**3. Defining the disease**

The diagnosis of PDAC often remains a challenge. The utilization of various imaging modal‐ ities in the diagnosis and staging of PDAC continue to be utilized. Computed tomography (CT), ultrasonography (US), magnetic resonance imaging (MRI), and endoscopic ultrasonog‐ raphy (EUS) are the routinely used modalities that are relatively accessible in hospitals and specialized cancer centers. As the management of PDAC has advanced and become more aggressive analogous to the nature of the disease, imaging modalities play an important role, not only as a noninvasive option in the diagnostic phase of the disease but also in the deter‐ mination of disease burden, resectability, and the monitoring of treatment efficacy [18].

CT scanning is the accepted first line investigative modality in PDAC suspected patients. This modality is usually preferred because it provides high‐resolution/quality images and relatively wide availability, and its complete studies are relatively quicker than other high‐resolution counterparts. CT scans are reported to provide 100% sensitivity and 72% specificity in predicting the resectability of PDAC [19]. This modality also allows for the ability to use a specific image‐attaining protocol for more thorough evaluation of the pancreas. This pancreas protocol utilizes thin‐sectioned slices and captures images during certain postcontrast injection time frames. Because PDAC is a hypovascular tumor, it is best detected in the late arterial phase at 35–40 s postcontrast injection, when the normal pancreatic parenchymal tissue is most optimally enhanced while the hypovascular tumor is not. At 70‐s postcontrast injection, the portal venous system is optimally enhanced, which can prove helpful in assessing any extent of venous involvement and identifying possible liver metastases. These two phases are typically obtained during a pancreatic protocol CT. Of note, when there is a concern for pancreatic islet cell (endocrine) tumor exists, an earlier (20–25‐s postcontrast injection), arterial phase scan is usually most beneficial, since these tumors are often hypervascular. Some of these endocrine tumors can be visualized in the portal venous phase as well, and thus dual phases of arterial and portal venous scanning are usually done for suspected pancreatic endocrine tumors. The pancreatic protocol CT scan produces images with PDAC classically appearing as a hypodense lesion relative to the pancreatic parenchyma [19, 20]. On an approximate, 10% of cases where PDAC lesions are isodense on imaging, distinguishing the tumor can be more difficult. Other signs can be present on CT imaging that increase detection of a pancreatic mass. Lesions present in the pancreatic head can produce a secondary finding of "double duct" sign, which is the presence of simultaneous dilation of the common bile and main pancreatic ducts. This is due to the tumor in the head portion of the pancreas compressing the ducts causing obstruction and fluid build‐up that result in dilation of both ducts. Tumor in the body or tail of the pancreas can result in stenosis and obstruction of the main pancreatic duct, resulting in an upstream dilation of the main pancreatic duct. These signs can be beneficial in distinguish‐ ing a more isodense lesion or in the confirmation of a smaller, hypodense PDAC lesion. However, this modality can be limited in its ability to differentiate an isodense lesion and to show possible metastatic disease when denoted by small lesions in certain areas such as the peritoneum or liver [18, 20, 21].

an aggressive cancer. Correspondingly, the inclusion of patients in clinical trials is another benefit of multidisciplinary team centers. Studies have shown up to a two times higher likelihood of patients participating in a clinical trial when seeing a multidisciplinary team. This plays an important role in acquiring a greater understanding of the disease and the develop‐

Ultimately, the historical lack of multidisciplinary care is only one of multiple factors attributed to the poor survivability curve seen in PDAC patients. However, in recent years, changes in the management of PDAC have started to shift the curve toward showing improvement in the

The diagnosis of PDAC often remains a challenge. The utilization of various imaging modal‐ ities in the diagnosis and staging of PDAC continue to be utilized. Computed tomography (CT), ultrasonography (US), magnetic resonance imaging (MRI), and endoscopic ultrasonog‐ raphy (EUS) are the routinely used modalities that are relatively accessible in hospitals and specialized cancer centers. As the management of PDAC has advanced and become more aggressive analogous to the nature of the disease, imaging modalities play an important role, not only as a noninvasive option in the diagnostic phase of the disease but also in the deter‐ mination of disease burden, resectability, and the monitoring of treatment efficacy [18].

