The management of intraductal papillary mucinous neoplasm (IPMN) continues to evolve. In particular, the indications for resection of branch duct IPMN have changed from early resection to more ...deliberate observation as proposed by the international consensus guidelines of 2006 and 2012. Another guideline proposed by the American Gastroenterological Association in 2015 restricted indications for surgery more stringently and recommended physicians to stop surveillance if no significant change had occurred in a pancreatic cyst after five years of surveillance, or if a patient underwent resection and a non-malignant IPMN was found. Whether or not it is safe to do so, as well as the method and interval of surveillance, has generated substantial debate. Based on a consensus symposium held during the meeting of the International Association of Pancreatology in Sendai, Japan, in 2016, the working group has revised the guidelines regarding prediction of invasive carcinoma and high-grade dysplasia, surveillance, and postoperative follow-up of IPMN. As the working group did not recognize the need for major revisions of the guidelines, we made only minor revisions and added most recent articles where appropriate. The present guidelines include updated information and recommendations based on our current understanding, and highlight issues that remain controversial or where further research is required.
Background In 2005, the International Study Group of Pancreatic Fistula developed a definition and grading of postoperative pancreatic fistula that has been accepted universally. Eleven years later, ...because postoperative pancreatic fistula remains one of the most relevant and harmful complications of pancreatic operation, the International Study Group of Pancreatic Fistula classification has become the gold standard in defining postoperative pancreatic fistula in clinical practice. The aim of the present report is to verify the value of the International Study Group of Pancreatic Fistula definition and grading of postoperative pancreatic fistula and to update the International Study Group of Pancreatic Fistula classification in light of recent evidence that has emerged, as well as to address the lingering controversies about the original definition and grading of postoperative pancreatic fistula. Methods The International Study Group of Pancreatic Fistula reconvened as the International Study Group in Pancreatic Surgery in order to perform a review of the recent literature and consequently to update and revise the grading system of postoperative pancreatic fistula. Results Based on the literature since 2005 investigating the validity and clinical use of the original International Study Group of Pancreatic Fistula classification, a clinically relevant postoperative pancreatic fistula is now redefined as a drain output of any measurable volume of fluid with an amylase level >3 times the upper limit of institutional normal serum amylase activity, associated with a clinically relevant development/condition related directly to the postoperative pancreatic fistula. Consequently, the former “grade A postoperative pancreatic fistula” is now redefined and called a “biochemical leak,” because it has no clinical importance and is no longer referred to a true pancreatic fistula. Postoperative pancreatic fistula grades B and C are confirmed but defined more strictly. In particular, grade B requires a change in the postoperative management; drains are either left in place >3 weeks or repositioned through endoscopic or percutaneous procedures. Grade C postoperative pancreatic fistula refers to those postoperative pancreatic fistula that require reoperation or lead to single or multiple organ failure and/or mortality attributable to the pancreatic fistula. Conclusion This new definition and grading system of postoperative pancreatic fistula should lead to a more universally consistent evaluation of operative outcomes after pancreatic operation and will allow for a better comparison of techniques used to mitigate the rate and clinical impact of a pancreatic fistula. Use of this updated classification will also allow for more precise comparisons of surgical quality between surgeons and units who perform pancreatic surgery.
Postoperative hyperamylasemia is a frequent finding after pancreatoduodenectomy, but its incidence and clinical implications have not yet been analyzed systematically. The aim of this review is to ...reappraise the concept of postoperative hyperamylasemia with postoperative acute pancreatitis, including its definition, interpretation, and correlation.
Online databases were used to search all available relevant literature published through June 2019. The following search terms were used: “pancreaticoduodenectomy,” “amylase,” and “pancreatitis.” Surgical series reporting data on postoperative hyperamylasemia or postoperative acute pancreatitis were selected and screened.
Among 379 screened studies, 39 papers were included and comprised data from a total of 9,220 patients. Postoperative hyperamylasemia was rarely defined in most of these series, and serum amylase values were measured at different cutoff levels and reported on different postoperative days. The actual levels of serum amylase activity and the representative cutoff levels required to reach a diagnosis of postoperative acute pancreatitis were markedly greater on the first postoperative days and tended to decrease over time. Most studies analyzing postoperative hyperamylasemia focused on its correlation with postoperative pancreatic fistula and other postoperative morbidities. The incidence of postoperative acute pancreatitis varied markedly between studies, with its definition completely lacking in 40% of the analyzed papers. A soft pancreatic parenchyma, a small pancreatic duct, and pathology differing from cancer or chronic pancreatitis were all predisposing factors to the development of postoperative hyperamylasemia.
