Factors Affecting Nonfunctioning Small Pancreatic Neuroendocrine Neoplasms and Proposed New Treatment Strategies.

BACKGROUND & AIMS: Despite previously reported treatment strategies for nonfunctioning small (≤20 mm) pancreatic neuroendocrine neoplasms (pNENs), uncertainties persist. We aimed to evaluate the surgically resected cases of nonfunctioning small pNENs (NF-spNENs) in a large Japanese cohort to elucidate an optimal treatment strategy for NF-spNENs. METHODS: In this Japanese multicenter study, data were retrospectively collected from patients who underwent pancreatectomy between January 1996 and December 2019, were pathologically diagnosed with pNEN, and were treated according to the World Health Organization 2019 classification. Overall, 1490 patients met the eligibility criteria, and 1014 were included in the analysis cohort. RESULTS: In the analysis cohort, 606 patients (59.8%) had NF-spNENs, with 82% classified as grade 1 (NET-G1) and 18% as grade 2 (NET-G2) or higher. The incidence of lymph node metastasis (N1) by grade was significantly higher in NET-G2 (G1: 3.1% vs G2: 15.0%). Independent factors contributing to N1 were NET-G2 or higher and tumor diameter ≥15 mm. The predictive ability of tumor size for N1 was high. Independent factors contributing to recurrence included multiple lesions, NET-G2 or higher, tumor diameter ≥15 mm, and N1. However, the independent factor contributing to survival was tumor grade (NET-G2 or higher). The appropriate timing for surgical resection of NET-G1 and NET-G2 or higher was when tumors were >20 and >10 mm, respectively. For neoplasms with unknown preoperative grades, tumor size >15 mm was considered appropriate. CONCLUSIONS: NF-spNENs are heterogeneous with varying levels of malignancy. Therefore, treatment strategies based on tumor size alone can be unreliable; personalized treatment strategies that consider tumor grading are preferable.

Reconsideration of the clinical impact of neoadjuvant therapy in resectable and borderline resectable pancreatic cancer: A dual-institution collaborative clinical study.

PURPOSE: We investigated true indication of neoadjuvant therapy (NAT) in resectable pancreatic cancer and the optimal surgical timing in borderline resectable pancreatic cancer. METHODS: A total of 687 patients with resectable or borderline resectable pancreatic cancer were enrolled. Survival analysis was performed by intention-to-treat analysis and propensity score matching (PSM) was conducted. RESULTS: In resectable disease, the NAT group showed better overall survival (OS) compared with the upfront group. Multivariate analysis identified CA19-9 level (≥100 U/mL) and lymph node metastasis to be prognostic factors, and a tumor size of 25 mm was the optimal cut-off value to predict lymph node metastasis. There was no significant survival difference between patients with a tumor size ≤25 mm and CA19-9 < 100 U/mL and those in the NAT group. In borderline resectable disease, OS in the NAT group was significantly better than that in the upfront group. CEA (≥5 ng/mL) and CA19-9 (≥100 U/mL) were identified as prognostic factors; however, the OS of patients fulfilling these factors was worse than that of the NAT group. CONCLUSIONS: NAT could be unnecessary in patients with tumor size ≤25 mm and CA19-9 < 100 U/mL in resectable disease. In borderline resectable disease, surgery should be delayed until tumor marker levels are well controlled.

The survival in octogenarians undergoing surgery for pancreatic cancer and its association with the nutritional status.

