Current status and perspectives of the future of pancreatic surgery: Establishment of evidence by integration of “art” and “science”

Abstract Pancreatic cancer surgery continues to be associated with a high operative morbidity rate, poor long‐term survival outcomes, and various challenges in obtaining high‐level evidence. Not only is the early postoperative morbidity rate high, but also late morbidity involves lifelong nutritional support for long‐term survivors. Due to poor survival outcomes even after curative surgery, pancreatic surgeons have doubts about the role of surgery as the definitive treatment for pancreatic cancer. Additionally, conducting clinical trials to obtain high‐level evidence in the field of pancreatic surgery is difficult, and the results have only had a moderate impact on clinical practice due to skepticism regarding their quality. Therefore, quality evidence regarding the extent of resection, mode of approach to dissection, reconstruction methods for pancreatico‐enteric anastomosis, determination of resectability, timing of surgery, and the definition of the resection margin is lacking. However, numerous innovative pancreatic surgical procedures have been developed, which may aptly have been called “art” when they were first introduced, regardless of whether they subsequently were supported by scientific evidence. In this review, we provide recent examples of the integration of art and science in the field of pancreatic surgery, which illustrate how the creative ideas of pancreatic surgeons evolved into generally accepted clinical practice. Pancreatic surgeons should be considered “surgical artists,” “surgical scientists,” and “surgical practitioners.” We look forward to more “surgical artists” educating future “surgical artists and scientists” to create a richer “spirit of innovation,” leading to a more beautiful integration of art and science in the field of pancreatic surgery.


| INTRODUC TI ON
Compared to other malignancies of the gastrointestinal tract, pancreatic cancer surgery is unique in terms of its associated high operative morbidity rate, poor long-term survival outcomes, and challenges in terms of obtaining high-level evidence based on randomized clinical trials (RCTs). Until recently, the pancreas has been referred to as "no man's land," which may explain why even the brightest thinkers in the East and West did not describe the pancreas in their anatomical diagrams ( Figure 1).
After pancreatectomy, early morbidity is associated with pancreatic leakage, bleeding, delayed gastric emptying, and local sepsis, which often result from complex surgical procedures requiring multiple anastomoses. 1 Moreover, survival outcomes for pancreatic cancer remain low and have not improved significantly over the past few decades. 6 Only 20%-30% of patients at the time of pancreatic cancer diagnosis are considered candidates for surgery, while 70%-80% of patients eventually fail to receive curative treatment mainly due to systemic metastasis. 6 Moreover, due to poor survival outcomes even after curative resection, pancreatic surgeons have doubts about the role of surgery as the definitive treatment for pancreatic cancer. For these reasons, pancreatic cancer is considered a systemic disease; however, surgeons should also focus on achieving safer and more complete local control of the tumor through surgery.
Nevertheless, there is a lack of high-level evidence in the field of pancreatic surgery. Consequently, we do not yet have detailed guidelines for pancreatic surgical procedures, partly due to limitations in conducting RCTs, especially those focused on pancreatic cancer. Despite a noticeable increase in the quantity and quality of RCTs focused on pancreatic surgery, many are limited in their design and reporting, including selective reporting, limited assessment of long-term effects, and the risk of small sample bias. 7,8 Specifically, given small differences in the expected effect of pancreatic surgery, the sample size can be "prohibitively large" while the number of pancreatic cancer patients is insufficient for case recruitment. 9 Moreover, standardization of surgical techniques is difficult due to the complexity of the procedures. 10 16 have yet to be provided for pancreatic surgery.
Each of the current issues in pancreatic surgery will be discussed below.
First, there is much debate regarding the appropriate extent of resection, which includes observation vs surgery, excision vs partial pancreatectomy, partial vs total pancreatectomy, the extent of gastric resection during pancreaticoduodenectomy ([PD]; standard Whipple operation, pylorus preservation, or pylorus resection), and organ preservation (duodenum, spleen, or splenic vessels; detailed in the "spleen-preserving distal pancreatectomy" section), depending on the nature and extent of the disease. 17,18 Additionally, the extent of lymphadenectomy, resection of major vessels, and nerve plexus dissection can be controversial for several reasons; for example, whether to include the resection or dissection of remote site lymph nodes, the portomesenteric vein, and major arteries including the celiac axis (detailed in the "modified Appleby operation for advanced pancreatic body cancer" section), superior mesenteric artery (SMA), and hepatic arteries. Previous RCTs have confirmed that prophylactic hemi-circumferential peri-SMA nerve plexus dissection was not beneficial for survival gain. [19][20][21][22] However, even though R0 resection can be achieved by adjusting the dissection level, no consensus has been achieved on the systematic criteria for the extent of resection according to the extent of the patient's primary disease. 23 Finally, although the definition remains controversial, the mesopancreas should also be considered when determining the extent of surgery (detailed in the "meso-pancreas excision" section). 24 Second, the various modes of approaching dissection require further discussion, which include different types of SMA (first) approaches mainly for pancreatic head cancer, 25 Minimally invasive pancreatectomy is recommended in high-volume centers, and the requirement for a structured training program for minimally invasive pancreatectomy must also be emphasized. 38 Third, a major factor contributing to morbidity after pancreatectomy is the leakage of pancreatic juice from the pancreaticoenterostomy or pancreatic stump. Therefore, pancreatic surgeons are continuously searching for the best techniques for anastomosis and stump closure, which include various methods of reconstruction, the site and route of anastomosis, the use and type of stent or surgical drain, the use of surgical tissue adhesives, and other innovative techniques to restore pancreatico-enteric continuity. 39 Furthermore, the appropriate timing of surgery (upfront or after neoadjuvant therapy) and conversion surgery is fiercely debated. 46 Lastly, the appropriate definition and assessment of the resec-

