Clinical outcomes of second-line therapy following disease progression on first-line modified FOLFIRINOX for borderline resectable and locally advanced pancreatic adenocarcinoma.

BACKGROUND: Modified FOLFIRINOX (mFOLFIRINOX) is one of the standard first-line therapies in borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAPC). However, there is no globally accepted second-line therapy following progression on mFOLFIRINOX. METHODS: Patients with BRPC and LAPC (n = 647) treated with first-line mFOLFIRINOX between January 2017 and December 2020 were included in this retrospective analysis. The details of the treatment outcomes and patterns of subsequent therapy after mFOLFIRINOX were reviewed. RESULTS: With a median follow-up duration of 44.2 months (95% confidence interval [CI], 42.3-47.6), 322 patients exhibited disease progression on mFOLFIRINOX-locoregional progression only in 177 patients (55.0%) and distant metastasis in 145 patients (45.0%). The locoregional progression group demonstrated significantly longer post-progression survival (PPS) than that of the distant metastasis group (10.1 vs. 7.3 months, p = 0.002). In the locoregional progression group, survival outcomes did not differ between second-line chemoradiation/radiotherapy and systemic chemotherapy (progression-free survival with second-line therapy [PFS-2], 3.2 vs. 4.3 months; p = 0.649; PPS, 10.7 vs. 10.2 months; p = 0.791). In patients who received second-line systemic chemotherapy following progression on mFOLFIRINOX (n = 211), gemcitabine plus nab-paclitaxel was associated with better disease control rates (69.2% vs. 42.3%, p = 0.005) and PFS-2 (3.8 vs. 1.7 months, p = 0.035) than gemcitabine monotherapy. CONCLUSIONS: The current study showed the real-world practice pattern of subsequent therapy and clinical outcomes following progression on first-line mFOLFIRINOX in BRPC and LAPC. Further investigation is necessary to establish the optimal therapy after failure of mFOLFIRINOX.

Comparison of EUS-guided ablation and surgical resection for nonfunctioning small pancreatic neuroendocrine tumors: a propensity score-matching study.

BACKGROUND AND AIMS: Treatment strategies for small pancreatic neuroendocrine tumors (PNETs) <2 cm in size are still under debate. The feasibility and safety of EUS-guided ethanol ablation (EUS-EA) have been demonstrated. However, sample sizes in previous studies were small with no comparative studies on surgery. Therefore, we aimed to compare the safety and long-term outcomes of EUS-EA with those of surgery for the management of nonfunctioning small PNETs. METHODS: We retrospectively reviewed patients with PNETs who were managed by EUS-EA (from 2011 to 2018) and surgery (from 2000 to 2018) at Asan Medical Center. Propensity score matching (PSM) was performed to increase comparability. The primary outcome was early and late major adverse events (Clavien-Dindo grade ≥III) after treatment. Secondary outcomes were 10-year overall (OS) and disease-specific survival (DSS) rates, length of hospital stay, and development of endocrine pancreatic insufficiency. RESULTS: Of all patients, 97 and 188 patients were included in the EUS-EA and surgery groups, respectively. PSM created 89 matched pairs. EUS-EA was associated with a significantly lower rate of early major adverse events (0% vs 11.2%, P = .003). Late major adverse events occurred more frequently after surgery, with no significant difference between groups (3.4% vs 10.1%, P = .07). Both treatment modalities showed comparable 10-year OS and DSS rates. The length of hospital stay was significantly shorter in the EUS-EA group (4 days vs 14.1 days, P < .001), and endocrine pancreatic insufficiency was less common after EUS-EA than after surgery (33.3% vs 48.6%, P = .121). CONCLUSIONS: EUS-EA had fewer adverse events and a shorter hospital stay with similar OS and DSS rates compared with surgery, suggesting that EUS-EA may be a preferred alternative to surgical resection in selected patients with nonfunctioning small PNETs.

Minimally invasive versus open pancreaticoduodenectomy for distal bile duct cancer: an inverse probability of treatment weighting analysis of outcomes.

