Ral GTPase promotes metastasis of pancreatic ductal adenocarcinoma via elevation of TGF-ß1 production.

Pancreatic ductal adenocarcinoma (PDAC), caused by activating mutations in K-Ras, is an aggressive malignancy due to its early invasion and metastasis. Ral GTPases are activated downstream of Ras and play a crucial role in the development and progression of PDAC. However, the underlying mechanisms remain unclear. In this study, we investigated the mechanism of Ral-induced invasion and metastasis of PDAC cells using RalGAPß-deficient PDAC cells with highly activated Ral GTPases. Array analysis and ELISA revealed increased expression and secretion of TGF-ß1 in RalGAPß-deficient PDAC cells compared to control cells. Blockade of TGF-ß1 signaling suppressed RalGAPß deficiency-enhanced migration and invasion in vitro and metastasis in vivo to levels similar to controls. Phosphorylation of c-Jun N-terminal kinase, a repressor of TGF-ß1 expression, was decreased by RalGAPß deficiency. These results indicate that Ral contributes to invasion and metastasis of PDAC cells by elevating autocrine TGF-ß1 signaling at least in part by decreasing c-Jun N-terminal kinase activity.

GATA6 and CK5 Stratify the Survival of Patients With Pancreatic Cancer Undergoing Neoadjuvant Chemotherapy.

Relevant protein expression of GATA6, CK5, vimentin, and mucins using immunohistochemistry was assessed for predicting the prognosis of and chemotherapy efficacy in patients with pancreatic cancers (PCs). The protein expression was examined in 159 PCs resected after neoadjuvant chemotherapy (NAC-PCs) and compared with that of 120 matched biopsy specimens taken before NAC. KRAS mutations were assessed by digital PCR. NAC-PCs were classified by GATA6 expression initially and CK5 expression subsequently into 4 types: classical-type (n = 22) with GATA6-high (≥50%)/CK5-low (<10%) PCs; hybrid-type (n = 45) with GATA6-high/CK5-high (≥10%) PCs; basal-like-type (n = 53) with GATA6-low (<50%)/CK5-high (≥30%) PCs; and null-type (n = 39) with GATA6-low/CK5-low (<30%) PCs, which resulted in clear stratification of patient prognosis. The classical-type was associated with the most favorable prognosis, whereas the null-type was associated with the worst prognosis (multivariate hazard ratio: 3.56; 95% CI, 1.63-7.77; P = .0015). The hybrid and basal-like types correlated with in-between levels of prognosis. The risk of hepatic recurrence was lower in the classical-type than in null (multivariate odds ratio [mOR]: 0.18; 95% CI, 0.04-0.96; P = .0449) and basal-like (mOR: 0.24; 95% CI, 0.05-1.16; P =.0750) types. By contrast, the risk of locoregional recurrence was higher in the classical-type than in the basal-like-type (mOR: 5.03; 95% CI, 1.20-21.1; P = .0272). The hybrid-type was subclassified into transition and coexpression patterns with different gastric mucin expression levels. High levels of vimentin (≥10%, n = 30) in pre-NAC-PC tissues was associated with poor prognosis (P = .0256). Phenotypic transitions between pre-NAC and post-NAC-PCs were common (73/120; 61%). PCs with NAC regression grades 2 and 3 showed a transition to poorer prognostic phenotypes (P = .0497). KRAS mutations were not associated with these phenotypes. In conclusion, GATA6 and CK5 immunohistochemical expression phenotypes may stratify the survival of patients with NAC-PCs and reflect post-NAC phenotypic transitions associated with poor prognosis. Prompt evaluation of immunohistochemical phenotypes may contribute to designing a precision therapeutic strategy for patients with PCs.

Reduced expression of phosphorylated ataxia-telangiectasia mutated gene is related to poor prognosis and gemcitabine chemoresistance in pancreatic cancer.

