Diagnostic Accuracy of Lipase as Early Predictor of Postoperative Pancreatic Fistula: Results from the LIPADRAIN study.

Objective: To evaluate the diagnostic accuracy of drain fluid lipase as an early predictor of postoperative pancreatic fistula and establish the most appropriate day for their measure. Background: Clinically relevant postoperative pancreatic fistula remains a potentially life-threatening complication after pancreatic surgery. Early detection strategies remain key to reduce both the incidence and the burden of pancreatic fistula. Methods: The LIPAse DRAIN (LIPADRAIN) study is a multicenter, prospective diagnostic study conducted in 7 tertiary university hospitals. Drain fluid values to detect clinically relevant postoperative pancreatic fistula from postoperative day 1 to postoperative day 6 were evaluated using receiver operating characteristic curve analysis. A biomarker was considered to be relevant for clinical use if its area under the curve (AUC) was greater than 0.75. Results: Of the 625 patients included in the analysis, clinically relevant postoperative pancreatic fistula occurred in 203 (32%) patients. On postoperative days 3 and 4, drain fluid lipase was a reliable biomarker to detect clinically relevant postoperative pancreatic fistula (AUC: 0.761; 95% confidence interval [CI]: 0.761-0.799 and AUC: 0.784; 95% CI: 0.743-0.821, respectively). On postoperative day 3, with a threshold of 299 units/L, drain fluid lipase yielded a negative predictive value of 51%, sensitivity of 78%, and specificity of 63% for the detection of clinically relevant postoperative pancreatic fistula. Conclusions: In this multicenter prospective study, drain fluid lipase is a reliable biomarker at postoperative days 3 and 4 for the diagnosis of clinically relevant postoperative pancreatic fistula after pancreatic surgery and should be systematically measured on postoperative day 3.

Stapfer I and II duodenal perforations after endoscopic procedures: how surgical delay impacts outcomes.

BACKGROUND: Post-endoscopic duodenal perforation is a severe adverse event with high morbidity and mortality rates. Managing this rare event is challenging owing to limited clear guidelines. This retrospective study aimed to examine the relationship between time-to-treatment and morbidity among patients with post-endoscopic duodenal perforations. METHODS: Over 20 years, 78 consecutive patients with post-endoscopic duodenal perforations were analyzed. Among these, most patients underwent endoscopic procedures at the Paoli-Calmettes Institute, whereas some were referred from other centers after a diagnosis of perforation. We described the characteristics of patients who underwent medical treatment alone or interventional procedures. Among patients who underwent interventional management, we compared the outcomes following early or delayed procedures (later than 24 h post-duodenal perforation diagnosis). RESULTS: Overall, 78 patients with post-endoscopic duodenal perforation were identified between September 2003 and September 2022. Of these, 17 (22%) patients underwent non-operative management, and 61 (78%) with peritonitis or adverse clinical features were treated with endoscopic or surgical procedures. Additionally, among these patients, 40 (65%) underwent immediate invasive procedures, surgically (n = 20) or endoscopically (n = 20). Patients with delayed procedures experienced more major Clavien-Dindo ≥ 3 complications and had an increase by 21 of the median comprehensive complication index. Overall, mortality occurred in 7 (8.9%) patients in the entire cohort and in 3 (14.3%) with delayed invasive procedures. CONCLUSIONS: Delayed decision-making is a key factor complicating post-endoscopic duodenal perforation. Therefore, invasive procedures should be performed promptly in cases of adverse conditions requiring additional procedures, ideally within the first 24 h of perforation diagnosis.

Impact on survival of sarcopenia, systemic inflammatory response and anthropometric factors after pancreatectomy for resectable pancreatic adenocarcinoma.

INTRODUCTION: Pancreatic adenocarcinoma (PDAC) is becoming a public health issue with a 5-years survival rate around 10%. Patients with PDAC are often sarcopenic, which impacts postoperative outcome. At the same time, overweight population is increasing and adipose tissue promotes tumor related-inflammation. With several studies supporting independently these data, we aimed to assess if they held an impact on survival when combined. METHODS: We included 232 patients from two university hospitals (CHU de Lille, Institut Paoli Calmette), from January 2011 to December 2018, who underwent Pancreaticoduodenectomy (PD) for resectable PDAC. Preoperative CT scan was used to measure sarcopenia and visceral fat according to international cut-offs. Neutrophil to lymphocyte (NLR) and platelet to lymphocyte ratios (PLR) were used to measure inflammation. For univariate and multivariate analyses, the Cox proportional-hazard model was used. P-values below 0.05 were considered significant. RESULTS: Sarcopenic patients with visceral obesity were less likely to survive than the others in multivariate analysis (OS, HR 1.65, p= 0.043). Cutaneous obesity did not influence survival. We also observed an influence on survival when we studied sarcopenia with visceral obesity (OS, p= 0.056; PFS, p = 0.014), sarcopenia with cutaneous obesity (PFS, p= 0.005) and sarcopenia with PLR (PFS, p= 0.043). This poor prognosis was also found in sarcopenic obese patients with high PLR (OS, p= 0.05; PFS, p= 0.01). CONCLUSION: Sarcopenic obesity was associated with poor prognosis after PD for PDAC, especially in patients with systemic inflammation. Pre operative management of these factors should be addressed in pancreatic cancer patients.