BACKGROUND: Minimally invasive pancreaticoduodenectomy (MIPD) has been extended to periampullary cancers, but the oncologic outcome of MIPD for distal bile duct cancer (DBDC) has not been confirmed yet. METHODS: Patients who underwent pancreaticoduodenectomy (PD) for DBDC of stage I-IIb from 2015 to 2019 at a tertiary referral center were identified and divided into open PD (OPD) and MIPD groups, the latter including laparoscopic and robotic procedures. Survival was compared between the two groups after inverse probability of treatment weighting (IPTW) using predetermined factors, and exploratory mediation analysis was performed using surgery-derived outcomes. RESULTS: MIPD (n = 81) group had more female patients (46.9% vs 31.6%, p = 0.011) and longer operation time (366.2 min vs. 279.1 min, p < 0.001) than the OPD (n = 288) group before IPTW. Otherwise, intraoperative and immediate postoperative outcomes were comparable between the two groups. In oncologic outcomes, MIPD group showed comparable 3-year overall survival (78.2% vs 75.0%, p = 0.062) and recurrence-free survival (51.2% vs 53.4%, p = 0.871) rates with OPD group before IPTW, and MIPD was not related with survival (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.29-1.26, p = 0.18) and recurrence (HR 1.01, 95% CI 0.67-1.53, p = 0.949) after IPTW with consideration of potential mediators. Sensitivity analysis using propensity score matching also showed similar results for survival (HR 0.68, 95% CI 0.32-1.44, p = 0.312) and recurrence (HR 1.12, 95% CI 0.67-1.88, p = 0.653). CONCLUSION: MIPD and OPD groups showed similar postoperative and oncologic outcomes. MIPD could be a considerable treatment option without oncological compromise in high-volume centers.

The clinical implication of minimally invasive versus open pancreatoduodenectomy for non-pancreatic periampullary cancer: a systematic review and individual patient data meta-analysis.

BACKGROUND: Most studies on minimally invasive pancreatoduodenectomy (MIPD) combine patients with pancreatic and periampullary cancers even though there is substantial heterogeneity between these tumors. Therefore, this study aimed to evaluate the role of MIPD compared to open pancreatoduodenectomy (OPD) in patients with non-pancreatic periampullary cancer (NPPC). METHODS: A systematic review of Pubmed, Embase, and Cochrane databases was performed by two independent reviewers to identify studies comparing MIPD and OPD for NPPC (ampullary, distal cholangio, and duodenal adenocarcinoma) (01/2015-12/2021). Individual patient data were required from all identified studies. Primary outcomes were (90-day) mortality, and major morbidity (Clavien-Dindo 3a-5). Secondary outcomes were postoperative pancreatic fistula (POPF), delayed gastric emptying (DGE), postpancreatectomy hemorrhage (PPH), blood-loss, length of hospital stay (LOS), and overall survival (OS). RESULTS: Overall, 16 studies with 1949 patients were included, combining 928 patients with ampullary, 526 with distal cholangio, and 461 with duodenal cancer. In total, 902 (46.3%) patients underwent MIPD, and 1047 (53.7%) patients underwent OPD. The rates of 90-day mortality, major morbidity, POPF, DGE, PPH, blood-loss, and length of hospital stay did not differ between MIPD and OPD. Operation time was 67 min longer in the MIPD group (P = 0.009). A decrease in DFS for ampullary (HR 2.27, P = 0.019) and distal cholangio (HR 1.84, P = 0.025) cancer, as well as a decrease in OS for distal cholangio (HR 1.71, P = 0.045) and duodenal cancer (HR 4.59, P < 0.001) was found in the MIPD group. CONCLUSIONS: This individual patient data meta-analysis of MIPD versus OPD in patients with NPPC suggests that MIPD is not inferior in terms of short-term morbidity and mortality. Several major limitations in long-term data highlight a research gap that should be studied in prospective maintained international registries or randomized studies for ampullary, distal cholangio, and duodenum cancer separately. PROTOCOL REGISTRATION: PROSPERO (CRD42021277495) on the 25th of October 2021.

Robotic versus laparoscopic distal pancreatectomy for pancreatic ductal adenocarcinoma: A propensity score-matched analysis.

BACKGROUND: Minimally invasive surgery is becoming increasingly popular in the field of pancreatic surgery. However, there are few studies of robotic distal pancreatectomy (RDP) for pancreatic ductal adenocarcinoma (PDAC). This study aimed to investigate the efficacy and feasibility of RDP for PDAC. METHODS: Patients who underwent RDP or laparoscopic distal pancreatectomy (LDP) for PDAC between January 2015 and September 2020 were reviewed. Propensity score matching analyses were performed. RESULTS: Of the 335 patients included in the study, 24 underwent RDP and 311 underwent LDP. A total of 21 RDP patients were matched 1:1 with LDP patients. RDP was associated with longer operative time (209.7 vs. 163.2 min; P = 0.003), lower open conversion rate (0% vs. 4.8%; P < 0.001), higher cost (15 722 vs. 12 699 dollars; P = 0.003), and a higher rate of achievement of an R0 resection margin (90.5% vs. 61.9%; P = 0.042). However, postoperative pancreatic fistula grade B or C showed no significant inter-group difference (9.5% vs. 9.5%). The median disease-free survival (34.5 vs. 17.3 months; P = 0.588) and overall survival (37.7 vs. 21.9 months; P = 0.171) were comparable between the groups. CONCLUSIONS: RDP is associated with longer operative time, a higher cost of surgery, and a higher likelihood of achieving R0 margins than LDP.