PURPOSES: This study explored the association between the nutritional status and survival outcomes after pancreatic cancer surgery and reconsidered surgical indications in octogenarians. METHODS: Three hundred and ninety-three consecutive pancreatic cancer patients who underwent resection were analyzed and grouped according to age (< 70 years old; septuagenarians [70-79 years old], and octogenarians [80-89 years old]). The Charlson age comorbidity index and nutritional parameters were recorded. Survival outcomes and their association with nutritional parameters and prognostic factors were examined. RESULTS: The overall survival was worse in the octogenarians than in other patients. The median overall survivals in the < 70 years old group, septuagenarians, and octogenarians were 27.2, 26.4, and 15.3 months, respectively (P = 0.0828). DUPAN-2 ≥ 150 U/mL, borderline resectable/unresectable tumors, blood loss volume ≥ 500 mL, and blood transfusion were predictors of the overall survival among octogenarians. Nutritional parameter values were worse in the octogenarians than in other patients. The octogenarian age group was not an independent predictor of postoperative complications in a univariate analysis. CONCLUSIONS: Survival outcomes were poor in octogenarians. However, an age ≥ 80 years old alone should not be considered a contraindication for pancreatic cancer surgery. The maintenance of perioperative nutritional status is an important factor associated with the survival.

Prognostic factors in conversion surgery following nab-paclitaxel with gemcitabine and subsequent chemoradiotherapy for unresectable locally advanced pancreatic cancer: Results of a dual-center study.

Background: In pancreatic ductal adenocarcinoma (PDAC), only radical surgery improves long-term survival. We focused on surgical outcome after induction gemcitabine along with nab-paclitaxel (GnP) and subsequent chemoradiotherapy (CRT) with S-1 administration for unresectable locally advanced (UR-LA) PDAC. Methods: We retrospectively analyzed 144 patients with UR-LA PDAC between 2014 and 2020. The first-line regimen of induction chemotherapy was GnP for 125 of the 144 patients. Of the 125 patients who received GnP, 41 who underwent radical resection after additional preoperative CRT were enrolled. We evaluated the prognostic factors for this treatment strategy. Results: The median length of preoperative GnP was 8.8 months, and 30 (73%) patients had normalized CA19-9 levels. R0 resection was achieved in 36 (88%) patients. Postoperative major complications of ≥Clavien-Dindo grade IIIa developed in 16 (39%) patients. With a median follow-up of 35.2 months, 14 (34%) patients developed distant metastasis postoperatively. Using the Kaplan-Meier method, prognostic analysis of the 41 cases revealed the 3-y overall survival rate (OS) was 77.4% and the 5-y OS was 58.6%. In univariate analysis, length of preoperative GnP (≥8 months), CA19-9 normalization, and good nutritional status at operation (prognostic nutritional index ≥41.7) were significantly associated with favorable prognosis. Multivariate analysis revealed CA19-9 normalization (hazard ratio [HR] 0.23; P = .032) and prognostic nutritional index ≥41.7 (HR 0.05; P = .021) were independent prognostic factors. Conclusion: For surgical outcome after induction GnP and subsequent CRT for UR-LA PDAC, CA19-9 normalization and maintenance of good nutritional status during treatment until surgery were important for prolonged prognosis.

The malignant potential of pancreatic intraductal papillary mucinous neoplasm is reflected in expression levels of fucosylated glycans in α1 -acid glycoprotein.

BACKGROUND: Pancreatic intraductal papillary mucinous neoplasm (IPMN) involves multiple histopathological stages from benign to malignant lesions. Further, a biomarker to diagnose the malignant IPMN (IPMC) is clinically relevant. Recently, we found that serum fucosylated α1 -acid glycoprotein (fAGP) level markedly elevated along with disease progression in large cohorts of patients with various cancers. METHODS: The fAGP level was retrospectively analyzed in preoperative sera from 109 patients with IPMN, and the clinical relevance of fAGP was compared with currently available predictors as standard. RESULTS: The fAGP level in IPMC was found to be significantly higher than in benign IPMN (P = .0012). At a cutoff value of 27.04 U/µg, its sensitivity, specificity, and accuracy for IPMC were determined to be 83.61%, 65.96%, and 75.93%, respectively. Multivariate analyses revealed that the fAGP level was the only independent risk factor for predicting IPMC. Additionally, a combination of the fAGP level and 18 F-fluorodeoxyglucose uptake on the PET/CT imaging in the lesions seemed to offer the best diagnosis of IPMN. Accordingly, 27 of the 28 patients who were positive in both tests had IPMC, while patients who are negative had benign IPMN. CONCLUSIONS: The fAGP level appeared to be a relevant biomarker for malignant potential of IPMN.