BACKGROUND: Loss of expression of the gene ataxia-telangiectasia mutated (ATM), occurring in patients with multiple primary malignancies, including pancreatic cancer, is associated with poor prognosis. In this study, we investigated the detailed molecular mechanism through which ATM expression affects the prognosis of patients with pancreatic cancer. METHODS: The levels of expression of ATM and phosphorylated ATM in patients with pancreatic cancer who had undergone surgical resection were analyzed using immunohistochemistry staining. RNA sequencing was performed on ATM-knockdown pancreatic-cancer cells to elucidate the mechanism underlying the invlovement of ATM in pancreatic cancer. RESULTS: Immunohistochemical analysis showed that 15.3% and 27.8% of clinical samples had low levels of ATM and phosphorylated ATM, respectively. Low expression of phosphorylated ATM substantially reduced overall and disease-free survival in patients with pancreatic cancer. In the pancreatic cancer cell lines with ATM low expression, resistance to gemcitabine was demonstrated. The RNA sequence demonstrated that ATM knockdown induced the expression of MET and NTN1. In ATM knockdown cells, it was also revealed that the protein expression levels of HIF-1α and antiapoptotic BCL-2/BAD were upregulated. CONCLUSIONS: These findings demonstrate that loss of ATM expression increases tumor development, suppresses apoptosis, and reduces gemcitabine sensitivity. Additionally, loss of phosphorylated ATM is associated with a poor prognosis in patients with pancreatic cancer. Thus, phosphorylated ATM could be a possible target for pancreatic cancer treatment as well as a molecular marker to track patient prognosis.

Negative prognostic impact of sarcopenia before and after neoadjuvant chemotherapy for pancreatic cancer.

OBJECTIVES: To elucidate the prognostic impact of sarcopenia before and after neoadjuvant chemotherapy (NAC) for pancreatic cancer (PC). METHODS: We retrospectively studied 75 consecutive PC patients who underwent neoadjuvant gemcitabine plus S-1 combination therapy followed by pancreatectomy between 2008 and 2016. According to the skeletal muscle volume index (SMI), the patients were divided into the muscle attenuation group (MAG) and normal group (NG) before or after NAC. Prognostic factors for overall survival (OS) were analyzed by Cox proportional hazards models. RESULTS: The MAG showed significantly poorer OS than the NG before and after NAC. Pre-NAC, median OS was 20.0 months in the MAG versus 49.0 months in the NG (p = 0.006). Post-NAC, median OS was 21.3 months in the MAG versus 48.8 months in the NG (p = 0.014). Multivariate analysis, excluding muscle attenuation after NAC because of confounding factors and lower hazard ratio (2.08, 95% confidence interval: 1.14-3.78, p = 0.016) than that before NAC (2.14, 1.23-3.70, p = 0.007) by univariate analysis, revealed the following independent prognostic factors: muscle attenuation pre-NAC (2.25, 1.26-4.05, p = 0.007); borderline resectability (1.96, 1.04-3.69, p = 0.038); operative blood loss (2.60, 1.38-4.88, p = 0.003); and distant metastasis (3.31, 1.40-7.82, p = 0.006). CONCLUSIONS: Sarcopenia before and after NAC for PC is suggested to be a poor prognostic factor, with a stronger impact before than after NAC.

Chronic Glucocorticoid Use is a Potential Risk Factor for Delayed Pancreatic Fistula after Laparoscopic Distal Pancreatectomy: A Retrospective Analysis.

Pancreatic fistula is a potentially morbid complication after distal pancreatectomy. Chronic glucocorticoid use is one of the risk factors for pancreatic fistula in pancreaticoduodenectomy, though it has not been reported in distal pancreatectomy. We explored whether chronic glucocorticoid use can be a risk factor for pancreatic fistula in distal pancreatectomy. We reviewed 408 consecutive patients who underwent elective distal pancreatectomy from 2011 to 2021. We evaluated two kinds of pancreatic fistula (postoperative pancreatic fistula and delayed pancreatic fistula). We defined delayed pancreatic fistula as a patient who was re-admitted for pancreatic fistula after the first discharge from the hospital. Preoperative characteristics and postoperative outcomes were analyzed. Two hundred sixty-seven patients underwent open distal pancreatectomy, while 141 patients had laparoscopic distal pancreatectomy. A comparison of patient with and without chronic glucocorticoid use showed that only patients with chronic glucocorticoid use developed delayed pancreatic fistula (0% vs. 16.7%; p < 0.001). In addition, delayed pancreatic fistula occurred in only laparoscopic distal pancreatectomy patients with chronic glucocorticoid use (0% vs. 25.0%; p < 0.001). Although sample size is small, it is reasonable to presume that chronic glucocorticoid use is a potential risk factor for delayed pancreatic fistula in laparoscopic distal pancreatectomy.