Endoplasmic stress-inducing variants in CPB1 and CPA1 and risk of pancreatic cancer: A case-control study and meta-analysis.

Gene variants that encode pancreatic enzymes with impaired secretion can induce pancreatic acinar endoplasmic reticulum (ER) stress, cellular injury and pancreatitis. The role of such variants in pancreatic cancer risk has received little attention. We compared the prevalence of ER stress-inducing variants in CPA1 and CPB1 in patients with pancreatic ductal adenocarcinoma (PDAC cases), enrolled in the National Familial Pancreas Tumor Registry, to their prevalence in noncancer controls in the Genome Aggregation Database (gnomAD). Variants of unknown significance were expressed and variants with reduced secretion assessed for ER stress induction. In vitro assessments were compared with software predictions of variant function. Protein variant software was used to assess variants found in only one gnomAD control ("n-of-one" variants). A meta-analysis of prior PDAC case/control studies was also performed. Of the 1385 patients with PDAC, 0.65% were found to harbor an ER stress-inducing variant in CPA1 or CPB1, compared to 0.17% of the 64 026 controls (odds ratio [OR]: 3.80 [1.92-7.51], P = .0001). ER stress-inducing variants in the CPA1 gene were identified in 4 of 1385 PDAC cases vs 77 of 64 026 gnomAD controls (OR: 2.4 [0.88-6.58], P = .087), and variants in CPB1 were detected in 5 of 1385 cases vs 33 of 64 026 controls (OR: 7.02 [2.74-18.01], P = .0001). Meta-analysis demonstrated strong associations for pancreatic cancer and ER-stress inducing variants for both CPA1 (OR: 3.65 [1.58-8.39], P < .023) and CPB1 (OR: 9.51 [3.46-26.15], P < .001). Rare variants in CPB1 and CPA1 that induce ER stress are associated with increased odds of developing pancreatic cancer.

Predictive Performance of Current Nodal Staging Systems in Various Categories of Pancreatic Cancer.

BACKGROUND: Nodal staging systems (NSS) for pancreatic ductal adenocarcinoma (PDAC) classify patients on the basis of number of metastatic lymph nodes (MLN), metastatic/retrieved lymph node ratio (LNR), and log odds of positive LN (LODDS). The relative prognostic performance of these NSS, however, remains unclear. PATIENTS AND METHODS: We identified 2584 patients who underwent surgery for PDAC between 2010 and 2019. Subgroups of each staging system were classified using K-adaptive partitioning method and assessed by comparing time-dependent areas under the curve (AUC) 5 years after surgery. RESULTS: Patients were subgrouped by MLN (0, 1-3, ≥ 4), LNR (0, 0-0.23, > 0.23), and LODDS (< - 3.5, - 3.5 to - 0.970, > - 0.97). All three NSS were independent prognostic factors for overall survival (OS) and recurrence-free survival (RFS). The AUCs for OS were comparable for the MLN (0.622), LNR (0.609), and LODDS (0.596) systems. Subgroup evaluation based on 12 retrieved lymph nodes (RLN), R1 resection, and extent of resection showed that the AUCs of the MLN and LNR NSS were comparable for OS and RFS regardless of the number of RLNs, R1 resection, and extent of resection. By contrast, the AUCs of the LODDS NSS were lower. CONCLUSION: The NSS based on the number of MLN is the best prognostic indicator, with prognostic performance comparable to the other NSS and greater convenience for practical use. This NSS was applicable regardless of the numbers of RLN, R1 resection, and extent of resection.

Clinical outcomes of EUS-guided transluminal drainage with a novel lumen-apposing metal stent for postoperative pancreatic fluid collection after pancreatic surgery.

BACKGROUND AND AIMS: EUS-guided transluminal drainage (EUS-TD) is increasingly used for the treatment of postoperative pancreatic fluid collections (POPFCs). A novel lumen-apposing metal stent (LAMS) was recently developed and used for the drainage of POPFCs. This study aimed to evaluate the efficacy and safety of a novel LAMS in patients with POPFCs. METHODS: Forty-seven patients with symptomatic POPFCs who underwent EUS-TD with a novel LAMS (Niti-S SPAXUS; Taewoong Medical Co, Ltd, Ilsan, South Korea) between April 2019 and July 2020 were included in this study. Clinical outcomes, including technical success, clinical success, and adverse events, were retrospectively evaluated. RESULTS: EUS-TD was technically successful in 41 of 47 patients (87.2%). Clinical success was achieved in 37 of 41 patients (90.2%). The mean procedure time was 13.7 ± 3.5 minutes. The mean POPFC size was 59 ± 18.9 mm. The mean time interval from surgery to EUS-TD was 24.2 ± 37.6 days. Five patients experienced 6 procedural adverse events (12.8%): 4 (8.5%) POPFC infections and 2 (4.3%) distal stent migrations. The 4 patients with POPFC infection underwent additional endoscopic interventions. Of the 2 patients with stent migration, 1 underwent laparoscopic exploration and surgical extraction of the stent and 1 (2.1%) experienced POPFC recurrence, which was managed with percutaneous drainage. CONCLUSIONS: EUS-TD for symptomatic POPFCs with a novel LAMS is technically feasible and effective, with an acceptable adverse event rate. Further larger-scale prospective studies are required to confirm the findings of this study.