Organ sparing to cure stage IV rectal cancer: A case report and review of literature.

BACKGROUND: Rectal sparing is an option for some rectal cancers with complete or good response after chemoradiotherapy (CRT); however, it has never been evaluated in patients with metastases. We assessed long-term outcomes of a rectal-sparing approach in a liver-first strategy for patients with rectal cancer with resectable liver metastases. CASE SUMMARY: We examined patients who underwent an organ-sparing approach for rectal cancer with synchronous liver metastases using a liver-first strategy during 2010-2015 (n = 8). Patients received primary chemotherapy and pelvic CRT. Liver surgery was performed during the interval between CRT completion and rectal tumor re-evaluation. Clinical and oncological characteristics and long-term outcomes were assessed.All patients underwent liver metastatic resection with curative intent. The R0 rate was 100%. Six and two patients underwent local excision and a watch-and-wait (WW) approach, respectively. All patients had T3N1 tumors at diagnosis and had good clinical response after CRT. The median survival time was 60 (range, 14-127) mo. Three patients were disease free for 5, 8, and 10 years after the procedure. Five patients developed metastatic recurrence in the liver (n = 5) and/or lungs (n = 2). Only one patient developed local recurrence concurrent with metastatic recurrence 24 mo after the WW approach. Two patients died during follow-up. CONCLUSION: The results suggest good local control in patients undergoing organ-sparing strategies for rectal cancer with synchronous liver metastasis. Prospective trials are required to validate these data and identify good candidates for these strategies.

Peak Risk of Recurrence Occurs during the First Two Years after a Pancreatectomy in Patients Receiving Neoadjuvant FOLFIRINOX.

No codified/systematic surveillance program exists for borderline/locally advanced pancreatic ductal carcinoma treated with neoadjuvant FOLFIRINOX and a secondary resection. This study aimed to determine the trend of recurrence in patients who were managed using such a treatment strategy. From 2010, 101 patients received FOLFIRINOX and underwent a pancreatectomy, in a minimum follow-up of 5 years. Seventy-one patients (70%, R group) were diagnosed with recurrence after a median follow-up of 11 months postsurgery. In the multivariable analysis, patients in the R-group had a higher rate of weight loss (p = 0.018), higher carbohydrate antigen (CA 19-9) serum levels at diagnosis (p = 0.012), T3/T4 stage (p = 0.017), and positive lymph nodes (p < 0.01) compared to patients who did not experience recurrence. The risk of recurrence in patients with T1/T2 N0 R0 was the lowest (19%), and all recurrences occurred during the first two postoperative years. The peak risk of recurrence for the entire population was observed during the first two postoperative years. The probability of survival decreased until the second year and rebounded to 100% permanently, after the ninth postoperative year. Close monitoring is needed at reduced intervals during the first 2 years following a pancreatectomy and should be extended to later than 5 years for those with unfavorable pathological results.

An optimised liver-first strategy for synchronous metastatic rectal cancer leads to higher protocol completion and lower surgical morbidity.

INTRODUCTION: The optimal management of rectal cancer with synchronous liver metastases remains debatable. Thus, we propose an optimised liver-first (OLF) strategy that combines concomitant pelvic irradiation with hepatic management. This study aimed to evaluate the feasibility and oncological quality of the OLF strategy. MATERIALS AND METHODS: Patients underwent systemic neoadjuvant chemotherapy followed by preoperative radiotherapy. Liver resection was performed in one step (between radiotherapy and rectal surgery) or in two steps (before and after radiotherapy). The data were collected prospectively and analysed retrospectively as intent to treat. RESULTS: Between 2008 and 2018, 24 patients underwent the OLF strategy. The rate of treatment completion was 87.5%. Three patients (12.5%) did not proceed to the planned second-stage liver and rectal surgery because of progressive disease. The postoperative mortality rate was 0%, and the overall morbidity rates after liver and rectal surgeries were 21% and 28.6%, respectively. Only two patients developed severe complications. Liver and rectal complete resection was performed in 100% and 84.6%, respectively. A rectal-sparing strategy was performed in 6 patients who underwent local excision (n = 4) or a watch and wait strategy (n = 2). Among patients who completed treatment, the median overall and disease-free survivals were 60 months (range 12-139 months) and 40 months (range 10-139 months), respectively. Eleven patients (47.6%) developed recurrence, among whom five underwent further treatment with curative intent. CONCLUSION: The OLF approach is feasible, relevant, and safe. Organ preservation was feasible for a quarter of patients and may be associated with reduced morbidity.