| WHAT IS "ART," " SCIEN CE ," AND THEIR INTEG R ATI ON?
Some of the abovementioned current issues have reached some level of consensus, while others are still under debate. As evidence accumulates over time, the level of consensus will likely increase in the future. However, by reflecting on past experiences, we can speculate on how this process will unfold in the future; the process required not only the mechanical accumulation of evidence, but also innovation and imagination that could be described as "art" beyond the boundaries of science.
Based on these concepts, a sample diagram integrating "art" and "science" in the field of surgery is presented in Figure 2. illustrates how an innovative procedure adopted from other surgical disciplines overcame problems specific to pancreatic surgery.
The third example shows the continuous integration of art and science regarding the meso-pancreas, whose concept has not yet been fully established; the innovative concept, along with the development of a variety of surgical approaches in the area, is being evidenced through ongoing trials. The last example describes the integration of physiology and pancreatic surgery, which goes beyond the limits of the anatomical or technical perspective of surgery, often overlooked by surgeons.

| Spleen-preserving distal pancreatectomy
Overwhelming post-splenectomy infection (OPSI) is a rare but fatal complication after distal pancreatectomy with splenectomy ( Figure 3a). 54 The first solution introduced to manage this problem was the Warshaw procedure, in which the spleen is preserved (though not the splenic vessels) during distal pancreatectomy. 55 However, many surgeons had concerns about splenic infarction and gastric varix, which can develop after splenic vessel resection. 55,56 Therefore, the Kimura procedure, which involves the preservation of both the spleen and splenic vessels, was proposed. 57  However, OPSI were discovered to be more rare and preventable than expected, and splenic infarction and gastric varices were also rare, with little clinical significance. 59