[A Case of an Elderly Patient Who Underwent Conversion Resection for Pancreatic Cancer with Positive Peritoneal Cytology].

We report a case of an elderly patient, 82 years-old, with initially-unresectable pancreatic head cancer, who successfully underwent complete resection of the primary lesion after systemic chemotherapy for 6 months. The patient had a history of pancreatic body-tail resection for intraductal papillary mucinous carcinoma in 2005. In 2020, a routine examination revealed an increased CA19-9 value of 1,958 U/mL and showed a pancreatic head tumor of 35 mm on CT images. Finally, the tumor was pathologically diagnosed as pancreatic cancer by a biopsied sample. Although CT images showed no distant metastasis, peritoneal lavage cytology was indicated as positivity(H0P0CY1)in the staging laparoscopy. We implanted a peritoneal port and introduced systemic chemotherapy of gemcitabine and nab-paclitaxel combination therapy. This treatment for 6 months induced tumor shrinkage to 30 mm on the CT image, normalized CA19-9 value to 22.6 U/mL, and negative cytology in the collected lavage fluid from the peritoneal port. The patient's general condition was maintained even after the chemotherapy and the lavage cytology was pathologically diagnosed as negative(H0P0CY0)in the repeated staging laparoscopy, therefore we decided to perform pancreaticoduodenectomy as a conversion surgery. The patient was discharged on the 21st postoperative day with an uneventful course and underwent adjuvant chemotherapy of S-1 for 6 months. No recurrence was found in 8 months after the surgery. In such a case of the selected elderly patient with a maintained general condition, it is feasible to undergo multimodal treatments including conversion surgery for an initially-unresectable pancreatic cancer with positive peritoneal cytology.

What is the impact of zinc deficiency for pancreatectomies in patients with pancreatic ductal adenocarcinoma?

BACKGROUND: and purpose: Zinc is an essential element for human health and plays an important role in metabolic, immunological and other biological processes. The present study was conducted to investigate the association between zinc deficiency (ZD) and the perioperative clinical course in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Of 216 patients with PDAC who underwent elective pancreatectomy between 2013 and 2017 at our institution, 206 patients with sufficient clinical data were retrospectively reviewed. The perioperative variables were compared and the risk factors associated with infectious complications were identified. RESULTS: ZD was preoperatively present in 36 (17.5%) of 206 patients with PDAC. In the patients of the ZD group, a higher proportion of males, higher preoperative modified Glasgow prognostic scores, a higher neutrophil-to-lymphocyte ratio, and a higher occurrence of postoperative infectious complications after pancreatectomy were observed, compared to the non-ZD group. By a univariate analysis, three risk factors were significantly associated with infectious complications after pancreatectomy: ZD (vs non-ZD: p = 0.002), serum albumin <3.5 g/dl (vs ≥ 3.5 g/dl: p = 0.005), and the procedure of pancreaticoduodenectomy (vs others: p = 0.013). By multivariate logistic regression analysis, the occurrence of infectious complications was significantly associated with ZD (OR 3.430, 95%CI 1.570 to 7.490, p = 0.002) and the procedure of pancreaticoduodenectomy (OR 2.030, 95%CI 1.090 to 3.770, p = 0.025). CONCLUSIONS: The current study newly demonstrated that ZD could serve as a preoperative predictor of infectious complications after pancreatectomies in the patients with PDAC.

Laparoscopic and robot-assisted surgery for adult congenital biliary dilatation achieves favorable short-term outcomes without increasing the risk of late complications.