Clinical significance and functional role of adhesion G-protein-coupled receptors in human pancreatic ductal adenocarcinoma.

BACKGROUND: The adhesion G-protein-coupled receptors (GPCRs) play crucial roles in tumour pathogenesis, however, their clinical significance in pancreatic ductal adenocarcinoma (PDAC) remains unclear. METHODS: We analysed 796 PDAC patients, including 331 from public data sets (TCGA, ICGC and GSE57495) and 465 from independent cohorts (training: n = 321, validation: n = 144). Using in-vitro studies, we confirmed the biological function of the candidate GPCRs. RESULTS: Analysis of all 33 adhesion GPCRs, led to identify GPR115, as the only significant prognostic factor in all public data sets. The patients with high GPR115 expression exhibited significantly poorer prognosis for OS and RFS, in training (P < 0.01, P < 0.01) and validation cohort (P < 0.01, P = 0.04). Multivariate analysis indicated that GPR115 high expression was an independent prognostic factor in both cohorts (HR = 1.43; P = 0.01, HR = 2.55; P < 0.01). A risk-prediction model using Cox regression by incorporating GPR115 and clinicopathological factors accurately predicted 5-year survival following surgery. In addition, GPR115 silencing inhibited cell proliferation and migration in PDAC cells. CONCLUSION: We demonstrated that GPR115 has important prognostic significance and functional role in tumour progression; providing a rationale that this may be a potential therapeutic target in patients with PDAC.

Clinical practice guidelines for duodenal cancer 2021.

Duodenal cancer is considered to be a small intestinal carcinoma in terms of clinicopathology. In Japan, there are no established treatment guidelines based on sufficient scientific evidence; therefore, in daily clinical practice, treatment is based on the experience of individual physicians. However, with advances in diagnostic modalities, it is anticipated that opportunities for its detection will increase in future. We developed guidelines for duodenal cancer because this disease is considered to have a high medical need from both healthcare providers and patients for appropriate management. These guidelines were developed for use in actual clinical practice for patients suspected of having non-ampullary duodenal epithelial malignancy and for patients diagnosed with non-ampullary duodenal epithelial malignancy. In this study, a practice algorithm was developed in accordance with the Minds Practice Guideline Development Manual 2017, and Clinical Questions were set for each area of epidemiology and diagnosis, endoscopic treatment, surgical treatment, and chemotherapy. A draft recommendation was developed through a literature search and systematic review, followed by a vote on the recommendations. We made decisions based on actual clinical practice such that the level of evidence would not be the sole determinant of the recommendation. This guideline is the most standard guideline as of the time of preparation. It is important to decide how to handle each case in consultation with patients and their family, the treating physician, and other medical personnel, considering the actual situation at the facility (and the characteristics of the patient).

Clip-guided local duodenectomy for safe and minimal local resection of nonampullary duodenal neoplasms.