Postoperative hyperamylasemia has been proposed as the biochemical expression of pancreatic parenchymal injury related to localized ischemia and inflammation of the pancreatic stump. Such phenomena, analogous to those associated with acute pancreatitis, could perhaps be renamed as postoperative acute pancreatitis from a clinical standpoint. Patients with postoperative acute pancreatitis experienced an increased rate of all postoperative complications, particularly postoperative pancreatic fistula. Taken together, the discrepancies among previous studies of postoperative hyperamylasemia and postoperative acute pancreatitis outlined in the present review may provide a basis for stronger evidence necessary for the development of universally accepted definitions for postoperative hyperamylasemia and postoperative acute pancreatitis.
The management of small and incidental branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) still is of concern. The aim is assessing the safety of a surveillance protocol through the ...evaluation of their progression to malignancy.
All presumed BD-IPMNs observed from 2000 to 2016 were included. Only patients presenting without worrisome features (WFs) and high-risk stigmata (HRS) at diagnosis were included. Development of WF, HRS, pancreatic cancer (PC), and survival were analyzed. BD-IPMNs were defined as trivial in the continuing absence of WF/HRS after 5 years of surveillance. The age-specific standardized incidence ratio of PC in the general population was used for comparison.
A total of 1,036 BD-IPMNs without WF/HRS at diagnosis were included, 4.2% developed WF or HRS, and 1.1% developed PC after a median of 62 months. The median cyst growth rate was 0 mm/yr. A growth rate ≥2.5 mm/yr and the development of WF resulted independent predictors of PC. The standardized incidence ratio of PC for trivial BD-IPMN (n = 378) was 22.45 (95% confidence interval 8.19-48.86), but considering only patients aged >65 years (n = 198), it decreased to 3.84 (95% confidence interval 0.77-11.20).
Surveillance of the vast majority of presumed BD-IPMNs is safe, as the risk of PC is comparable to postoperative mortality of pancreatic surgery. A growth rate ≥2.5 mm/yr is the main predictor of PC, reinforcing the role of repeated observations. A trivial BD-IPMN in patients aged >65 years might not increase the risk of developing PC compared with general population, identifying potential targets for follow-up discontinuation.
Background
Neoadjuvant therapy (NAT) is used for borderline-resectable or locally advanced pancreatic cancer (PDAC) and exhibits promising results in terms of pathological outcomes. However, little ...is known about its effect on surgical complications.
Methods
We analyzed 445 pancreatic resections for PDAC from 2014 to 2016 at The Pancreas Institute, Verona University Hospital. The Modified Accordion Severity Grading System and average complication burden (ACB) were used to compare patients treated with NAT with patients who underwent upfront surgery (UFS).
Results
Of 305 pancreaticoduodenectomies (PD), patients treated with NAT (
n
= 99) had less pancreatic fistula (POPF, 9.1% vs. 15.6%,
p
= 0.05) without grade C cases, but grade B ACB was increased (0.28 for NAT vs. 0.24 for UFS,
p
= 0.05). The postpancreatectomy hemorrhage (PPH) rate was lower in the NAT group (9.1% vs. 14.6%,
p
= 0.02), but ACB grades B (0.37 for NAT vs. 0.26 for UFS,
p
= 0.03) and C (0.43 for NAT vs. 0.29 for UFS,
p
= 0.05) were increased. Delayed gastric emptying (DGE) was increased in NAT cases (15.2% vs. 8.3%,
p
= 0.04), with higher grade C ACB (0.43 for NAT vs. 0.29 for UFS,
p
= 0.03). Of 94 distal pancreatectomies (DP), NAT patients (
n
= 26) developed more grade C POPF (11.5% vs. 1.5%,
p
= 0.04) and DGE (11.5% vs. 2.9%,
p
= 0.01) without differences in ACB.
Conclusions
Patients undergoing PD for PDAC after NAT exhibited reduced incidence of POPF and PPH but increased incidence of DGE compared with patients treated with UFS. Among patients developing postoperative complications after PD, those receiving NAT were associated with increased clinical burden.
This multicenter study sought to prospectively evaluate a drain management protocol for pancreatoduodenectomy (PD).
Recent evidence suggests value for both selective drain placement and early drain ...removal for PD. Both strategies have been associated with reduced rates of clinically relevant pancreatic fistula (CR-POPF)-the most common and morbid complication after PD.