PURPOSE: Minimally invasive surgery (MIS) is the optimal treatment for congenital biliary dilatation (CBD), but few studies on adults have been reported. We compared the postoperative outcomes of MIS with those of open surgery (OS) in adult patients with CBD. METHODS: The subjects of this retrospective study were 36 adult patients who underwent surgery for CBD. We compared the postoperative outcomes of 20 patients who underwent laparoscopic (n = 15) or robotic (n = 5) surgery with those of 16 patients who underwent OS. RESULTS: MIS was associated with a significantly higher rate of type I (p < 0.001), significantly less blood loss (p < 0.001), a significantly lower rate of internal stents (p = 0.048), significantly longer operation times (p = 0.009), and a significantly shorter postoperative hospital stay (p = 0.007) than OS. The postoperative outcomes of MIS for type I CBD were similar to those of the whole cohort. There were no significant differences in late complications between the groups. The robotic procedure had a significantly shorter operative time than laparoscopic surgery for hepaticojejunostomy (HJ; p = 0.029). CONCLUSIONS: MIS achieved favorable short-term outcomes without compromising mid-term outcomes compared to OS and is appropriate for adult patients with CBD. Robotic HJ may be more ideal than its laparoscopic counterpart.

Ral GTPase-activating protein regulates the malignancy of pancreatic ductal adenocarcinoma.

The small GTPases RalA and RalB are members of the Ras family and activated downstream of Ras. Ral proteins are found in GTP-bound active and GDP-bound inactive forms. The activation process is executed by guanine nucleotide exchange factors, while inactivation is mediated by GTPase-activating proteins (GAPs). RalGAPs are complexes that consist of a catalytic α1 or α2 subunit together with a common ß subunit. Several reports implicate the importance of Ral in pancreatic ductal adenocarcinoma (PDAC). However, there are few reports on the relationship between levels of RalGAP expression and malignancy in PDAC. We generated RalGAPß-deficient PDAC cells by CRISPR-Cas9 genome editing to investigate how increased Ral activity affects malignant phenotypes of PDAC cells. RalGAPß-deficient PDAC cells exhibited several-fold higher Ral activity relative to control cells. They had a high migratory and invasive capacity. The RalGAPß-deficient cells grew more rapidly than control cells when injected subcutaneously into nude mice. When injected into the spleen, the RalGAPß-deficient cells formed larger splenic tumors with more liver metastases, and unlike controls, they disseminated into the abdominal cavity. These results indicate that RalGAPß deficiency in PDAC cells contributes to high activities of RalA and RalB, leading to enhanced cell migration and invasion in vitro, and tumor growth and metastasis in vivo.

MicroRNA-593-3p Expression in Peritoneal Lavage Fluid as a Prognostic Marker for Pancreatic Cancer Patients Undergoing Staging Laparoscopy.

BACKGROUND: Some presumed resectable pancreatic cancer patients harbor radiographically occult metastases that are incidentally identified at the time of abdominal exploration. This study aims to identify novel diagnostic or predictive microRNA (miRNA) markers for subclinical peritoneal dissemination in patients with pancreatic cancer undergoing abdominal exploration. METHODS: Peritoneal lavage fluid samples were harvested from 74 patients with pancreatic cancer at the time of staging laparoscopy. Microarray analysis was performed using peritoneal lavage fluids with positive and negative cytology. Candidate microRNA expression was quantified and validated by droplet-digital PCR assays. RESULTS: In the miRNA array analysis, miR-593-3p showed significant upregulation in peritoneal lavage fluids with positive cytology. Of the 74 patients validated, peritoneal lavage fluids with positive cytology had significantly higher expression of miR-593-3p than those with negative cytology (P < 0.001). Even in cases with no peritoneal dissemination and negative cytology, multivariate analysis revealed that elevated miR-593-3p expression was significantly correlated with worse overall survival than those with low expression (hazard ratio: 3.474, P = 0.042). Of the 48 patients who underwent pancreatectomy, multivariate analysis also demonstrated that higher expression of miR-593-3p in peritoneal lavage was the only significant poor prognostic marker influencing both overall survival (hazard ratio: 23.38, P = 0.005) and recurrence-free survival (hazard ratio: 5.700, P = 0.002). CONCLUSIONS: Elevated miR-593-3p expression in peritoneal lavage suggests the presence of subclinical micrometastasis even in cases with localized pancreatic cancer, and miR-593-3p could be a useful prognostic predictor for pancreatic cancer patients undergoing staging laparoscopy.