BACKGROUND: Local duodenectomy and primary closure is a simple option for some nonampullary duodenal neoplasms. Minimizing the resection area while ensuring curability is necessary for safe primary duodenal closure. However, it is often difficult to determine the appropriate resection line from the serosal side. We developed clip-guided local duodenectomy to easily determine the resection range and perform local duodenectomy safely, then performed a retrospective observational study to confirm the safety of clip-guided local duodenectomy. METHODS: The procedure is as follows: placing endoscopic metal clips at four points on the margin around the tumor within 3 days before surgery, identifying the tumor extent with the clips under X-ray imaging during surgery, making an incision to the duodenum just outside of the clips visualized by X-ray imaging, full-thickness resection of the duodenum with the clips as guides of tumor demarcation, and transversely closure by Gambee suture. We evaluated clinicopathological data and surgical outcomes of patients who underwent clip-guided local duodenectomy at two surgical centers between January 2010 and May 2020. RESULTS: Eighteen patients were included. The pathological diagnosis was adenoma (11 cases), adenocarcinoma (6 cases), and GIST (1 case). The mean ± SD tumor size was 18 ± 6 mm, and the tumor was mainly located in the second portion of the duodenum (66%). In all cases, the duodenal defect was closed with primary sutures. The mean operation time and blood loss were 191 min and 79 mL, respectively. The morbidity was 22%, and all complications were Clavien-Dindo grade II. No anastomotic leakage or stenosis was observed. In the 6 adenocarcinoma patients, all were diagnosed with pT1a, and postoperative recurrence was not observed. The 1-year overall and recurrence free survival rate was 100%. CONCLUSIONS: Clip-guided local duodenectomy is a safe and useful surgical option for minimally local resection of nonampullary duodenal neoplasms such as duodenal adenoma, GIST, and early adenocarcinoma.

An Exosome-based Transcriptomic Signature for Noninvasive, Early Detection of Patients With Pancreatic Ductal Adenocarcinoma: A Multicenter Cohort Study.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) incidence is rising worldwide, and most patients present with an unresectable disease at initial diagnosis. Measurement of carbohydrate antigen 19-9 (CA19-9) levels lacks adequate sensitivity and specificity for early detection; hence, there is an unmet need to develop alternate molecular diagnostic biomarkers for PDAC. Emerging evidence suggests that tumor-derived exosomal cargo, particularly micro RNAs (miRNAs), offer an attractive platform for the development of cancer-specific biomarkers. Herein, genomewide profiling in blood specimens was performed to develop an exosome-based transcriptomic signature for noninvasive and early detection of PDAC. METHODS: Small RNA sequencing was undertaken in a cohort of 44 patients with an early-stage PDAC and 57 nondisease controls. Using machine-learning algorithms, a panel of cell-free (cf) and exosomal (exo) miRNAs were prioritized that discriminated patients with PDAC from control subjects. Subsequently, the performance of the biomarkers was trained and validated in independent cohorts (n = 191) using quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. RESULTS: The sequencing analysis initially identified a panel of 30 overexpressed miRNAs in PDAC. Subsequently using qRT-PCR assays, the panel was reduced to 13 markers (5 cf- and 8 exo-miRNAs), which successfully identified patients with all stages of PDAC (area under the curve [AUC] = 0.98 training cohort; AUC = 0.93 validation cohort); but more importantly, was equally robust for the identification of early-stage PDAC (stages I and II; AUC = 0.93). Furthermore, this transcriptomic signature successfully identified CA19-9 negative cases (<37 U/mL; AUC = 0.96), when analyzed in combination with CA19-9 levels, significantly improved the overall diagnostic accuracy (AUC = 0.99 vs AUC = 0.86 for CA19-9 alone). CONCLUSIONS: In this study, an exosome-based liquid biopsy signature for the noninvasive and robust detection of patients with PDAC was developed.

Downregulation of ROBO4 in Pancreatic Cancer Serves as a Biomarker of Poor Prognosis and Indicates Increased Cell Motility and Proliferation Through Activation of MMP-9.