CT scanning is the accepted first line investigative modality in PDAC suspected patients. This modality is usually preferred because it provides high‐resolution/quality images and relatively wide availability, and its complete studies are relatively quicker than other high‐resolution counterparts. CT scans are reported to provide 100% sensitivity and 72% specificity in predicting the resectability of PDAC [19]. This modality also allows for the ability to use a specific image‐attaining protocol for more thorough evaluation of the pancreas. This pancreas protocol utilizes thin‐sectioned slices and captures images during certain postcontrast injection time frames. Because PDAC is a hypovascular tumor, it is best detected in the late arterial phase at 35–40 s postcontrast injection, when the normal pancreatic parenchymal tissue is most optimally enhanced while the hypovascular tumor is not. At 70‐s postcontrast injection, the portal venous system is optimally enhanced, which can prove helpful in assessing any extent of venous involvement and identifying possible liver metastases. These two phases are typically obtained during a pancreatic protocol CT. Of note, when there is a concern for pancreatic islet cell (endocrine) tumor exists, an earlier (20–25‐s postcontrast injection), arterial phase scan is usually most beneficial, since these tumors are often hypervascular. Some of these endocrine tumors can be visualized in the portal venous phase as well, and thus dual phases of arterial and portal venous scanning are usually done for suspected pancreatic endocrine tumors. The pancreatic protocol CT scan produces images with PDAC classically appearing as a hypodense lesion relative to the pancreatic parenchyma [19, 20]. On an approximate, 10% of cases where PDAC lesions are isodense on imaging, distinguishing the tumor can be more difficult. Other signs can be present on CT imaging that increase detection of a pancreatic mass.

acute care of patients as well as increasing the number of long‐term outcomes [17].

ment of more effective therapies [7, 16].

**3. Defining the disease**

162 Challenges in Pancreatic Pathology

One of the most sensitive and high‐quality image producing modalities to date is the MRI. The MRI modality in comparison to CT scans provides greater soft tissue quality. This allows for superiority in imaging of smaller tumors and fatty infiltration of the pancreatic parenchyma, and in distinguishing lesions that would show as isodense lesion on CT scan. The most effective MRI‐weighted imaging sequence for assessing the pancreas is the T1‐weighted, fat suppressed sequence. In this sequence, PDAC usually appears hypointense [18]. Other sequences (T2‐ weighted, DWI, and GRE) have been shown to be relatively inconsistent in the PDAC intensity seen on imaging; however, they are still useful in assisting thorough evaluation of the pancre‐ atic tissue. Another advantage of the MRI is the ability to perform a more in‐depth examination of the pancreatic ducts utilizing magnetic resonance cholangiopancreatography (MRCP). This technique allows for inspection of the ductal systems and ability to discern small ductal narrowing secondary to a small lesion or to detect confounding etiologies to ductal dilation such as a stone obstructing either the common bile or main pancreatic duct. MRCP, in con‐ junction with the MRI, can result in more efficacious detection in early stage pancreatic disease by allowing more detailed study of the pancreatic parenchyma and ductal system. Limitations of this modality in the diagnosis and interventional benefits in PDAC disease include significant time for study completion, fairly high cost, easy susceptibility to artifact and difficult accessibility in areas with limited resources [18, 21].

Ultrasonography (US) is a most likely and readily available modality than all other applicable modalities in visualizing the pancreas. US can also be done very quickly with low cost and increased portability. However, US scan of the pancreas is fairly low in quality, requires specific preimaging preparation for the patient, and requires trained and experienced people for the operation to be most effectively utilized. A minimum 6‐h fast is required to better visualize the pancreas; this fast preparation improves visualization by limiting bowel gas and ensuring an empty stomach. The scan protocol evaluates different sectional cuts (transverse, oblique, and sagittal) along the pancreatic duct in the search for signs of obstruction or stenosis. This can often visualize the pathognomonic observation of double duct sign in PDAC of the pancreatic head. The PDAC lesion is often evident as a hypoechoic lesion on imaging. However, diag‐ nostic utility of US is highly dependent upon the operator's training and experience, the burden or progression of disease, and the habitus of a patient [18, 21].

Endoscopic ultrasound (EUS) has been considered as a modality producing highly accurate detection of small (greater than 3 cm) lesions. This modality provides visualization of the pancreatic tissue and parenchyma from the stomach or duodenum. It allows for higher quality images to be obtained in comparison to standard US. EUS also has the benefit of being able to obtain specimens via fine needle aspiration. On its own, EUS is not highly effective in differentiating a chronic pancreatic disease such as chronic pancreatitis and pancreatic cancer, with evidence showing the accuracy at 76% for detecting cancer and 46% for detecting a local inflammation, whereas the combination of EUS and fine needle aspiration has shown to increase the detection percentage of pancreatic cancer to 90% and above [18]. Limitations of this modality include the necessity of conjoined procedures, including a more invasive, albeit minimally, technique. Fine need aspiration is also not a widely and readily available resource amongst all hospital and care centers.