Preceding Systemic Chemotherapy for Patients with Pancreatic Ductal Adenocarcinoma with Positive Peritoneal Cytology Provides Survival Benefit Compared with Up-Front Surgery.

BACKGROUND: The significance of surgical resection in pancreatic ductal adenocarcinoma (PDAC) with positive peritoneal cytology (PPC) is controversial. This study aimed to evaluate whether preceding chemotherapy could be beneficial for patients with PDAC with PPC. METHODS: Between 2017 and 2019, 34 consecutive PDAC patients diagnosed with PPC without distant metastasis were retrospectively reviewed. Twenty-three patients did not receive neoadjuvant treatment (NAT) and 11 received NAT. All patients received systemic chemotherapy after PPC was confirmed, and they underwent surgical resection if PPC turned negative. The treatment course, ratio of conversion surgery (CS), and prognosis were evaluated. Moreover, the prognosis of PPC patients who underwent up-front surgery without NAT between 2003 and 2016 was analyzed as a comparative cohort. RESULTS: The median survival time (MST) of the patients without NAT was 31.4 months. CS was performed in 52.2% of the patients. Patients who underwent CS had better prognoses than those who did not undergo CS (p = 0.005). The CS rate was significantly higher in resectable PDAC (78.5%) than in borderline/unresectable PDAC (11.1%) (p = 0.002). The prognosis of patients with resectable PDAC was improved with preceding chemotherapy compared with up-front surgery (MST 13.0 months; p = 0.016). After NAT, the CS rate was low (27.3%), and the MST was only 14.1 months. CONCLUSIONS: As an initial treatment for PDAC patients with PPC, chemotherapy may lead to a favorable prognosis. Especially, resectable PDAC is associated with a greater chance of improved prognosis. Future studies are required to ascertain whether up-front surgery or preceding chemotherapy should be performed for these patients.

Silencing of LRRFIP1 enhances the sensitivity of gemcitabine in pancreatic cancer cells by activating JNK/c-Jun signaling.

BACKGROUND: The epithelial-mesenchymal transition (EMT) in cancer cells has been shown to closely associate with the survival and drug resistance of cancer cells. We recently provided evidence that Wnt signal activator leucine-rich repeat in flightless-1-interacting protein 1 (LRRFIP1) regulates EMT in pancreatic cancer. LRRFIP1 silencing inhibits the translocation of ß-catenin to the nucleus, which led to reverse EMT in cancer cells. It was suggested that LRRFIP1 was implicated in gemcitabine sensitivity by regulating EMT signaling. METHODS: Gemcitabine chemosensitivity was investigated in LRRFIP1-knockdown pancreatic cancer cells (PANC-1 and MIA Paca-2). In addition, the effects of LRRFIP1 knockdown on JNK/SAPK (stress activated-protein kinase) signaling and apoptosis were evaluated. RESULTS: LRRFIP1 silencing accelerates gemcitabine-induced caspase activity and cell death in pancreatic cancer cells. It was also revealed that gemcitabine-induced phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun were increased in LRRFIP1 knockdown cells. The activation of JNK/c-Jun in LRRFIP1-knockdown cells was significantly diminished by the inhibition of Rac activity. It was confirmed that the acquisition of gemcitabine sensitivity by LRRFIP1 silencing largely depends on the stimulation of JNK/SAPK (stress activated-protein kinase) signaling. CONCLUSIONS: Our findings suggest that reversing EMT and transient activation of JNK might be essential for the gemcitabine sensitivity in LRRFIP1 knockdown pancreatic cancer cells. Our discoveries highlight the potential role of LRRFIP1 in the chemosensitivity related to the regulation of EMT signaling.

Prognostic value of an inflammation-based nutritional score for patients with initially unresectable pancreatic adenocarcinoma undergoing conversion surgery following chemo-/radiotherapy.

