute left heart failure underwent emergency CABG, so the great saphenous vein was selected as the grafting vessel. The patient of case 5 was younger, had a relatively early preoperative tumor stage, and has colorectal cancer.
Therefore, two arterial grafts from the left internal mammary artery and radial artery were used.
Except in case 2, the remaining four patients in this study were all associated with unstable angina. Before surgery, aspirin and clopidogrel were stopped for seven days according to relevant guidelines, and low molecular weight heparin was injected subcutaneously for bridging 27 . Gastric cancer patients were given a nutrient solution and antiplatelet drugs through the nasal feeding tube on the rst day after surgery. Patients with colorectal cancer were given intravenous nutrition after surgery, and low molecular weight heparin was given subcutaneously before eating while oral antiplatelet drugs were given after eating. By following this principle of discontinuation and administration, none of the four patients experienced perioperative severe angina pectoris or severe gastrointestinal bleeding. Case 4 showed signs of gastrointestinal bleeding after antiplatelet drugs were given following surgery. When the antiplatelet drugs were stopped and conservative treatment was provided, the patient improved after four days. No cardiovascular symptoms such as chest tightness or shortness of breath were seen during the withdrawal. According to our experience, an indwelling small intestinal nutrition tube placed during the operation has many advantages; not only can nutrition be supplied through the tube as soon as possible to promote the early recovery of digestive tract function, it can also be used to infuse antiplatelet drugs early to reduce the risk of acute thrombosis of the coronary anastomosis.
We found that the concurrent radical resection of the gastrointestinal tumor was performed under stable hemodynamics, and the radical resection of the operation was not affected 28 . The follow-up data also suggest that the overall survival and relapse-free survival after the concurrent surgeries are equivalent to those of radical gastrointestinal surgery alone 29 . A study of concurrent surgery for gastric cancer and CABG suggested that the long-term prognosis depends on the staging status of the gastric cancer at the time of diagnosis 10 .
Anastomotic leakage is a common and serious complication. There has been no signi cant difference reported in the proportion of anastomotic leakage between staged and simultaneous surgeries 15,30 .
However, there are some special considerations for concurrent surgeries, such as the location of the advanced tumor, that in uence whether or not to perform the extended radical operation. If there is incomplete colonic obstruction before the operation, the surgeons need to consider the pros and cons to decide whether to anastomose. Tsuji et al. recommended that aggressive concurrent surgical interventions might bring a bene t to the patients whose survival periods are expected to be more than six months 10 . In our group of patients, incomplete colonic obstruction was found preoperatively in case 5, and tumor invasion of a section of the small intestine was discovered during the operation. Considering the high risk of the combined operations in the same period, OPCAB + colorectal cancer resection + affected small intestinal resection + descending colostomy were performed in the rst stage, and then the colon was anastomosed after the patient's condition was improved. In addition, wound infection and treatment are also issues that need to be considered. The incidence of incision infection and mediastinal infection may be reduced by closing the thoracic incision rst, re-disinfecting strictly and then performing the gastrointestinal surgery, isolating the thoracoabdominal incision, and prophylactic use of antibiotics prior to the operation. Timely reoperation for debridement, colostomy and omentum packing is conducive to early wound healing and effective control of mediastinal infection 10,15 .
This study still has some limitations. Firstly, because this study is a retrospective analysis and the number of included cases is small, there is a certain bias. Secondly, due to the limitation of the length of follow-up, the long-term effect of the concurrent surgery needs to be further followed up and observed. Additional in-depth studies are necessary to provided more solid evidence.

Conclusions
For the treatment of patients with gastrointestinal tumors and severe coronary heart disease, concurrent surgery is being accepted by a growing number of surgeons. This study provides a useful exploration of treatment strategies for patients with gastrointestinal tumors and severe coronary heart disease.