The protocol was applied to 260 consecutive PDs performed at two institutions over 17 months. Risk for ISGPF CR-POPF was determined intraoperatively using the Fistula Risk Score (FRS); drains were omitted in negligible/low risk patients and drain fluid amylase (DFA) was measured on postoperative day 1 (POD 1) for moderate/high risk patients. Drains were removed early (POD 3) in patients with POD 1 DFA ≤5,000 U/L, whereas patients with POD 1 DFA >5,000 U/L were managed by clinical discretion. Outcomes were compared with a historical cohort (N = 557; 2011-2014).
Fistula risk did not differ between cohorts (median FRS: 4 vs 4; P = 0.933). No CR-POPFs developed in the 70 (26.9%) negligible/low risk patients. Overall CR-POPF rates were significantly lower after protocol implementation (11.2 vs 20.6%, P = 0.001). The protocol cohort also demonstrated lower rates of severe complication, any complication, reoperation, and percutaneous drainage (all P < 0.05). These patients also experienced reduced hospital stay (median: 8 days vs 9 days, P = 0.001). There were no differences between cohorts in the frequency of bile or chyle leaks.
Drains can be safely omitted for one-quarter of PDs. Drain amylase analysis identifies which moderate/high risk patients benefit from early drain removal. This data-driven, risk-stratified approach significantly decreases the occurrence of clinically relevant pancreatic fistula.
To analyze the prevalence of homologous recombination deficiency (HRD) in patients with pancreatic ductal adenocarcinoma (PDAC).
We conducted a systematic review and meta-analysis of the prevalence ...of HRD in PDAC from PubMed, Scopus, and Cochrane Library databases, and online cancer genomic data sets. The main outcome was pooled prevalence of somatic and germline mutations in the better characterized HRD genes (
,
,
,
,
,
,
, and the
genes). The secondary outcomes were prevalence of germline mutations overall, and in sporadic and familial cases; prevalence of germline
mutations in Ashkenazi Jewish (AJ); and prevalence of HRD based on other definitions (ie, alterations in other genes, genomic scars, and mutational signatures). Random-effects modeling with the Freeman-Tukey transformation was used for the analyses. PROSPERO registration number: (CRD42020190813).
Sixty studies with 21,842 participants were included in the systematic review and 57 in the meta-analysis. Prevalence of germline and somatic mutations was
: 0.9%,
: 3.5%,
: 0.2%,
: 2.2%,
: 0.3%,
: 0.5%,
: 0.0%, and
: 0.1%. Prevalence of germline mutations was
: 0.9% (2.4% in AJ),
: 3.8% (8.2% in AJ),
: 0.2%,
: 2%,
: 0.3%, and
: 0.4%. No significant differences between sporadic and familial cases were identified. HRD prevalence ranged between 14.5%-16.5% through targeted next-generation sequencing and 24%-44% through whole-genome or whole-exome sequencing allowing complementary genomic analysis, including genomic scars and other signatures (surrogate markers of HRD).
Surrogate readouts of HRD identify a greater proportion of patients with HRD than analyses limited to gene-level approaches. There is a clear need to harmonize HRD definitions and to validate the optimal biomarker for treatment selection. Universal HRD screening including integrated somatic and germline analysis should be offered to all patients with PDAC.
Background A recent randomized trial used the Fistula Risk Score (FRS) to develop guidelines for selective drainage based on clinically relevant fistula (CR-POPF) risk. Additionally, postoperative ...day (POD) 1 drain and serum amylase have been identified as accurate postoperative predictors of CR-POPF. This study sought to identify patients who may benefit from selective drainage, as well as the optimal timing for drain removal after pancreatoduodenectomy. Study Design One hundred six pancreatoduodenectomies from a previously reported RCT were assessed using risk-adjustment. The incidence of CR-POPF was compared between FRS risk cohorts. Drain and serum amylase values from POD 1 were evaluated using receiver operating characteristic (ROC) analysis to establish cut-offs predictive of CR-POPF occurrence. A regression analysis compared drain removal randomizations (POD 3 vs POD 5). Results Three-quarters of patients had moderate/high CR-POPF risk. This group had a CR-POPF rate of 36.3% vs 7.7% among negligible/low risk patients (p = 0.005). The areas under the ROC curve for CR-POPF prediction using POD 1 drain and serum amylase values were 0.800 (p = 0.000001; 95% CI 0.70–0.90) and 0.655 (p = 0.012; 95% CI 0.55–0.77), respectively. No significant serum amylase cut-offs were identified. Moderate/high risk patients with POD 1 drain amylase ≤5,000 U/L had significantly lower rates of CR-POPF when randomized to POD 3 drain removal (4.2% vs 38.5%; p = 0.003); moreover, these patients experienced fewer complications and shorter hospital stays. Conclusions A clinical care protocol is proposed whereby drains are recommended for moderate/high FRS risk patients, but may be omitted in patients with negligible/low risk. Drain amylase values in moderate/high risk patients should then be evaluated on POD 1 to determine the optimal timing for drain removal. Moderate/high risk patients with POD 1 drain amylase ≤5,000 U/L have lower rates of CR-POPF with POD 3 (vs POD ≥ 5) drain removal; early drain removal is recommended for these patients.