PURPOSE: To clarify the prognostic value of the preoperative nutrition status of patients undergoing conversion surgery (CS) for initially unresectable pancreatic adenocarcinoma (UR-PA). METHODS: The subjects of this retrospective study were 41 consecutive patients with initially UR-PA treated with chemo-/radiotherapy and subsequent CS between 2007 and 2014, at Tohoku University Hospital. The preoperative Glasgow Prognostic Score (GPS) was 0, conveying normal nutrition, in 25 patients (N group) and 1-2, conveying malnutrition, in 16 patients (M group). The clinicopathological factors influencing overall survival were defined by uni- and multivariate analyses. RESULTS: The M group had a significantly worse prognosis than the N group (median overall survival (mOS) 9.6 vs 40.7 months, p = 0.001). Multivariate analysis identified a GPS of 1-2 as an independent predictor of worse prognosis [hazard ratio (HR)3.437, p = 0.032], followed by CA19-9 elevation before CS (HR4.089, p = 0.012) and pathological lymph node metastases (HR2.314, p = 0.046). Patients who maintained a favorable nutritional status (GPS 0) during preoperative treatment had a significantly better prognosis, whereas those whose nutritional status deteriorated (elevated to GPS 1-2) had poorer survival (mOS 40.7 vs. 9.7 months, p = 0.003) CONCLUSION: Preoperative malnutrition status (GPS 1-2) is considered an independent predictor of a worse prognosis for patients undergoing CS for initially UR-PA.

Liver resections in patients with prior bilioenteric anastomosis are predisposed to develop organ/space surgical site infections and biliary leakage: results from a propensity score matching analysis.

PURPOSE: The aims of this study were to compare the perioperative outcomes after hepatectomy with prior bilioenteric anastomosis to those without prior anastomosis, and to elucidate the mechanisms and preventative measures of its characteristic complications. METHODS: The demographic data and perioperative outcomes of 525 hepatectomies performed between January 2007 and December 2018, including 40 hepatectomies with prior bilioenteric anastomosis, were retrospectively analyzed. RESULTS: A propensity score matching analysis demonstrated that hepatectomies with prior bilioenteric anastomosis were associated with a higher frequency of major complications (p = 0.015), surgical site infection (p = 0.005), organ/space surgical site infection (p = 0.003), and bile leakage (p = 0.007) compared to those without. A multivariate analysis also elucidated that prior bilioenteric anastomosis was one of the independent risk factors of organ/space surgical site infection. In the patients with prior bilioenteric anastomosis, bile leakage was associated with organ/space surgical site infection at a significantly higher rate than those without prior bilioenteric anastomosis (p < 0.001). CONCLUSIONS: Prior bilioenteric anastomosis is a strong risk factor for organ/space surgical site infections, which might be induced by bile leakage. To prevent infectious complications after hepatectomy with prior bilioenteric anastomosis, meticulous liver transection to reduce bile leakage rate is thus considered to be mandatory.

Staging laparoscopy is mandatory for the treatment of pancreatic cancer to avoid missing radiologically negative metastases.

PURPOSE: Staging laparoscopy is considered useful for determining treatment plans for advanced pancreatic cancer. However, the indications for staging laparoscopy are not clear. This study aimed to evaluate the safety of staging laparoscopy and its usefulness for detecting distant metastases in patients with pancreatic cancer. METHODS: A total of 146 patients with pancreatic cancer who underwent staging laparoscopy between 2013 and 2019 were analyzed. Staging laparoscopy was performed in all pancreatic cancer patients in whom surgery was considered possible. RESULTS: In this cohort, 42 patients (29%) were diagnosed with malignant cells on peritoneal lavage cytology, 9 (6%) had peritoneal dissemination, and 11 (8%) had liver metastases. A total of 48 (33%) had radiologically negative metastases. On a multivariate analysis, body and tail cancer [odds ratio (OR) 5.00, 95% confidence interval (CI) 2.15-11.6, p < 0.001], high CA19-9 level [OR 4.04, 95% CI 1.74-9.38, p = 0.001], and a resectability status of unresectable (OR 2.31, 95% CI 1.03-5.20, p = 0.04) were independent risk factors for radiologically negative metastases. CONCLUSIONS: Staging laparoscopy can be safely performed and is useful for the diagnosis of radiologically negative metastases. Staging laparoscopy should be routinely performed for the accurate diagnosis of pancreatic cancer patients before pancreatectomy and/or local treatment, such as radiotherapy.