One of the most important components of a multidisciplinary team is that the presenting state of the disease is agreed upon, and a treatment plan is constructed in accordance with national guidelines for care while also taking into account distinctive patient factors. The expertise of the multidisciplinary team and standardized national definitions regarding disease staging are associating factors best utilized concurrently in determining disease burden and the initial steps in optimizing patient management. Although pathologic staging criteria for PDAC have long been established through the American Joint Commission on Cancer (AJCC), clinical staging criteria has not been as well defined. For an extensive period of time, common language was lacking for defining the degree of tumor involvement with surrounding vasculature and the subsequent classification of whether or not it is safely resectable. From a surgical perspec‐ tive, the determination for surgical intervention is based on the tumor's determined resecta‐ bility. By classifying patient tumors as resectable, borderline resectable, locally advanced, and metastatic, the care team is better able to standardize treatment regimens for patients. Fur‐ thermore, more defined classifications allow for greater adherence to national guidelines [20, 22].

Although several definitions of resectability have emerged over the years, the most widely accepted classification, which has also subsequently been incorporated in the National Comprehensive Cancer Network (NCCN) criteria, was defined by Callery et al. [22]. They constructed a consensus criterion based on radiographic CT findings in the preoperative staging phase. Resectable tumors are those that (1) had demonstrated no distant metastases; (2) had shown no radiographic evidence of superior mesenteric vein (SMV) and portal vein abutment, distortion, tumor thrombus, or venous encasement; and (3) had shown clear fat planes around the celiac axis, hepatic artery, and superior mesenteric artery. Borderline resectable tumors are defined as those that (1) had shown no distant metastases; (2) demon‐ strated either some venous involvement of SMV/portal vein (a) with tumor abutment with or without (i) impingement and narrowing of the lumen, (ii) encasement of the SMV/portal vein without encasement of the nearby arteries, or (iii) short segment venous occlusion resulting from either tumor thrombus or encasement, (b) but with suitable vessel proximal and distal to the area of vessel involvement, which allows for safe resection and reconstruction; (3) demonstrated some gastroduodenal artery encasement up to the hepatic artery with either short segment encasement or direct abutment of the hepatic artery, without extension to the celiac axis; and (4) demonstrated tumor abutment of the SMA not to exceed more than 180° of the circumference of the vessel wall. Locally advanced tumors were defined as those that fell outside the definition of borderline resectable. Metastatic tumors were defined as those with any evidence of metastatic disease [22].

Despite the relatively high accuracy in predicting unresectable disease, current imaging modalities still lack indisputable certainty in predicting the degree of resectable disease. A complimentary tool for increasing sensitivity in assessing a tumor's resectability and stage is diagnostic laparoscopy. Per guidelines, for apparent resectable disease, utilization of laparo‐ scopy should be used with clinical predictors that optimize yield including pancreatic head tumors greater than 3 cm, tumors of the pancreas body and tail, ambiguous findings on CT scan, or high CA 19‐9 levels (>100 U/mL). In addition, locally advanced and unresectable pancreatic cancer, without radiographic evidence of distant metastasis, should also be further evaluated with laparoscopy in order to rule out subclinical metastatic disease so that the care team's therapeutic management can be optimized [20, 22].

### **4. High‐volume centers**

pancreatic tissue and parenchyma from the stomach or duodenum. It allows for higher quality images to be obtained in comparison to standard US. EUS also has the benefit of being able to obtain specimens via fine needle aspiration. On its own, EUS is not highly effective in differentiating a chronic pancreatic disease such as chronic pancreatitis and pancreatic cancer, with evidence showing the accuracy at 76% for detecting cancer and 46% for detecting a local inflammation, whereas the combination of EUS and fine needle aspiration has shown to increase the detection percentage of pancreatic cancer to 90% and above [18]. Limitations of this modality include the necessity of conjoined procedures, including a more invasive, albeit minimally, technique. Fine need aspiration is also not a widely and readily available resource

One of the most important components of a multidisciplinary team is that the presenting state of the disease is agreed upon, and a treatment plan is constructed in accordance with national guidelines for care while also taking into account distinctive patient factors. The expertise of the multidisciplinary team and standardized national definitions regarding disease staging are associating factors best utilized concurrently in determining disease burden and the initial steps in optimizing patient management. Although pathologic staging criteria for PDAC have long been established through the American Joint Commission on Cancer (AJCC), clinical staging criteria has not been as well defined. For an extensive period of time, common language was lacking for defining the degree of tumor involvement with surrounding vasculature and the subsequent classification of whether or not it is safely resectable. From a surgical perspec‐ tive, the determination for surgical intervention is based on the tumor's determined resecta‐ bility. By classifying patient tumors as resectable, borderline resectable, locally advanced, and metastatic, the care team is better able to standardize treatment regimens for patients. Fur‐ thermore, more defined classifications allow for greater adherence to national guidelines [20,