BACKGROUND: The axon guidance gene family, SLIT/ROBO pathway, controls neural network formation, which correlates with the development of several cancers. METHODS: We found through analysis of the public database that ROBO4, one of the axon guidance molecules among the SLIT/ROBO family, is significantly downregulated in primary pancreatic cancer tissues compared with adjacent normal tissues. We carried out transfection experiments using three pancreatic cancer cell lines (MiaPaCa-2, BxPC-3, and SW1990) and one pancreatic duct epithelial cell line (HPDE6c7). A total of 51 clinical samples were then examined by immunohistochemical staining to find an association between ROBO4 expression at the protein level, clinical characteristics, and surgical outcomes. RESULTS: ROBO4 overexpression suppressed the invasion and migration abilities in MiaPaCa-2 and BxPC-3, while ROBO4 siRNA transfection to SW1990 and HPDE6c7 enhanced those activities. PCR-based profiling detected MMP-9 as a candidate downstream target of ROBO4, which was validated by decreased MMP-9 activity after the ROBO4 overexpression assay. High ROBO4 expression clinical samples had significantly better overall survival rather than low ROBO4 cases (P = 0.048). CONCLUSION: These findings suggest that decreased ROBO4 expression activates malignant phenotypes in cancer cells and is correlated with poor survival outcomes in pancreatic cancer.

Results of a Phase II Study on the Use of Neoadjuvant Chemotherapy (FOLFIRINOX or GEM/nab-PTX) for Borderline-resectable Pancreatic Cancer (NUPAT-01).

OBJECTIVE: Given the frequent adverse events with multidrug chemotherapy, not only the survival benefit but also the feasibility of using neoadjuvant chemotherapy to treat pancreatic cancer need to be clarified. SUMMARY OF BACKGROUND DATA: Although the development of multidrug chemotherapy regimens has improved the survival outcomes of patients with unresectable pancreatic cancer, the benefits of these treatments in the neo-adjuvant setting remain controversial. METHODS: Patients with borderline-resectable pancreatic cancer were enrolled and randomly assigned to receive neoadjuvant chemotherapy with either FOLFIRINOX or gemcitabine with nab-paclitaxel (GEM/nab-PTX). After the completion of chemotherapy, patients underwent surgical resection when feasible. This study (NUPAT-01) was a randomized phase II trial, and the primary endpoint was the R0 resection rate. RESULTS: Fifty-one patients were enrolled in this study [FOLFIRINOX (n = 26) and GEM/nab-PTX (n = 25)]. A total of 84.3% (n = 43/51) of the patients eventually underwent surgery, and R0 resection was achieved in 67.4% (n = 33/ 51) of the patients. Adverse events (grade >3) due to neoadjuvant treatment were observed in 45.1% of the patients (n = 23/51), and major surgical complications occurred in 30.0% (n = 13/43), with no mortality noted. The intention-to-treat analysis showed that the 3-year overall survival rate was 54.7%, with a median survival time of 39.4 months, and a significant difference in overall survival was not observed between the FOLFIRINOX and GEM/nab-PTX groups. CONCLUSIONS: These results indicate that neoadjuvant chemotherapy with FOLFIRINOX or GEM/nab-PTX is feasible and well tolerated, achieving an R0 resection rate of 67.4%. The survival of patients was even found to be favorable in the intention-to-treat analysis.

Efficacy of active hexose correlated compound on survival of patients with resectable/borderline resectable pancreatic cancer: a study protocol for a double-blind randomized phase II study.