Preoperative liver arterial conditioning in patients scheduled for a Mayo Clinic class Ia distal pancreatectomy: embolization or ligation?

BACKGROUND: Liver ischemia may occur during intraoperative common hepatic artery ligation in Mayo Clinic class I distal pancreatectomy with en bloc celiac axis resection (DP-CAR). Preoperative liver arterial conditioning could be used to avoid this outcome. This retrospective study compared arterial embolization (AE) or laparoscopic ligation (LL) of the common hepatic artery before class Ia DP-CAR. METHODS: From 2014 to 2022, 18 patients were scheduled for class Ia DP-CAR after neoadjuvant FOLFIRINOX treatment. Two were excluded due to hepatic artery variation, six underwent AE, ten underwent LL. RESULTS: Two procedural complications occurred in the AE group: an incomplete dissection of the proper hepatic artery and a distal migration of coils in the right branch of the hepatic artery. Neither complication prevented surgery. The median delay between conditioning and DP-CAR was 19 days; decreased to five days in the last six patients. None required arterial reconstruction. Morbidity and 90-day mortality rates were 26.7% and 12.5%, respectively. No patient developed postoperative liver insufficiency after LL. CONCLUSION: Preoperative AE and LL seem comparable in averting arterial reconstruction and postoperative liver insufficiency in patients scheduled for class Ia DP-CAR. However, serious complications that may arise during AE led us to prefer the LL technique.

Establishment and external validation of neutrophil-to-lymphocyte ratio in excluding postoperative pancreatic fistula after pancreatoduodenectomy.

BACKGROUND: Factors excluding postoperative pancreatic fistula (POPF), facilitating early drain removal and hospital discharge represent a novel approach in patients undergoing enhanced recovery after pancreatic surgery. This study aimed to establish the relevance of neutrophil-to-lymphocyte ratio (NLR) in excluding POPF after pancreatoduodenectomy (PD). METHODS: A prospectively maintained database of patients who underwent PD at two high-volume centres was used. Patients were divided into three cohorts (training, internal, and external validation). The primary endpoints of this study were accuracy, optimal timing, and cutoff values of NLR for excluding POPF after PD. RESULTS: From 2012 to 2020, in a 2:1 ratio, 451 consecutive patients were randomly sampled as training (n = 301) and validation (n = 150) cohorts. Additionally, the external validation cohort included 197 patients between 2018 and 2020. POPF was diagnosed in 135 (20.8 per cent) patients. The 90-day mortality rate was 4.1 per cent. NLR less than 8.5 on postoperative day 3 (OR, 95 per cent c.i.) was significantly associated with the absence of POPF in the training (2.41, 1.19 to 4.88; P = 0.015), internal validation (5.59, 2.02 to 15.43; P = 0.001), and external validation (5.13, 1.67 to 15.76; P = 0.004) cohorts when adjusted for relevant clinical factors. Postoperative outcomes significantly differed using this threshold. CONCLUSION: NLR less than 8.5 on postoperative day 3 may be a simple, independent, cost-effective, and easy-to-use criterion for excluding POPF.

Readmission after pancreaticoduodenectomy: Birmingham score validation.

BACKGROUND: The Birmingham score predicts the risk of hospital readmission after pancreaticoduodenectomy (PD). This study aimed to validate the risk score in a different healthcare cohort. METHODS: From 2017 to 2021, 301 patients underwent PD. The Birmingham score was applied to 276 patients. Postoperative deceased patients (n = 7) or those requiring a completion of pancreatectomy (n = 18) were excluded. RESULTS: Forty-seven (17%) patients were readmitted after a median delay of 9 (range 1-49) days and stayed for 5 (range 1-27) days; 4 (8.5%) died during the hospital stay. The leading cause of readmission was a septic condition (53%), mostly resolved by medical treatment (77%). A multivariate analysis identified the occurrence of a clinically relevant postoperative pancreatic fistula, the score criteria, and the score itself as independent factors favouring readmission. Readmission rates in patients with low [n = 97 (35%)], intermediate [n = 98 (36%)], and high [n = 81 (29%)] scores were 5%, 17%, and 31%, respectively (P < 0.01). CONCLUSION: This study confirmed the relevance and robustness of the Birmingham risk score. Patients with a high risk of readmission after PD, identified based on the score, were discharged to a partnership medical centre close to the pancreatic centre to plan readmission and avoid futile unplanned hospitalisation.