Although several definitions of resectability have emerged over the years, the most widely accepted classification, which has also subsequently been incorporated in the National Comprehensive Cancer Network (NCCN) criteria, was defined by Callery et al. [22]. They constructed a consensus criterion based on radiographic CT findings in the preoperative staging phase. Resectable tumors are those that (1) had demonstrated no distant metastases; (2) had shown no radiographic evidence of superior mesenteric vein (SMV) and portal vein abutment, distortion, tumor thrombus, or venous encasement; and (3) had shown clear fat planes around the celiac axis, hepatic artery, and superior mesenteric artery. Borderline resectable tumors are defined as those that (1) had shown no distant metastases; (2) demon‐ strated either some venous involvement of SMV/portal vein (a) with tumor abutment with or without (i) impingement and narrowing of the lumen, (ii) encasement of the SMV/portal vein without encasement of the nearby arteries, or (iii) short segment venous occlusion resulting from either tumor thrombus or encasement, (b) but with suitable vessel proximal and distal to the area of vessel involvement, which allows for safe resection and reconstruction; (3) demonstrated some gastroduodenal artery encasement up to the hepatic artery with either short segment encasement or direct abutment of the hepatic artery, without extension to the celiac axis; and (4) demonstrated tumor abutment of the SMA not to exceed more than 180° of

amongst all hospital and care centers.

164 Challenges in Pancreatic Pathology

22].

The outside referral to pancreatic cancer specialist, hospital, and institutional volume of patients treated for pancreas cancer matters as well. The volume of patients treated and cases seen directly correlate with the experience gained by the providers in the management care team [13, 23]. The pancreaticoduodenectomy (PD) was classically a very morbid operation with mortality after PD nearing 25% in the 1960s [6, 17]. The morbidity associated with the operation was multifactorial. However, the factor most attributable to the morbidity is the risk of pancreatic fistula development. Often unrecognized, and thus untreated, a pancreatic fistula is the development of an abnormal communication between the pancreas and other organs secondary to the leakage of pancreatic secretions from damaged pancreatic ducts. This communication can prove highly detrimental to the involved organs. A pancreatic fistula substantially contributes to the most morbid complications seen with the operation such as erosion of retroperitoneal vessels and hemorrhage, intra‐abdominal abscess, sepsis, multisys‐ tem organ failure, and death [24]. Over the years, PD morbidity and mortality have improved significantly, with mortality dropping to less than 3% in some high‐volume centers. The involvement of high‐volume pancreatic surgical centers has greatly contributed to this decline. Multiple studies have demonstrated a relationship between hospital surgical volume and outcomes for pancreatectomy [24, 25]. Specifically illustrating that as hospital volume for pancreatic surgery increases, perioperative mortality, postoperative complications, length of stay, and overall cost decreases, and long‐term survival improves [6]. In 2011, a 10‐year observational study (1999–2008) examined the relationship between cancer center volume and particular cancer operations. PD was compared to several other cancer and high‐risk opera‐ tions including esophagectomy, lung resection, cystectomy, AAA repair, and carotid endar‐ tectomy, among others. The study found an increase in the median number of cancer and high‐ risk operations performed at hospitals. Pancreatic cancer surgery exhibited the greatest observed median increase, with an approximate 200% national increase in the median number of patients receiving pancreatic cancer surgery at each hospital, an increase of 5 patients per center to 16 per center. This figure is most notably influenced by the 56% national increase in patients seen for pancreatic disease, and the 25% national decrease in the number of hospitals performing the PD procedure, which does not detract from the fact that more pancreatic cancer patients are being seen and more PD procedures are being done. The most encouraging finding is that with this increase in PDAC patients seen and PD cases performed, there has been an almost 20% decrease in the postpancreatectomy mortality (death prior to hospital discharge or within 30 days after surgery). These findings denote a strong correlation observed between the operative risk incurred and the hospital's relevant surgical case volume [25–27]. While some high‐risk operations examined in the study showed minimal volume‐outcome relationship, there was substantial evidence that the volume‐outcome relationship for PD is particularly strong. It has also been suggested that differences in surgical technique, such as margin involvement with resection, might be influential on the volume‐based differences seen in PD mortality and morbidity. Resected margins showing cancerous involvement (margin‐positive) are a poor prognostic factor after PD. The study found that patients undergoing PD at low‐ volume pancreatic cancer centers are more likely to have margin‐positive resections, either macroscopic (R2), microscopic (R1), or both [26, 27]. These findings support the concept of improved morbidity and mortality of PD at high‐volume centers and emphasize the impor‐ tance of PDAC patient referral to specialized, high‐volume centers.