BACKGROUND: The prognosis of pancreatic ductal adenocarcinoma remains very poor. One possible reason for the short survival of patients with this disease is malnutrition, which can be present at the initial diagnosis, and continue after pancreatectomy. Then, it is important to improve nutritional status and to decrease adverse events during neoadjuvant and adjuvant chemotherapy. Active hexose correlated compound (AHCC) is a standardized extract of cultured Lentinula edodes mycelia, and is considered a potent biological response modifier in the treatment of cancer. To evaluate the survival impact of AHCC on the patients with pancreatic ductal adenocarcinoma, we plan to perform this trial. METHODS: This is a prospective multicenter phase II trial in patients with resectable/borderline resectable pancreatic ductal adenocarcinoma to investigate the efficacy of AHCC regarding survival. Patients will begin taking AHCC or placebo on the first day of neoadjuvant therapy. AHCC or placebo will be continued until 2 years after surgery. The primary endpoint will be 2-year disease-free survival. The secondary endpoints are the completion rate, dose intensity, and adverse event profile of preoperative chemotherapy; response rate to preoperative chemotherapy; rate of decrease in tumor marker (carbohydrate antigen 19-9, carcinoembryonic antigen) concentrations during preoperative chemotherapy; entry rate, completion rate, dose intensity, and adverse event profile of adjuvant chemotherapy; safety of the protocol therapy (adverse effect of AHCC); 2-year overall survival rate; and nutrition score before and after preoperative chemotherapy, and before and after adjuvant chemotherapy. We will enroll 230 patients, and the study involves eight leading Japanese institutions that are all high-volume centers in pancreatic surgery. DISCUSSION: AHCC is expected to function as a supportive food in patients with pancreatic ductal adenocarcinoma, to reduce the proportion of severe adverse events related to neoadjuvant chemotherapy, and to increase the completion proportion of multimodal treatments, resulting in improved survival. TRIAL REGISTRATION: The trial protocol has been registered in the protocol registration system at the Japan Registry of Clinical Trials (Trial ID: jRCTs051200029 ). At the time of the submission of this paper (October 2020), the protocol version is 2.0. The completion date is estimated to be November 2024.

Surgical results of non-ampullary duodenal cancer: a nationwide survey in Japan.

BACKGROUND: As non-ampullary duodenal cancer is relatively rare, the optimal treatment strategy, including the appropriate surgical procedure and efficacy of adjuvant chemotherapy, remains unclear. This nationwide survey aimed to clarify the actual lymph node spread pattern and determine the optimal treatment strategy for this disease, using a large-scale database. METHODS: We used a questionnaire and a retrospective registry of 1083 patients with non-ampullary duodenal cancer who had undergone surgery during 2008-2017 in 114 high-volume Japanese Society of Hepatobiliary and Pancreatic Surgery-certified training institutions. Propensity score-matched analyses were conducted to minimise background bias. Cox regression was performed to identify covariates associated with recurrence-free survival. There were distinct disparities in the nodal dissection rate according to the predominant tumor location and tumor invasion depth. Metastases were frequently observed in the peripancreatic nodes and those along the superior mesenteric artery, irrespective of tumor location. Their dissection seemed to be beneficial for improved survival. In the overall cohort, no survival benefit was observed in patients who received adjuvant chemotherapy when compared with that in patients who underwent surgery alone. Nevertheless, in the matched cohort, adjuvant chemotherapy for > 6 months was associated with a significant improvement in recurrence-free survival (median: 43.5 vs. 22.5 months, p = 0.016), particularly in patients with tumor invasion of the subserosa or deeper tumor invasion, lymph node metastasis, or elevated serum carbohydrate antigen 19-9 levels. CONCLUSION: Pancreatoduodenectomy should be the standard procedure for advanced non-ampullary duodenal cancer. Adjuvant chemotherapy for > 6 months, especially for advanced tumors, significantly improves survival.

Transcriptomic Profiling Identifies an Exosomal microRNA Signature for Predicting Recurrence Following Surgery in Patients With Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: We performed genome-wide expression profiling to develop an exosomal miRNA panel for predicting recurrence following surgery in patients with PDAC. SUMMARY OF BACKGROUND DATA: Pretreatment risk stratification is essential for offering individualized treatments to patients with PDAC, but predicting recurrence following surgery remains clinically challenging. METHODS: We analyzed 210 plasma and serum specimens from 4 cohorts of PDAC patients. Using a discovery cohort (n = 25), we performed genome-wide sequencing to identify candidate exosomal miRNAs (exo-miRNAs). Subsequently, we trained and validated the predictive performance of the exo-miRNAs in two clinical cohorts (training cohort: n = 82, validation cohort: n = 57) without neoadjuvant therapy (NAT), followed by a post-NAT clinical cohort (n = 46) as additional validation. RESULTS: We performed exo-miRNA expression profiling in plasma specimens obtained before any treatment in a discovery cohort. Subsequently we optimized and trained a 6-exo-miRNA risk-prediction model, which robustly discriminated patients with recurrence [area under the curve (AUC): 0.81, 95% confidence interval (CI): 0.70-0.89] and relapse-free survival (RFS, P < 0.01) in the training cohort. The identified exo-miRNA panel was successfully validated in an independent validation cohort (AUC: 0.78, 95% CI: 0.65- 0.88, RFS: P < 0.01), where it exhibited comparable performance in the post-NAT cohort (AUC: 0.72, 95% CI: 0.57-0.85, RFS: P < 0.01) and emerged as an independent predictor for RFS (hazard ratio: 2.84, 95% CI: 1.30-6.20). CONCLUSIONS: We identified a novel, noninvasive exo-miRNA signature that robustly predicts recurrence following surgery in patients with PDAC; highlighting its potential clinical impact for optimized patient selection and improved individualized treatment strategies.