| Modified Appleby operation for advanced pancreatic body cancer
Pancreatic body cancers frequently infiltrate the celiac artery due to its proximity to the tumor. Originally designed for advanced gastric cancer, the Appleby operation includes a total gastrectomy and celiac artery resection ( Figure 3-b). 62 The modified Appleby procedure, which involves preserving the right gastric artery and right gastroepiploic vessel to preserve the entire stomach, has been proposed and shown to be technically feasible as a treatment for pancreatic body cancer. 63,64 Additionally, hepatic and gastric blood flow is expected to be preserved by collateral blood flow from the SMA through the gastroduodenal and pancreaticoduodenal arteries after celiac and common hepatic artery resections.
However, understandably, many pancreatic surgeons are concerned about hepatic and gastric ischemia, which have been reported but are extremely rare. 65 Therefore, innovative procedures have been developed to address these issues, including preoperative common hepatic artery embolization to ensure hepatic blood flow 34,66 and the preservation or reconstruction of the left gastric artery to prevent gastric ischemia. 67,68 Since these innovative techniques have only been reported in a limited number of cases, RCTs are required to confirm their technical feasibility and safety.

| Meso-pancreas excision
Based on our understanding of pancreatic anatomy and the definition of the mesentery, meso-colon, and meso-rectum, the concept of the mesopancreas has emerged (Figure 3-c). 69 Although the anatomical concept of the meso-pancreas is still controversial, some surgeons perform mesopancreas excision during PD for pancreatic head cancer to remove all soft tissue from this area since tumor involvement of retroperitoneal resection margin (R1 resection) and local recurrence is frequently reported after surgery. 70,71 In addition, innovative SMA-first approaches that emphasize the principles of oncological surgery have been introduced to facilitate meso-pancreas excision. One example is the MAPLE-PD (mesenteric approach versus conventional approach for pancreatic cancer during Pancreaticoduodenectomy) trial currently in progress in Japan. 72 Another example is the concept of "en bloc proximal peri-mesenteric clearance," which was proposed due to cancer recurrence at the SMA left-side lymph node, located outside of the meso-pancreas, and for which RCT-based evidence is expected in the future. 35 Through the above process, we can speculate how art and science are integrated to refine the establishment of innovative surgical procedures. All surgeons who have proposed this concept and attempted meso-pancreas excision should be considered "surgical artists" as well as "surgical scientists."

| Preventing atrophy of the remnant pancreas after pancreatic head resection
Atrophy of the distal remnant pancreas is a frequently observed phenomenon after PD due to pancreaticojejunostomy stricture, postoperative radiation therapy, or the presence of an altered route for food passage, among others (Figure 3-d). 73 Additionally, the physiological change in gastrin/cholecystokinin (CKK) secretion has emerged as another potential cause of atrophy. This is based on the understanding that gastrin/CCK secretion is reduced after PD or pylorus-preserving PD (PPPD) and through the growth-stimulating effect that gastrin/CCK has on the pancreas that has clearly been identified in animal models. 74 Therefore, it has been theorized that one of the causes of remnant pancreatic atrophy after PD/PPPD could be a decrease in gastrin/CCK secretion after PD and a decrease in CCK secretion after PPPD. Gastrin is secreted from the gastric antrum, and CCK is secreted from the duodenum; therefore, a consequence of both PD and PPPD is the removal of the source of these hormones. 75 Therefore, we wondered if there was any way to prevent pan-

| CON CLUS ION
This review illustrates how the creative ideas of pancreatic surgeons have evolved into generally accepted clinical practice.
Surgeons should be considered "surgical artists," "surgical scientists," and "surgical practitioners" due to their capacity to combine art and science in clinical practice. We look forward to witnessing more "surgical artists" educating future "surgical artists and scientists" to continue the rich "spirit of innovation" in pancreatic surgery, which will lead to more innovative ideas and the development of more efficient methods of establishing high levels of evidence, and, thus, a more beautiful integration of art and science in the field of pancreatic surgery.

ACK N OWLED G M ENTS
The figure work was supported by the Creative Media Service of the National Cancer Center Korea. We would like to thank Editage (www.edita ge.co.kr) for English language editing.

D I SCLOS U R E
Funding: The authors received no specific funding for this study.