#### **5. Improvement in surgical care of the patient**

Over the last 20 years, significant advances in preoperative evaluation, surgical techniques, and postoperative care have reduced the perioperative morbidity and mortality associated with pancreatic surgery. Mortality after pancreaticoduodenectomy has dropped from 25% in the 1960s to less than 3% in some high‐volume centers, with recent studies suggesting postresection long‐term survival rates approaching 30%.While numerous studies and guide‐ lines establish pancreatectomy as the primary intervention for localized PDAC, pessimism concerning pancreatic cancer disease is the likely cause of continued skepticism in the efficacy of resection. In opposition to this belief, surgeon cumulative and yearly volume in the treatment of pancreatic diseases has emerged as a surrogate marker for quality outcomes. Surgical volume produces surgical experience, and, as Birk et al. illustrated, higher volume pancreatic centers result in lower operative mortality [25]. While the number of pancreatic cancer centers is declining, the increase in case number correlating with the decrease in morbidity and mortality suggests that the market concentration of cases is providing the opportunity to obtain more experience for the surgeons performing them [25]. There has been documentation illustrating that personal surgical volume can affect patient outcome [23, 24]. This concept illustrates the importance of surgical proficiency as a contributing factor on operative morbidity and mortality, despite the complexity or high‐risk nature of the operation. High‐volume centers offer the opportunity for pancreatic specialized surgeons to become more experienced with the cancer operations as well as more accustomed to varying surgical expectations and complications, thus resulting in reduced operative mortality and improved outcomes. Evidence has emphasized the correlation of operative experience and case load, surgical benchmarks and the pancreatic surgical learning curve [23–25]. One study looking at approximately 2200 pancreatic surgeries performed during 1984–1991 showed a significant correlation between a surgeon's number of cases done and the mortality rate. Low‐volume surgeons (<10 resections) exhibited a 16% mortality rate in comparison to higher volume surgeons (>40 resections), who exhibited a 5% mortality rate (Fisher, list paper). Fisher et al. also showed this concept to be true. The author looked at the first 11‐year period of a particular surgeon's pancreatic practice, examining 162 Whipple procedures performed, divided into two categories of low‐volume era (0–11 cases/year) and high‐volume era (>22 cases/year). Patients in the low‐volume era had a higher likelihood of exhibiting one or more complications when compared to patients in the high‐volume era (58% low volume vs 46% high volume) (Fisher). Training environment, in addition to case volume, is important in acquiring and strengthening the proficiency desired for preferred pancreatic surgical outcomes [16, 23, 25]. Surgeons at academic or more specialized centers appeared to significantly progress at a greater rate, likely due to the substantial experience of the providers available to initially assist in training or mentoring more inexperienced surgeons.

#### **6. Improvements in perioperative care**

center to 16 per center. This figure is most notably influenced by the 56% national increase in patients seen for pancreatic disease, and the 25% national decrease in the number of hospitals performing the PD procedure, which does not detract from the fact that more pancreatic cancer patients are being seen and more PD procedures are being done. The most encouraging finding is that with this increase in PDAC patients seen and PD cases performed, there has been an almost 20% decrease in the postpancreatectomy mortality (death prior to hospital discharge or within 30 days after surgery). These findings denote a strong correlation observed between the operative risk incurred and the hospital's relevant surgical case volume [25–27]. While some high‐risk operations examined in the study showed minimal volume‐outcome relationship, there was substantial evidence that the volume‐outcome relationship for PD is particularly strong. It has also been suggested that differences in surgical technique, such as margin involvement with resection, might be influential on the volume‐based differences seen in PD mortality and morbidity. Resected margins showing cancerous involvement (margin‐positive) are a poor prognostic factor after PD. The study found that patients undergoing PD at low‐ volume pancreatic cancer centers are more likely to have margin‐positive resections, either macroscopic (R2), microscopic (R1), or both [26, 27]. These findings support the concept of improved morbidity and mortality of PD at high‐volume centers and emphasize the impor‐