Despite improvements in perioperative care, mortality and morbidity rates associated with pancreatic operation still reach 2% and >50%, respectively. Infectious complications after ...pancreaticoduodenectomy occur in about one-third of the cases. The aim of the study is to define the real burden of infectious complications after pancreaticoduodenectomy and to analyze the risk factors associated with their onset.
Data of consecutive pancreaticoduodenectomies performed at the authors' institution from January 2011 to June 2016 were retrieved from a prospectively maintained database. Based on the presence of infectious complications, the population was separated into 2 groups (infection group positive IG+ and infection group negative IG−) and then compared.
During the study period 893 pancreaticoduodenectomies were performed. Overall, infectious complications were detected in 409 out of 893 patients (45.8%). Preoperative biliary drain was the only independent preoperative risk factor for the development of infectious complications (P < .001, odds ratio 3.8). Each complication was found to be statistically more frequent in IG+. In addition, IG+ also had a prolonged hospital stay (P < .020, odds ratio 1.1) and all deaths occurred in this group. The overall multisite infection rate was 41.6%. Multidrug-resistant bacteria were detected in 78.5% of patients. The development of multisite infection was the best predictor of outcome after pancreaticoduodenectomy.
The development of postoperative infectious complications is a major determinant of outcome after pancreaticoduodenectomy. In this setting, the reliable negative predictors of the outcome include preoperative biliary drain, site of infection, multidrug-resistant bacteria infections and type of bacteria. Multisite infection was found to be the best predictor of a worse postoperative course after pancreaticoduodenectomy.
Chemotherapy is the recommended induction strategy in borderline resectable and locally advanced pancreatic ductal adenocarcinoma. However, the associated results on an intention-to-treat basis are ...poorly understood.
To investigate pragmatically the treatment compliance, conversion to surgery, and survival outcomes of patients with borderline resectable and locally advanced pancreatic ductal adenocarcinoma undergoing primary chemotherapy.
This prospective study took place in a national referral center for pancreatic diseases in Italy. Consecutive patients with borderline resectable and locally advanced pancreatic ductal adenocarcinoma were enrolled at the time of diagnosis (January 2013 through December 2015) and followed up to June 2018.
The chemotherapy regimen, assigned based on multidisciplinary evaluation, was delivered either at a hub center or at spoke centers. By convention, primary chemotherapy was considered completed after 6 months. After restaging, surgical candidates were selected based on radiologic and biochemical response. All surgeries were carried out at the hub center.
Rates of receipt and completion of chemotherapy, rates of conversion to surgery, and disease-specific survival.
Of 680 patients, 267 (39.3%) had borderline resectable and 413 (60.7%) had locally advanced pancreatic ductal adenocarcinoma. Overall, 66 patients (9.7%) were lost to follow-up. The rate of chemotherapy receipt was 92.9% (n = 570). The chemotherapeutic regimens most commonly used included FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) (260 45.6%) and gemcitabine plus nanoparticle albumin-bound-paclitaxel (123 21.6%). Nineteen patients (3.3%) receiving chemotherapy died within 6 months, mainly for disease progression. The treatment completion rate was 71.6% (408 of 570). The overall rate of resection was 15.1% (93 of 614) (borderline resectable, 60 of 249 24.1%; locally advanced, 33 of 365 9%; resection:exploration ratio, 63.3%). Independent predictors of resection were age, borderline resectable disease, chemotherapy completion, radiologic response, and biochemical response. The median survival for the whole cohort was 12.8 (95% CI, 11.7-13.9) months. Factors independently associated with survival were completion of chemotherapy, receipt of complementary radiation therapy, and resection. In patients who underwent resection, the median survival was 35.4 (95% CI, 27.0-43.7) months for initially borderline resectable and 41.8 (95% CI, 27.5-56.1) months for initially locally advanced disease. No pretreatment and posttreatment factors were associated with survival after pancreatectomy.
This pragmatic observational cohort study with an intention-to-treat design provides real-world evidence of outcomes associated with the most current primary chemotherapy regimens used for borderline resectable and locally advanced pancreatic ductal adenocarcinoma.
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