Management and outcomes of brain metastases from pancreatic adenocarcinoma: a pooled analysis and literature review.

Background: Brain metastases (BM) are rare in pancreatic ductal adenocarcinoma (PDAC) and little data exists concerning these patients and their outcomes. Aim: We aimed to analyze the management, practices, and outcomes of patients presenting BM from PDAC both in our institution and in all cases reported in the literature. Methods: We conducted a retrospective, monocentric analysis using a data mining tool (ConSoRe) to identify all patients diagnosed with PDAC and BM in our comprehensive cancer center (Paoli-Calmettes Institute), from July 1997 to June 2022 (cohort 1). Simultaneously, we reviewed and pooled the case reports and case series of patients with PDAC and BM in the literature (cohort 2). The clinical characteristics of patients in each cohort were described and survival analyses were performed using the Kaplan-Meier method. Results: In cohort 1, 19 patients (0.3%) with PDAC and BM were identified with a median age of 69 years (range: 39-81). Most patients had metastatic disease (74%), including 21% with BM, at diagnosis. Lung metastases were present in 58% of patients. 68% of patients had neurological symptoms and 68% were treated by focal treatment (surgery: 21%, radiotherapy: 42%, Gamma Knife radiosurgery: 5%). In cohort 2, among the 61 PDAC patients with BM described in the literature, 59% had metastatic disease, including 13% with BM at diagnosis. Lung metastases were present in 36% of patient and BM treatments included: surgery (36%), radiotherapy (36%), radiosurgery (3%), or no local treatment (25%). After the pancreatic cancer diagnosis, the median time to develop BM was 7.8 months (range: 0.0-73.9) in cohort 1 and 17.0 months (range: 0.0-64.0) in cohort 2. Median overall survival (OS) in patients of cohort 1 and cohort 2 was 2.9 months (95% CI [1.7,4.0]) and 12.5 months (95% CI [7.5,17.5]), respectively. Conclusion: BM are very uncommon in PDAC and seem to occur more often in younger patients with lung metastases and more indolent disease. BM are associated with poor prognosis and neurosurgery offers the best outcomes and should be considered when feasible.

LATE POSTPANCREATICODUODENECTOMY HEMORRHAGE: INCIDENCE, RISK FACTORS, MANAGEMENT AND OUTCOME.

ABSTRACT: Background:Postpancreaticoduodenectomy (PD) hemorrhage (PPH) is a life-threatening complication after PD. The main objective of this study was to evaluate incidence and factors associated with late PPH as well as the management strategy and outcomes. Methods: Between May 2017 and March 2020, clinical data from 192 patients undergoing PD were collected prospectively in the CHIRPAN Database (NCT02871336) and retrospectively analyzed. In our institution, all patients scheduled for a PD are routinely admitted for monitoring and management in intensive/intermediate care unit (ICU/IMC). Results: The incidence of late PPH was 17% (32 of 192), whereas the 90-day mortality rate of late PPH was 19% (6 of 32). Late PPH was associated with 90-day mortality (P = 0.001). Using multivariate analysis, independent risk factors for late PPH were postoperative sepsis (P = 0.036), and on day 3, creatinine (P = 0.025), drain fluid amylase concentration (P = 0.023), lipase concentration (P < 0.001), and C-reactive protein (CRP) concentration (P < 0.001). We developed two predictive scores for PPH occurrence, the PANCRHEMO scores. Score 1 was associated with 68.8% sensitivity, 85.6% specificity, 48.8% predictive positive value, 93.2% negative predictive value, and an area under the receiver operating characteristic curves of 0.841. Score 2 was associated with 81.2% sensitivity, 76.9% specificity, 41.3% predictive positive value, 95.3% negative predictive value, and an area under the receiver operating characteristic curve of 0.859. Conclusions: Routine ICU/IMC monitoring might contribute to a better management of these complications. Some predicting factors such as postoperative sepsis and biological markers on day 3 should help physicians to determine patients requiring a prolonged ICU/IMC monitoring.