Increased neutrophil-lymphocyte ratio predicts recurrence in patients with well-differentiated pancreatic neuroendocrine neoplasm based on the 2017 World Health Organization classification.

BACKGROUND: The prognostic values of inflammation-based markers in well-differentiated pancreatic neuroendocrine neoplasms, diagnosed according to the new 2017 World Health Organization classification, have remained unclear. Therefore, we assessed the ability to predict the recurrence of such markers after curative resection in patients with these neoplasms. METHODS: Circulating/systemic neutrophil-lymphocyte, monocyte-lymphocyte, platelet-lymphocyte, and platelet-white cell ratios were evaluated in 120 patients who underwent curative resection for well-differentiated pancreatic neuroendocrine neoplasms without synchronous distant metastasis between 2001 and 2018. Recurrence-free-survival and overall survival were compared using Kaplan-Meier analysis and log-rank tests. Univariate or multivariate analyses, using a Cox proportional hazards model, were used to calculate hazard ratios with 95% confidence intervals. RESULTS: Univariate analysis demonstrated that preoperative neutrophil-lymphocyte ratio, tumor size, European Neuroendocrine Tumor Society TMN classification, 2017 World Health Organization classification, and venous invasion were associated with recurrence. The optimal preoperative neutrophil-lymphocyte ratio cut-off value was 2.62, based on receiver operating characteristic curve analysis. In multivariate analysis, a higher preoperative neutrophil-lymphocyte ratio (HR = 3.49 95% CI 1.05-11.7; P = 0.042) and 2017 World Health Organization classification (HR = 8.81, 95% CI 1.46-168.2; P = 0.015) were independent recurrence predictors. CONCLUSIONS: The circulating/systemic neutrophil-lymphocyte ratio is a useful and convenient preoperative prognostic marker of recurrence in patients with well-differentiated pancreatic neuroendocrine neoplasm based on the 2017 World Health Organization classification.

[A Successful Case of Pancreaticoduodenectomy after Neoadjuvant Therapy for Pancreatic Head Cancer with Acute Pancreatitis Due to Iatrogenic Injury of the Pancreatic Duct].

A 64-year-old woman was referred to our hospital for treatment of pancreatic head cancer with acute pancreatitis due to iatrogenic injury of the pancreatic duct during endoscopic retrograde cholangiopancreatography. In addition to a 28 mm pancreatic head tumor, soft tissue shadow and fluid collection surrounding the superior mesenteric artery(SMA)due to pancreatitis were observed in the abdominal CT scan. The tumor was histologically diagnosed as adenocarcinoma by endoscopic ultrasound-guided fine needle aspiration. Neoadjuvant chemotherapy with gemcitabine and S-1 was performed to control the progression of the pancreatic cancer and improve the inflammatory changes for reduction of the operative risk. After 2 courses of neoadjuvant chemotherapy, abdominal CT scan revealed stable disease according to the Response Evaluation Criteria in Solid Tumors and attenuation of the inflammatory changes surrounding the SMA. Then, subtotal stomach- preserving pancreaticoduodenectomy was performed without the difficulty of peeling around the SMA in spite of the old inflammatory changes. Histological examination of the resected specimen showed R0 resection. The patient was discharged 18 days after surgery without any complications and is surviving 9 months postoperatively without any recurrence. Neoadjuvant chemotherapy was helpful for disease control and improvement of the inflammatory changes.

[Reconstruction of Portal Vein and Superior Mesenteric Vein Using Superficial Femoral Vein Graft in Surgical Resection of Pancreatic Head Cancer-A Case Report].