Over the last 20 years, significant advances in preoperative evaluation, surgical techniques, and postoperative care have reduced the perioperative morbidity and mortality associated with pancreatic surgery. Mortality after pancreaticoduodenectomy has dropped from 25% in the 1960s to less than 3% in some high‐volume centers, with recent studies suggesting postresection long‐term survival rates approaching 30%.While numerous studies and guide‐ lines establish pancreatectomy as the primary intervention for localized PDAC, pessimism concerning pancreatic cancer disease is the likely cause of continued skepticism in the efficacy of resection. In opposition to this belief, surgeon cumulative and yearly volume in the treatment of pancreatic diseases has emerged as a surrogate marker for quality outcomes. Surgical volume produces surgical experience, and, as Birk et al. illustrated, higher volume pancreatic centers result in lower operative mortality [25]. While the number of pancreatic cancer centers is declining, the increase in case number correlating with the decrease in morbidity and mortality suggests that the market concentration of cases is providing the opportunity to obtain more experience for the surgeons performing them [25]. There has been documentation illustrating that personal surgical volume can affect patient outcome [23, 24]. This concept illustrates the importance of surgical proficiency as a contributing factor on operative morbidity and mortality, despite the complexity or high‐risk nature of the operation. High‐volume centers offer the opportunity for pancreatic specialized surgeons to become more experienced with the cancer operations as well as more accustomed to varying surgical expectations and complications, thus resulting in reduced operative mortality and improved outcomes. Evidence has emphasized the correlation of operative experience and case load,

tance of PDAC patient referral to specialized, high‐volume centers.

**5. Improvement in surgical care of the patient**

166 Challenges in Pancreatic Pathology

The perioperative phases of the surgically treated pancreatic cancer patient have substantially improved due to the establishment of multidisciplinary care teams, the advancement of diagnostic and interventional techniques, and the continued progression of surgical experience and proficiency. While much of this can be attributed to the development of extensive technical modalities and abilities, proper and successful recovery is also an essential factor in improving postsurgical patient outcomes. The enhanced recovery after surgery (ERAS) program is a multimodal strategy that attempts to mitigate functional loss and morbidity, while improving recovery and progression of functional capabilities in the perioperative setting. The pathways included in the ERAS strategy include various preoperative and postoperative recommenda‐ tions that have significant effect on a patient's morbidity development and hospital course [28].

Significant preoperative strategies include preoperative counseling, preoperative smoking and alcohol cessation, decision to use oral bowel preparation, and anticoagulation and antimicro‐ bial prophylaxis [28–32]. Preoperative counseling, including procedural expectations and postoperative objectives, allows for the subduing of surgical anxiety and fear. This in turn results in improved postsurgical course [28]. Preoperative smoking and alcohol cessation can substantially improve a patient's outcome. At least 1 month of abstainence from smoking and alcohol reduces the otherwise two‐ to threefold postoperative morbidity increase seen in these patients. Also, this concept results in a considerable reduction in the pulmonary and wound complications often present in this group [28, 29]. Oral bowel preparation is thought to reduce complications of the surgery. However, evidence has shown that there is no clinical benefit to performing mechanical bowel preparation. Data actually show that there is more of an increased risk of dehydration or electrolyte imbalance, particularly in elderly patients [28]. Thus, it is strongly recommended that mechanical bowel preparation not be used as a preop‐ erative strategy. The malignancy of pancreatic disease in conjunction with the major surgical procedure of PD puts the patient at a substantially higher risk of acquiring a venous throm‐ boembolic event (VTE). The evidence strongly supports the beneficial use of a heparin, preferably low‐molecular‐weight heparin due to its 1× daily administration, in preventing or significantly reducing the risk of VTE. Standard prophylaxis involves administration 2–12 h prior to surgery and continuation until patient has fully mobilized, with some evidence suggesting benefit of continuation until 4 weeks after discharge. Mechanical preventative measures should also be utilized in even higher risk patients. Preoperative antibiotics are another highly recommended strategy for improving postoperative course and outcome of patients. Usual antibiotic prophylaxis recommended for pancreatic surgery include either 2 g (30 mg/kg peds) of Ancef (cefazolin, first‐line), clindamycin( 900 mg, 10 mg/kg peds)/vanco‐ mycin (15 mg/kg adult/ped) plus gentamicin (5 mg/kg, 2.5 mg/kg peds), or the addition of 400 mg (6 mg/kg peds) Diflucan (fluconazole) for patients at high risk of acquiring fungal infection such as in cases where there is enteric drainage of the pancreas [30]. Evidence indicates that antibiotic prophylaxis should be initiated 30–60 min prior to skin incision for optimal efficacy with repeated doses intraoperatively, depending on half‐life of the utilized drug.