Effect of the Use of Reinforced Stapling on the Occurrence of Pancreatic Fistula After Distal Pancreatectomy: Results of the REPLAY (REinforcement of the Pancreas in distaL pAncreatectomY) Multicenter Randomized Clinical Trial.

OBJECTIVE: The aim of the study was to evaluate the impact of the use of a reinforced stapler (RS) during distal pancreatectomy (DP) on postoperative outcomes. BACKGROUND: DP remains associated with significant postoperative morbidity owing to pancreatic fistula (PF). To date, there is no consensus on the management of the pancreatic stump. The use of an RS potentially represents a simple way to decrease the rate of PF. METHODS: The REPLAY study (NCT03030170) is a prospective, multicenter, randomized study. Patients who underwent DP were randomized (1:1 ratio) in 2 groups for the use of a standard stapler (SS) or an RS to close remnant pancreatic parenchyma. The primary endpoint was the rate of overall PF. Secondary endpoints included severity of PF, length of hospital stay, overall morbidity, and rate of readmission for a PF within 90 days. Participants were blinded to the procedure actually carried out. RESULTS: A total of 199 were analyzed (SS, n=99; RS, n=100). One patient who did not undergo surgery was excluded. Baseline characteristics were comparable in both groups. The rate of overall PF was higher in RS group (SS: 67.7%, RS: 83%, P =0.0121), but the rate of clinically relevant PF was similar (SS: 11.1%, RS: 14%, P =0.5387). Mean length of total hospital stay, readmission for PF, postoperative morbidity, and mortality at 90 days were similar. CONCLUSION: The results of this randomized clinical trial did not favor the use of RS during DP to reduce the rate of PF.

Local Ablative Therapy Associated with Immunotherapy in Locally Advanced Pancreatic Cancer: A Solution to Overcome the Double Trouble?-A Comprehensive Review.

Pancreatic ductal adenocarcinoma (PDAC) remains a major killer and is a challenging clinical research issue with abysmal survival due to unsatisfactory therapeutic efficacy. Two major issues thwart the treatment of locally advanced nonresectable pancreatic cancer (LAPC): high micrometastasis rate and surgical inaccessibility. Local ablative therapies induce a systemic antitumor response (i.e., abscopal effect) in addition to local effects. Thus, the incorporation of additional therapies could be key to improving immunotherapy's clinical efficacy. In this systematic review, we explore recent applications of local ablative therapies combined with immunotherapy to overcome immune resistance in PDAC and discuss future perspectives and challenges. Particularly, we describe four chemoradiation studies and nine reports on irreversible electroporation (IRE). Clinically, IRE is the ablative therapy of choice, utilized in all but two clinical trials, and may create a favorable microenvironment for immunotherapy. Various immunotherapies have been used in combination with IRE, such as NK cell- or γδ T cell-based therapy, as well as immune checkpoint inhibitors. The results of the clinical trials presented in this review and the advancement potential of these therapies to phase II/III trials remain unknown. A multiple treatment approach involving chemotherapy, local ablation, and immunotherapy holds promise in overcoming the double trouble of LAPC.

Will Patients With Liver Metastasis From Aggressives Cancers Benefit From Surgical Resection?

Background: We aimed to evaluate the outcomes of resections for liver metastases (LMs) originating from pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and esophagus/gastric cancers (EGCs), which we label as major killers (MKs; overall survival (OS) under 10%). We hypothesized that LM resection must provide the patient with almost a year of OS postoperatively that is considered beneficial. Methods: From January 2005 to December 2020, 23 patients underwent resection for isolated LM from MKs. These patients underwent surgery after a multidisciplinary discussion about their performance status, disease evolution during prolonged medical treatment, and the existence or absence of extrahepatic metastases. Results: LM originated from an PDAC, EGC, or NSCLC in 10 patients (43%), nine patients (39%), and four patients (18%), respectively. The median delay between primary cancer and LM diagnoses was 12 months, and the median delay between LM diagnosis and liver resection was 10 months. Most patients, who had objectively responded to medical treatment (57%), had a solitary (61%) and unilobar (70%) LM. Severe morbidity and 90-day mortality rates were 13% and 4.3%, respectively. Margin-free resection was achieved in 16 patients (70%). After liver resection, the median OS was 24 months without a statistical difference when considering the primary tumor site; 1, 3-, and 5-year OS were 70%, 23%, and 23%, respectively. Conclusion: Selection based on criteria such as good clinical condition, response to treatment, and long observation period helped identify patients with LM of MKs who seemed to benefit from resection.