We report a case of reconstruction of the portal vein(PV)and superior mesenteric vein(SMV)using a superficial femoral vein graft in total pancreatectomy for pancreatic cancer. A 62-year-old man visited a previous hospital due to epigastric pain and bilirubinuria and was diagnosed with pancreatic cancer. The patient was referred to our hospital for further examination and treatment. Abdominal CT scan revealed a 30 mm pancreatic head tumor with an abutment of almost 360 degrees around the superior mesenteric artery(SMA)and extensive involvement from the PV to branches of the SMV, radiologically classified as locally advanced unresectable pancreatic cancer. Although gemcitabine plus nab-paclitaxel combination therapy(GnP)was performed, the patient developed drug-induced lung injury after 3 courses. GnP was stopped, and chemoradiation therapy with S-1 was performed. After chemoradiation therapy, the tumor shrank to 14 mm, while no change of the abutment around SMA was observed. After 8 months from the initial diagnosis, total pancreatectomy and resection of the PV/SMV were performed. Approximately 70 mm of the PV/SMV was surgically removed and was reconstructed using a graft from the left superficial femoral vein in consideration of the length and diameter. Although delayed gastric emptying was postoperatively observed, the patient was discharged 39 days after operation, then received adjuvant therapy with S-1. The patient is alive without recurrence and the patency of PV/SMV was well maintained.

Prognostic impact of intraoperative peritoneal cytology after neoadjuvant therapy for potentially resectable pancreatic cancer.

BACKGROUND: Neoadjuvant therapy (NAT) is considered a potential approach to improve survival for patients with pancreatic adenocarcinoma (PA). The objective of this study was to identify the clinical implications of washing peritoneal cytology (CY) status after NAT. METHODS: Between 2005 and 2016, 151 consecutive patients with resectable (R)/borderline resectable (BR) PA underwent NAT with intention of subsequent resection at our institution. Of them, 13 and 123 patients underwent pancreatectomies with positive (CY+) and negative (CY-) cytology, respectively, while the remaining 15 patients did not undergo resection due to gross metastases at laparotomy. The clinicopathological factors influencing overall survival were clarified by the uni- and multivariate analyses. RESULTS: The postoperative overall survival (OS) and disease-free survival (DFS) were markedly worse in patients who underwent resection with CY+, compared with those who were CY- (median OS, 14.8 m vs 30.8 m, p = 0.026, and median DFS 6.0 m vs 15.1 m, p = 0.008). According to the resectability by NCCN guidelines, CY+ indicates worse prognosis than CY- in R-PA patients (mOS: 30.1 m vs 71.1 m: p = 0.080). Similarly, in BR-PA patients, CY+ showed the significantly worse prognosis than CY- (mOS: 13.8 m vs 24.5 m: p = 0.048), which prognosis is comparable with patients who did not undergo resection. The multivariate analysis revealed that resectability, CY status and the induction of adjuvant therapy were significant predictors of postoperative OS (p = 0.007: Hazard ratio 2.264, 0.040:2.094 and 0.002:3.246, respectively). CONCLUSIONS: CY+ is a significant predictor of poorer prognosis in PA patients after NAT. The subsequent pancreatectomies with CY+ after NAT do not contribute to prolonged survival.

The superior approach with the stomach roll-up technique improves intraoperative outcomes and facilitates learning laparoscopic distal pancreatectomy: a comparative study between the superior and inferior approach.

PURPOSE: We introduced a superior approach and a unique technique to retract the stomach, called the "stomach roll-up technique", to standardize laparoscopic distal pancreatectomy and increase educational effectiveness. The aim of this study was to evaluate the clinical outcomes of these procedures. METHODS: Forty-five patients who underwent laparoscopic distal pancreatectomy by surgeons-in-training between January 2015 and December 2018 were included. Twenty laparoscopic distal pancreatectomies were performed using the inferior approach, and 25 procedures were performed using the superior approach. The stomach roll-up technique was used in all cases. The perioperative outcomes were retrospectively analyzed. RESULTS: Compared with the inferior approach, the superior approach was associated with a significantly shorter operation time (p < 0.001) and lower estimated blood loss (p = 0.011), and these differences were not affected by the exclusion of cases with conversion or concomitant procedures. In the univariate analysis adjusted for other covariates, a lower body mass index (p = 0.045), pancreatic tail tumor (p = 0.0178) and the superior approach (p = 0.0176) were significantly associated with a shorter operation time. CONCLUSION: The superior approach with the stomach roll-up technique is simple and will aid in educating surgeons on performing laparoscopic distal pancreatectomy.