The impact of preoperative EUS-FNA for distal resectable pancreatic cancer: Is it really effective enough to take risks?

BACKGROUND AND AIMS: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is frequently used for the preoperative histologic diagnosis of pancreatic cancer. However, debate continues regarding the clinical merits of preoperative EUS-FNA for the management of resectable pancreatic cancer. We aimed to evaluate the benefits and safety of preoperative EUS-FNA for resectable distal pancreatic cancer. METHODS: The medical records of 304 consecutive patients with suspected distal pancreatic cancer who underwent EUS-FNA were retrospectively reviewed to evaluate the clinical benefits of preoperative EUS-FNA. We also reviewed the medical records of 528 patients diagnosed with distal pancreatic cancer who underwent distal pancreatectomy with or without EUS-FNA. The recurrence rates and cancer-free survival periods of patients who did or did not undergo preoperative EUS-FNA were compared. RESULTS: The diagnostic accuracy of preoperative EUS-FNA was high (sensitivity, 87.5%; specificity, 100%; positive predictive value 100%; accuracy, 90.7%; negative predictive value, 73.8%). Among patients, 26.7% (79/304) avoided surgery based on the preoperative EUS-FNA findings. Of the 528 patients who underwent distal pancreatectomy, 193 patients received EUS-FNA and 335 did not. During follow-up (median 21.7 months), the recurrence rate was similar in the two groups (EUS-FNA, 72.7%; non-EUS-FNA, 75%; P = 0.58). The median cancer-free survival was also similar (P = 0.58); however, gastric wall recurrence was only encountered in the patients with EUS-FNA (n = 2). CONCLUSION: Preoperative EUS-FNA is not associated with increased risks of cancer-specific or overall survival. However, clinicians must consider the potential risks of needle tract seeding, and care should be taken when selecting patients.

Controversial benefit of 5-fluorouracil/leucovorin-based adjuvant chemotherapy for ampullary cancer: a propensity score-matched analysis.

BACKGROUND: Although surgery is the primary treatment for ampullary cancer (AC), the benefit of adjuvant chemotherapy (CTx) has not yet been confirmed. METHODS: AC patients who were administered 5-fluorouracil(FU)/leucovorin(LV)-based CTx after curative intent surgery between 2011 and 2019 were included. Prognosis was compared between the observation (OB) and CTx groups after propensity score matching (PSM) using perioperative variables to control differences in patient characteristics. RESULTS: Before PSM, of 475 patients, those in the CTx group (n = 281) had worse 5-year overall survival (OS) (82.1% vs. 78.5%, p = 0.017) and worse 5-year recurrence-free survival (RFS) (54.9% vs. 75.7%, p < 0.001) than those in the OB group (n = 194). In addition, the CTx group had a higher rate of poor prognostic factors such as a high T stage (p < 0.001), node metastasis (p < 0.001), and poor differentiation (p < 0.001). After PSM, perioperative outcomes were comparable. In addition, there were no significant differences in OS (hazard ratio [HR], 1.085; 95% confidence interval [CI], 0.688-1.710; p = 0.726) or RFS (HR, 0.883; 95% CI, 0.613 1.272; p = 0.505) between the CTx (n = 123) and OB (n = 123) groups even after stratification by TNM stage. Intestinal subtype showed better 5-year OS (83.7% vs 33.2%, p = 0.015) and RFS (46.5% vs 24.9%, p = 0.035) rate compared with pancreatobiliary/mixed subtype. CONCLUSION: Patients who received adjuvant chemotherapy based on 5-FU/LV showed comparable oncologic outcomes to patients in the OB group even after stratification by tumor stage. The patients with intestinal subtype showed oncologic benefit for adjuvant 5-FU/LV CTx compared with pancreatobiliary or mixed subtypes.

Minimally Invasive Versus Open Pancreatectomy for Right-Sided and Left-Sided G1/G2 Nonfunctioning Pancreatic Neuroendocrine Tumors: A Multicenter Matched Analysis with an Inverse Probability of Treatment-Weighting Method.