It is noteworthy that postoperative strategies are somewhat more extensive; however, strongly recommended strategies include adequate pain control, glycemic control, early diet advance‐ ment, early mobilization, and early removal of anastomotic drains (after 72 h). Pain control in the postoperative period is often highly important in patient cooperation with postoperative, recovery goals. While specific evidence for superiority between epidural, patient controlled analgesia, and other intravenous medications is less, proper pain control evidently results in earlier progression through postoperative objectives such as early mobilization. Postoperative morbidity and mortality are greatly influenced and increased by hyperglycemia and insulin resistance. Intensive care unit postoperative patients have been documented to exhibit a lower complication risk with a reduced hyperglycemic rate. Because abdominal surgery is associated with increased levels of insulin resistance, a significant increase in baseline postoperative morbidity risk occurs since the risk of hyperglycemia increases. Insulin administration is important in keeping glucose under control; however, caution must be taken for the prevention of hypoglycemia. While evidence indicating best glucose levels is controversial, basic hyper‐ glycemic prevention will is needed to improve outcomes despite the baseline level [28, 31]. Furthermore, optimizing nutrition, with early diet advancement, in the postoperative period remains a strongly recommended strategy as well. The majority of patients will be able to tolerate oral intake shortly after elective PD. Evidence has shown that early oral intake is safe. Recent evidence has shown that early initiation of regular diet is reasonable and safe, and that enteral tube feeds illustrate no additional or greater benefit. There is also no evidence of improved benefit or safety of provider‐controlled diet advancement (e.g., sips of liquids compared to regular diet), and a patient‐controlled advancement as tolerated [28]. Another often recommended postoperative strategy is early and/or scheduled patient ambulation or mobilization. Patients should begin mobilizing or trying to ambulate in the morning of postoperative day 1. This strategy significantly reduces standard postoperative complications resulting from patient inactivity such as atelectasis and VTE risk. This can be encouraged through removal of barriers to ambulating or mobilizing such as a foley, and setting incre‐ mental patient activity goals on a daily basis, such as laps around the hospital floor, moving

to a chair for a set period of time, among others. This has shown to reduce the rate of postop‐ erative complications as well as reduce hospital length of stay and improve recovery time [28, 32].

procedure of PD puts the patient at a substantially higher risk of acquiring a venous throm‐ boembolic event (VTE). The evidence strongly supports the beneficial use of a heparin, preferably low‐molecular‐weight heparin due to its 1× daily administration, in preventing or significantly reducing the risk of VTE. Standard prophylaxis involves administration 2–12 h prior to surgery and continuation until patient has fully mobilized, with some evidence suggesting benefit of continuation until 4 weeks after discharge. Mechanical preventative measures should also be utilized in even higher risk patients. Preoperative antibiotics are another highly recommended strategy for improving postoperative course and outcome of patients. Usual antibiotic prophylaxis recommended for pancreatic surgery include either 2 g (30 mg/kg peds) of Ancef (cefazolin, first‐line), clindamycin( 900 mg, 10 mg/kg peds)/vanco‐ mycin (15 mg/kg adult/ped) plus gentamicin (5 mg/kg, 2.5 mg/kg peds), or the addition of 400 mg (6 mg/kg peds) Diflucan (fluconazole) for patients at high risk of acquiring fungal infection such as in cases where there is enteric drainage of the pancreas [30]. Evidence indicates that antibiotic prophylaxis should be initiated 30–60 min prior to skin incision for optimal efficacy

168 Challenges in Pancreatic Pathology

with repeated doses intraoperatively, depending on half‐life of the utilized drug.