Synopsis of a clinical practice guideline for pancreatic ductal adenocarcinoma with peritoneal dissemination in Japan; Japan Peritoneal Malignancy Study Group.

Patients with pancreatic ductal adenocarcinoma (PDAC) with peritoneal dissemination have a dismal prognosis because discontinuation of systemic chemotherapy is required for massive ascites or poor performance status. The natural history, diagnosis and treatment of PDAC with peritoneal dissemination have not been fully investigated. We systematically reviewed published information on the clinical diagnosis and treatment of PDAC with peritoneal dissemination using the PubMed database (2000-2020) and provided recommendations in response to clinical questions. This guideline was created according to the "Minds Clinical Practice Guideline Development Guide 2017". The literature quality and body of evidence were evaluated with the GRADE System and classified into four levels ("strong", "medium", "weak", "very weak"). The strength of each final recommendation was decided by a vote of committee members based on the GRADE Grid method. These guidelines address three subjects: diagnostic, chemotherapeutic, and surgical approaches. They include nine clinical questions and statements with recommendation strengths, evidence levels, and agreement rates, in addition to one "column". This is the English synopsis of the 2021 Japanese clinical practice guideline for PDAC with peritoneal dissemination. It summarizes the clinical evidence for the diagnosis and treatment of PDAC with peritoneal dissemination and provides future perspectives.

ISOlation Procedure vs. conventional procedure during Distal Pancreatectomy (ISOP-DP trial): study protocol for a randomized controlled trial.

BACKGROUND: Radical antegrade modular pancreatosplenectomy (RAMPS) is an isolation procedure in pancreatosplenectomy for pancreatic body/tail cancer. Connective tissues around the bifurcation of the celiac axis are dissected, followed by median-to-left retroperitoneal dissection. This procedure has the potential to isolate blood and lymphatic flow to the area of the pancreatic body/tail and the spleen to be excised. This is achieved by division of the inflow artery, transection of the pancreas, and then division of the outflow vein in the early phases of surgery. In cases of pancreatic ductal adenocarcinoma (PDAC), the procedure has been shown to decrease intraoperative blood loss and increase R0 resection rate by complete clearance of the lymph nodes. This trial investigates whether the isolation procedure can prolong the survival of patients with pancreatic ductal adenocarcinoma who undergo distal pancreatosplenectomy (DPS) compared with those that undergo the conventional approach. METHODS/DESIGN: Patients with PDAC scheduled to undergo DPS are randomized before surgery to undergo either a conventional procedure (arm A) or to undergo the isolation procedure (arm B). In arm A, the pancreatic body, tail, and spleen are mobilized, followed by removal of the regional lymph nodes. The splenic vein is transected at the end of the procedure. The timing of division of the splenic artery (SA) is not restricted. In arm B, regional lymph nodes are dissected, then we transect the root of the SA, the pancreas, then the splenic vein. At the end of the procedure, the pancreatic body/tail and spleen are mobilized and removed. In total, 100 patients from multiple Japanese high-volume centers will be randomized. The primary endpoint is 2-year recurrence-free survival by intention-to-treat analysis. Secondary endpoints include intraoperative blood loss, R0 resection rate, and overall survival. DISCUSSION: If this trial shows that the isolation procedures can improve survival with a similar R0 rate and with a similar number of lymph node dissections to the conventional procedure, the isolation procedure is expected to become a standard procedure during DPS for PDAC. Conversely, if there were no significant differences in endpoints between the groups, it would demonstrate justification of either procedure from surgical and oncological points of view. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000041381 . Registered on 10 August 2020. ClinicalTrials.gov NCT04600063 . Registered on 22 October 2020.