BACKGROUND: Limited evidence exists for the safety and oncologic efficacy of minimally invasive surgery (MIS) for nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) according to tumor location. This study aimed to compare the surgical outcomes of MIS and open surgery (OS) for right- or left-sided NF-PNETs. METHODS: The study collected data on patients who underwent surgical resection (pancreatoduodenectomy, distal/total/central pancreatectomy, duodenum-preserving pancreas head resection, or enucleation) of a localized NF-PNET between January 2000 and July 2017 at 14 institutions. The inverse probability of treatment-weighting method with propensity scores was used for analysis. RESULTS: The study enrolled 859 patients: 478 OS and 381 MIS patients. A matched analysis by tumor location showed no differences in resection margin, intraoperative blood loss, or complications between MIS and OS. However, MIS was associated with a longer operation time for right-sided tumors (393.3 vs 316.7 min; P < 0.001) and a shorter postoperative hospital stay for left-sided tumors (8.9 vs 12.9 days; P < 0.01). The MIS group was associated with significantly higher survival rates than the OS group for right- and left-sided tumors, but survival did not differ for the patients divided by tumor grade and location. Multivariable analysis showed that MIS did not affect survival for any tumor location. CONCLUSION: The short-term outcomes offered by MIS were comparable with those of OS except for a longer operation time for right-sided NF-PNETs. The oncologic outcomes were not compromised by MIS regardless of tumor location or grade. These findings suggest that MIS can be performed safely for selected patients with localized NF-PNETs.

Metabolic activity by FDG-PET/CT after neoadjuvant chemotherapy in borderline resectable and locally advanced pancreatic cancer and association with survival.

BACKGROUND: The optimal prognostic markers for neoadjuvant chemotherapy in patients with borderline resectable or locally advanced pancreatic cancer are not yet established. METHOD: Patients who received neoadjuvant chemotherapy prior to surgery and underwent FDG-PET/CT between July 2012 and December 2017 were included. Metabolic parameters including standardized uptake value (SUV), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) on PET/CT, and response evaluations using PERCIST criteria, were investigated for its impact on survival and recurrence. Cox proportional hazards model was performed. Differences in risk were expressed as hazard ratio (HR) with 95 per cent confidence interval. RESULTS: The patients with borderline resectable (N = 106) or locally advanced pancreatic cancer (N = 82) were identified. The median survival was 33.6 months. Decreased metabolic parameters of PET/CT after neoadjuvant chemotherapy were associated with positive impacts on survival and recurrence such as SUVmax (HR 1.16, 95 per cent c.i. 1.01 to 1.32, P = 0.025), SUVpeak (HR 1.26, 95 per cent c.i. 1.05 to 1.51, P = 0.011), and MTV (HR 1.15, 95 per cent c.i. 1.04 to 1.26, P = 0.005). Large delta values were related to a positive impact on recurrence such as SUVmax (HR 1.21, 95 per cent c.i. 1.06 to 1.38, P = 0.005). Post-neoadjuvant chemotherapy SUVmax ≥3 (HR 3.46, 95 per cent c.i. 1.21 to 9.91; P = 0.036) was an independent prognostic factor for negative impact on survival. Patients with post-neoadjuvant chemotherapy SUVmax <3 showed more chemotherapy cycles (8.7 versus 6.2, P = 0.001), more frequent complete metabolic response (25 versus 2.2 per cent, P = 0.002), smaller tumour size (2.1 versus 3.1 cm, P = 0.002), and less frequent lymphovascular invasion (23.7 versus 51.1 per cent, P = 0.020) than patients with SUVmax ≥3. CONCLUSION: Reduction in metabolic tumour parameters of FDG- PET/CT after neoadjuvant chemotherapy indicates improved overall survival and recurrence-free survival.

Risk Factors for Recurrence in Pancreatic Neuroendocrine Tumor and Size as a Surrogate in Determining the Treatment Strategy: A Korean Nationwide Study.