It is noteworthy that postoperative strategies are somewhat more extensive; however, strongly recommended strategies include adequate pain control, glycemic control, early diet advance‐ ment, early mobilization, and early removal of anastomotic drains (after 72 h). Pain control in the postoperative period is often highly important in patient cooperation with postoperative, recovery goals. While specific evidence for superiority between epidural, patient controlled analgesia, and other intravenous medications is less, proper pain control evidently results in earlier progression through postoperative objectives such as early mobilization. Postoperative morbidity and mortality are greatly influenced and increased by hyperglycemia and insulin resistance. Intensive care unit postoperative patients have been documented to exhibit a lower complication risk with a reduced hyperglycemic rate. Because abdominal surgery is associated with increased levels of insulin resistance, a significant increase in baseline postoperative morbidity risk occurs since the risk of hyperglycemia increases. Insulin administration is important in keeping glucose under control; however, caution must be taken for the prevention of hypoglycemia. While evidence indicating best glucose levels is controversial, basic hyper‐ glycemic prevention will is needed to improve outcomes despite the baseline level [28, 31]. Furthermore, optimizing nutrition, with early diet advancement, in the postoperative period remains a strongly recommended strategy as well. The majority of patients will be able to tolerate oral intake shortly after elective PD. Evidence has shown that early oral intake is safe. Recent evidence has shown that early initiation of regular diet is reasonable and safe, and that enteral tube feeds illustrate no additional or greater benefit. There is also no evidence of improved benefit or safety of provider‐controlled diet advancement (e.g., sips of liquids compared to regular diet), and a patient‐controlled advancement as tolerated [28]. Another often recommended postoperative strategy is early and/or scheduled patient ambulation or mobilization. Patients should begin mobilizing or trying to ambulate in the morning of postoperative day 1. This strategy significantly reduces standard postoperative complications resulting from patient inactivity such as atelectasis and VTE risk. This can be encouraged through removal of barriers to ambulating or mobilizing such as a foley, and setting incre‐ mental patient activity goals on a daily basis, such as laps around the hospital floor, moving While the aforementioned concepts and strategies prove significant for the management of acute surgical patients, the overall management strategy for a pancreatic cancer patient has substantially changed. Historically, nasogastric decompression postpancreatectomy, particu‐ larly PD, was deemed necessary, not only to avoid tension on the gastrojejunostomy but also due to the concern of delayed gastric emptying, which was the most common complication after the procedure. However, it has been shown that foregoing nasogastric decompression after pancreatectomy (both PD and DP) is safe and does not result in increased frequency or severity of postoperative complications, including placement or replacement of a nasogastric tube after surgery. It also has no effect on length of stay or advancement to regular or post‐ gastrectomy diet [33].This evidence aligns with ERAS program recommendations for pan‐ createctomy patients. Nasogastric decompression should thus be reserved exclusively for selected patients, particularly approximately 10–25% [34] of patients who develop delayed gastric emptying (DGE) after PD.

Another topic of broad and current interest has been the use of intraperitoneal drains after pancreatectomy. Multiple high‐volume single‐institution studies have shown either no difference or a decreased overall complication rate with elimination of routine drainage. This is likely the result of the elimination of a portal of entry for bacteria and a potential source of strain on the anastomosis, the latter particularly with the use of closed suction drains. However, when routine elimination of drains was evaluated in a multicenter randomized controlled trial, there was an increase in the number of patients that had at least one? Grade 2 complication (drain 52% vs no drain 68%; *p* = 0.047) and a higher complication severity (*p* = 0.027). Not only was there an increase in morbidity, but also there was a fourfold increase in mortality from 3 to 12% in patients undergoing PD without intraperitoneal drain placement. It is important to emphasize that these results apply only to PD patients, but based on the evidence, abandon‐ ment of routine intraperitoneal drainage in this group of patients is not safe. More studies are needed to address the safety of early removal of drains in PD in compliance with ERAS protocols. As for DP, the safety of routine elimination of drains is currently being evaluated in a multicenter randomized controlled trial (NCT01441492, clinicaltrials.gov).

Finally, there is a strong recommendation for early removal of perianastomotic drains, usually within 72 h. The anastomotic drains are believed to reduce the consequential effects seen with minor pancreatic leaks. Evidence showed that early removal of a drain in low‐risk pancreatic fistula patients (drain fluid amylase <5000 U/L) was associated with a significantly reduced rate of pancreatic fistula formation, abdominal complications and pulmonary complications. There has also been increased scrutiny surrounding whether drain placement is even necessary to begin with. While there is data supporting this strategy, there is also data showing other‐ wise [32]. Van Buren et al. studied this concept by looking at 137 PD patients in a randomized prospective multicenter trial, 68 with drain placement and 69 without. From the Level 1 data provided, it was shown that elimination of the intraperitoneal drain in PD cases resulted in a significant increase in severity and frequency of postoperative complications. Furthermore, the study also illustrated a fourfold increase in mortality (3–12%) [35]. This raises skepticism toward findings in the previous literature and supports advocating caution against eliminating the use of drains altogether. However, per ERAS recommendations, early removal of the drain is associated with fewer and reduced rate of complications [28, 35].

These strategies provide a unified protocol for perioperative management of the PD procedure that could likely prove beneficial to centers through reducing postoperative complication rates, time of recovery and hospital length of stay [28, 32]. Ultimately, it is the summation of these factors that contribute to the improvement in the postoperative outcomes of pancreatic cancer patients. While the aforementioned concepts and strategies prove significant for the manage‐ ment of the acute surgical patient, the overall management strategy for a pancreatic cancer patient has substantially changed [23, 25, 28, 32].