Impact of molecular surgical margin analysis on the prediction of pancreatic cancer recurrences after pancreaticoduodenectomy.

BACKGROUND: Pancreatic cancer is one of the lethal cancers among solid malignancies. Pathological diagnosis of surgical margins is sometimes unreliable due to tissue shrinkage, invisible field cancerization and skipped lesions like tumor budding. As a result, tumor recurrences sometimes occur even from the pathologically negative surgical margins. METHODS: We applied molecular surgical margin (MSM) analysis by tissue imprinting procedure to improve the detection sensitivity of tiny cancerous cells on the surgical specimen surface after pancreatoduodenectomy. Surgical specimens were collected from 45 pancreatic cancer cases who received subtotal stomach preserving pancreatoduodenectomy at Nagoya University Hospital during 2017-2019. Quantitative methylation-specific PCR (QMSP) of the original methylation marker panel (CD1D, KCNK12, PAX5) were performed and analyzed with postoperative survival outcomes. RESULTS: Among 45 tumors, 26 cases (58%) were QMSP-positive for CD1D, 25 (56%) for KCNK12 and 27 (60%) for PAX5. Among the 38 tumors in which at least one of the three markers was positive, CD1D-positive cancer cells, KCNK12-positive cancer cells, and PAX5-positive cancer cells were detected at the surgical margin in 8 cases, 7 cases and 10 cases, respectively. Consequently, a total of 17 patients had at least one marker detected at the surgical margin by QMSP, and these patients were defined as MSM-positive. They were associated with significantly poor recurrence-free survival (p = 0.002) and overall survival (p = 0.005) than MSM-negative patients. Multivariable analysis showed that MSM-positive was the only significant independent factor for worse recurrence-free survival (hazard ratio: 3.522, 95% confidence interval: 1.352-9.179, p = 0.010). On the other hand, a significant proportion of MSM-negative cases were found to have received neoadjuvant chemotherapy (p = 0.019). CONCLUSION: Pancreatic cancer-specific methylation marker panel was established to perform MSM analysis. MSM-positive status might represent microscopically undetectable cancer cells on the surgical margin and might influence the postoperative long-term outcomes.

A Possible Definition of Oligometastasis in Pancreatic Cancer and Associated Survival Outcomes.

BACKGROUND: Oligometastatic cancer (OM) is possibly associated with relatively better survival outcomes. We attempted to identify cases in line with this OM concept. PATIENTS AND METHODS: A total of 130 cases with unresectable metastatic pancreatic cancer underwent non-curative surgery from April 2001 to December 2019. Sites of metastasis, clinicopathological information, and surgical outcomes were collected to formulate a better definition of OM. RESULTS: OM criteria were defined as having metastasis to a single organ, few countable lesions and low serum cancer antigen 19-9 level. The median overall survival after non-curative surgery of OM cases was 13.0 months and was significantly better than that of non-OM cases (8.4 months, p=0.003). CONCLUSION: We propose single-organ metastasis of limited tumor volume (H1 or P1/2 by the Japanese Society of Cancer of the Colon and Rectum classification) and low serum cancer antigen 19-9 level (<2,000 U/ml) as new criteria for defining OM pancreatic cancer.