INTRODUCTION: The prognostic factors of pancreatic neuroendocrine tumor (PNET) are unclear, and the treatment guidelines are insufficient. This study aimed to suggest a treatment algorithm for PNET based on risk factors for recurrence in a large cohort. METHODS: Data of 918 patients who underwent curative intent surgery for PNET were collected from 14 tertiary centers. Risk factors for recurrence and survival analyses were performed. RESULTS: The 5-year disease-free survival (DFS) rate was 86.5%. Risk factors for recurrence included margin status (R1, hazard ratio [HR] 2.438; R2, HR 3.721), 2010 WHO grade (G2, HR 3.864; G3, HR 7.352), and N category (N1, HR 2.273). A size of 2 cm was significant in the univariate analysis (HR 8.511) but not in the multivariate analysis (p = 0.407). Tumor size was not a risk factor for recurrence, but strongly reflected 2010 WHO grade and lymph node (LN) status. Tumors ≤2 cm had lower 2010 WHO grade, less LN metastasis (p < 0.001), and significantly longer 5-year DFS (77.9 vs. 98.2%, p < 0.001) than tumors >2 cm. The clinicopathologic features of tumors <1 and 1-2 cm were similar. However, the LN metastasis rate was 10.3% in 1-2-cm sized tumors and recurrence occurred in 3.0%. Tumors <1 cm in size did not have any LN metastasis or recurrence. DISCUSSION/CONCLUSION: Radical surgery is needed in suspected LN metastasis or G3 PNET or tumors >2 cm. Surveillance for <1-cm PNETs should be sufficient. Tumors sized 1-2 cm require limited surgery with LN resection, but should be converted to radical surgery in cases of doubtful margins or LN metastasis.

Large tumor size, lymphovascular invasion, and synchronous metastasis are associated with the recurrence of solid pseudopapillary neoplasms of the pancreas.

BACKGROUND: Solid pseudopapillary neoplasms (SPNs) of the pancreas have low malignant potential. However, malignant SPNs are not fully understood. METHODS: To evaluate risk factors affecting malignant potential, the clinicopathologic features of 375 surgically resected SPNs were compared. RESULTS: Fifty (13.3%) had malignant histologic features. Twenty-seven and 22 had perineural and lymphovascular invasions, respectively. Adjacent organ invasion was noted in 9 cases. Recurrence occurred in 8 cases. The median recurrence time after surgical resection was 67 months and was associated with a higher pT category (P = 0.001), lymphovascular invasion (P < 0.001), and synchronous metastasis (P < 0.001). SPN patients with malignant histologic features had worse recurrence-free survival (RFS; 10-year survival rate, 73.2%) than those without malignant histologic features (96.3%; P = 0.01). Patients with a higher pT category (P = 0.04), synchronous metastasis (P < 0.01), and lymphovascular invasion (P < 0.01) had worse RFS. Lymphovascular invasion (P = 0.042) and a higher T category (P = 0.002) were poor prognostic factors for recurrence. CONCLUSION: Lymphovascular invasion and a higher T category were worse prognostic factors for recurrence in SPN patients with malignant histologic features. For SPN patients with malignant histologic features, a longer follow-up may be required.

Neoadjuvant modified FOLFIRINOX followed by postoperative gemcitabine in borderline resectable pancreatic adenocarcinoma: a Phase 2 study for clinical and biomarker analysis.

BACKGROUND: Patients with borderline resectable pancreatic cancer (BRPC) have poor prognosis with upfront surgery. METHODS: This was a single-arm Phase 2 trial for clinical and biomarker analysis. The primary endpoint is 1-year progression-free survival (PFS) rate. Patients received 8 cycles of neoadjuvant modified (m) FOLFIRINOX. Up to 6 cycles of gemcitabine were given for patients who underwent surgery. Plasma immune cell subsets were measured for analysing correlations with overall survival (OS). RESULTS: Between May 2016 and March 2018, 44 chemotherapy- and radiotherapy-naïve patients with BRPC were included. With neoadjuvant mFOLFIRINOX, the objective response rate was 34.1%, and curative-intent surgery was done in 27 (61.4%) patients. With a median follow-up duration of 20.6 months (95% confidence interval [CI], 19.7-21.6 months), the median PFS and OS were 12.2 months (95% CI, 8.9-15.5 months) and 24.7 months (95% CI, 12.6-36.9), respectively. The 1-year PFS rate was 52.3% (95% CI, 37.6-67.0%). Higher CD14+ monocyte (quartile 4 vs 1-3) and lower CD69+ γδ T cell (γδ TCR+/CD69+) levels (quartiles 1-3 vs 4) were significantly associated with poor OS (p = 0.045 and p = 0.043, respectively). CONCLUSIONS: Neoadjuvant mFOLFIRINOX followed by postoperative gemcitabine were feasible and effective in BRPC patients. Monocyte and γδ T cells may have prognostic implications for patients with pancreatic cancer. ClinicalTrials.gov identifier: NCT02749136.

Gene Variants That Affect Levels of Circulating Tumor Markers Increase Identification of Patients With Pancreatic Cancer.

BACKGROUND & AIMS: Levels of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 125 (CA-125) in blood are used as markers to determine the response of patients with cancer to therapy, but are not used to identify patients with pancreatic cancer. METHODS: We obtained blood samples from 504 patients undergoing pancreatic surveillance from 2002 through 2018 who did not develop pancreatic cancer and measured levels of the tumor markers CA19-9, CEA, CA-125, and thrombospondin-2. Single-nucleotide polymorphisms (SNPs) in FUT3, FUT2, ABO, and GAL3ST2 that have been associated with levels of tumor markers were used to establish SNP-defined ranges for each tumor marker. We also tested the association between additional SNPs (in FUT6, MUC16, B3GNT3, FAM3B, and THBS2) with levels of tumor markers. To calculate the diagnostic specificity of each SNP-defined range, we assigned the patients under surveillance into training and validation sets. After determining the SNP-defined ranges, we determined the sensitivity of SNP-adjusted tests for the tumor markers, measuring levels in blood samples from 245 patients who underwent resection for pancreatic ductal adenocarcinoma (PDAC) from 2010 through 2017. RESULTS: A level of CA19-9 that identified patients with PDAC with 99% specificity had 52.7% sensitivity. When we set the cut-off levels of CA19-9 based on each SNP, the test for CA19-9 identified patients with PDAC with 60.8% sensitivity and 98.8% specificity. Among patients with FUT3 alleles that encode a functional protein, levels of CA19-9 greater than the SNP-determined cut-off values identified 66.4% of patients with PDAC, with 99.3% specificity. In the validation set, levels of CEA varied among patients with vs without SNP in FUT2, by blood group, and among smokers vs nonsmokers; levels of CA-125 varied among patients with vs without the SNP in GAL3ST2. The use of the SNPs to define the ranges of CEA and CA-125 did not significantly increase the diagnostic accuracy of the assays for these proteins. Combining data on levels of CA19-9 and CEA, CA19-9 and CA-125, or CA19-9 and thrombospondin-2 increased the sensitivity of detection of PDAC, but slightly reduced specificity. CONCLUSIONS: Including information on SNPs associated with levels of CA19-9, CEA, and CA-125 can improve the diagnostic accuracy of assays for these tumor markers in the identification of patients with PDAC. Clinicaltrials.gov no: NCT02000089.

Estimating Recurrence after Upfront Surgery in Patients with Resectable Pancreatic Ductal Adenocarcinoma by Using Pancreatic CT: Development and Validation of a Risk Score.

Background No preoperative model is available for predicting postsurgical prognosis of patients with resectable pancreatic ductal adenocarcinoma (PDAC). Purpose To develop and validate a preoperative risk scoring system using clinical and CT variables to predict recurrence-free survival (RFS) after upfront surgery in patients with resectable PDAC. Materials and Methods In this retrospective study, consecutive patients with resectable PDAC underwent upfront surgery from January 2014 to December 2015 (development set) and from January 2016 to January 2017 (test set). In the development set, multivariable Cox proportional hazard modeling with bootstrapping was used to select clinical and CT variables associated with RFS and to construct a risk scoring system. The discrimination capability of the risk score was assessed by using the Harrell C-index and compared with that of pathologic American Joint Committee on Cancer tumor stage. The risk score was validated in the test set. Results A total of 395 patients were evaluated, including 262 patients (mean age ± standard deviation, 64 years ± 10; 155 men) in the development set and 133 (mean age, 64 years ± 9; 79 men) in the test set. Five independent variables predicted risk of recurrence or death: tumor size (hazard ratio [HR], 1.23; 95% confidence interval [CI]: 1.05, 1.44; P = .009), hypodense tumor in the portal venous phase (HR, 1.66; 95% CI: 1.01, 2.73; P = .04), tumor necrosis (HR, 2.04; 95% CI: 1.38, 3.03; P < .001), peripancreatic tumor infiltration (HR, 1.50; 95% CI: 1.07, 2.11; P = .02), and suspicious metastatic lymph nodes (HR, 1.94; 95% CI: 1.38, 2.72; P < .001). In the test set, the risk score showed good discrimination capability (C-index of 0.68; 95% CI: 0.63, 0.74) and outperformed the pathologic tumor stage (C-index of 0.60; 95% CI: 0.55, 0.66; P = .03). Patients were categorized into favorable, intermediate, and poor prognosis groups with 1-year RFS of 0.87, 0.58, and 0.26, respectively. Conclusion The presented preoperative risk score can predict recurrence-free survival after upfront surgery in patients with resectable pancreatic ductal adenocarcinoma. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Pandharipande and Anderson in this issue.

Propensity score-matched analysis of internal stent vs external stent for pancreatojejunostomy during pancreaticoduodenectomy: Japanese-Korean cooperative project.

BACKGROUND: Several studies comparing internal and external stents have been conducted with the aim of reducing pancreatic fistula after PD. There is still no consensus, however, on the appropriate use of pancreatic stents for prevention of pancreatic fistula. This multicenter large cohort study aims to evaluate whether internal or external pancreatic stents are more effective in reduction of clinically relevant pancreatic fistula after pancreaticoduodenectomy (PD). METHODS: We reviewed 3149 patients (internal stent n = 1,311, external stent n = 1838) who underwent PD at 20 institutions in Japan and Korea between 2007 and 2013. Propensity score matched analysis was used to minimize bias from nonrandomized treatment assignment. The primary endpoint was the incidence of clinically relevant pancreatic fistula. This study was registered on the UMIN Clinical Trials Registry (UMIN000032402). RESULTS: After propensity score matched analysis, clinically relevant pancreatic fistula occurred in more patients in the external stents group (280 patients, 28.7%) than in patients in the internal stents group (126 patients, 12.9%) (OR 2.713 [95% CI, 2.139-3.455]; P < 0.001). In subset analysis of a high-risk group with soft pancreas and no dilatation of the pancreatic duct, clinically relevant pancreatic fistula occurred in 90 patients (18.8%) in internal stents group and 183 patients (35.4%) in external stents group. External stents were significantly associated with increased risk for clinically relevant pancreatic fistula (OR 2.366 [95% CI, 1.753-3.209]; P < 0.001). CONCLUSION: Propensity score matched analysis showed that, regarding clinically relevant pancreatic fistula after PD, internal stents are safer than external stents for pancreaticojejunostomy.

Laparoscopic pancreaticoduodenectomy for periampullary tumors: lessons learned from 500 consecutive patients in a single center.

BACKGROUND: Laparoscopic pancreaticoduodenectomy (LPD) is a feasible option in selected patients. However, its use has not yet been generalized since it is time-consuming, physically demanding, and technically challenging. It might be essential to share the experience of high-volume centers to understand its use. METHODS: We retrospectively reviewed the data of 500 consecutive patients who underwent LPD at a single institution between January 2007 and December 2017. RESULTS: The patients included 272 women and 228 men (mean age, 57.1 years). The most common indication for LPD was intraductal papillary neoplasm (n = 104, 20.8%). Overall and major (Clavien-Dindo grades III-V) complication rates were 37.2% and 4.8%, respectively. Fifty-four patients (10.8%) had clinically relevant (grade B/C) pancreatic fistulas. There were 3 (0.6%) 90-day mortalities. The most common late complication was bilioenteric stricture (25, 5%). Two hundred thirty patients were diagnosed with periampullary cancer. The 5-year overall survival rates of pancreatic cancer, common bile duct cancer, ampulla of Vater cancer, and duodenal cancer were 37.4, 63.2, 78, and 88.9%, respectively. We analyzed learning curves of first-generation and second-generation surgeons. A risk-adjusted cumulative sum analysis demonstrated a learning curve of 55 cases for LPD with the first-generation surgeon and earlier competency with the second-generation surgeon. CONCLUSIONS: LPD has the potential to become an alternative surgery to open pancreaticoduodenectomy for periampullary tumors with acceptable outcomes. We could reduce the steep learning curve with structured training, close supervision, and well-trained operation teams. Perioperative and oncologic outcomes of LPD will be optimized after overcoming the learning curve.

Robotic versus laparoscopic distal pancreatectomy for left-sided pancreatic tumors: a single surgeon's experience of 228 consecutive cases.

BACKGROUND: Laparoscopic distal pancreatectomy (LDP) has gained popularity for the treatment of left-sided pancreatic tumors. Robotic systems represent the most recent advancement in minimally invasive surgical treatment for such tumors. Theoretically, robotic systems are considered to have several advantages over laparoscopic systems. However, there have been few studies comparing both systems in the treatment of distal pancreatectomy. We compared perioperative and oncological outcomes between the two treatment modalities. METHODS: A retrospective analysis was conducted of all consecutive minimally invasive distal pancreatectomy cases performed by a single surgeon at a high-volume center between January 2015 and December 2017. RESULTS: The analysis included 228 consecutive patients (LDP, n = 182; Robotic-assisted laparoscopic distal pancreatectomy [R-LDP], n = 46). Operative time was significantly longer in the R-LDP group than in the LDP group (166.4 vs. 140.7 min; p = 0.001). In a subgroup analysis of patients who underwent the spleen-preserving approach, the spleen preservation rate associated with R-LDP was significantly higher than that associated with LDP (96.8% vs. 82.5%; p = 0.02). In another subgroup analysis of patients with pancreatic cancer, there were no significant differences in median overall and disease-free survival between the two groups. CONCLUSIONS: R-LDP is a safe and feasible approach with perioperative and oncological outcomes comparable to those of LDP. R-LDP offers an added technical advantage that enables the surgeon to perform a complex procedure with good ergonomic comfort.