Surgical site infection after laparoscopic resection of colorectal cancer is associated with compromised long-term oncological outcome.

BACKGROUND: We evaluated the influence of infectious complications, particularly surgical site infection (SSI), on long-term oncological results after elective laparoscopic resection of colorectal cancer. METHODS: A total of 199 patients who underwent laparoscopic elective resection with negative resection margins for stage I-III colorectal cancer were retrospectively examined. The postoperative course was recorded based on hospital records, and cancer relapse was diagnosed based on radiological or pathological findings under a standardized follow-up program. The severity of complications was graded using Clavien-Dindo (CD) classification. RESULTS: SSI was found in 25 patients (12.6%), with 12 (6.0%) showing anastomotic leak. The postoperative relapse-free survival (RFS) rate was significantly lower in patients with SSI (49.2%) than in patients without SSI (87.2%, P<0.001). Differences in RFS were found after both colectomy and rectal resection (P<0.001 and P<0.001, respectively). RFS did not differ between patients who had major SSI CD (grade III) and those who had minor SSI CD (grades I or II). Multivariate Cox regression analysis identified the occurrence of SSI and pathological stage as independent co-factors for RFS (P<0.001 and P=0.003). CONCLUSION: These results suggest that postoperative SSI compromises long-term oncological results after laparoscopic colorectal resection. Further improvements in surgical technique and refinements in perioperative care may improve long-term oncological results.

Sphingosine-1-phosphate Receptor-1 Promotes Vascular Invasion and EMT in Hepatocellular Carcinoma.

BACKGROUND: It remains unknown whether epithelial-mesenchymal transition (EMT)-mediated vascular invasion and cancer stemness are associated with sphingosine-1-phosphate receptor-1 (S1PR1) expression in human hepatocellular carcinoma (HCC). The aim of this study was to investigate the correlation between S1PR1 expression and prognosis of patients with primary HCC and to define the potential of S1PR as a therapeutic target. MATERIALS AND METHODS: We investigated 108 patients who underwent primary surgical resection for HCC treatment. Expression of S1PR1 and EMT markers was analyzed to predict prognosis of patients with HCC. Furthermore, three-dimensional organotypic culture, anoikis assay, and cell invasion were performed to validate the association of S1PR1 with EMT and cancer stemness. RESULTS: Among patients with HCC, the high S1PR1 expression group had significantly shorter overall survival than the low expression group. Moreover, high S1PR1 expression was significantly associated with shorter recurrence-free survival, increased risk of portal and hepatic vein invasion, and intrahepatic metastasis. Multivariate analyses revealed that S1PR1 overexpression was an independent prognostic factor in patients with HCC. S1PR1 overexpression positively correlated with vimentin and MMP-9 expression and negatively correlated with E-cadherin. In addition, S1PR1 overexpression induced EMT and enhanced tumor invasion and cancer stemness. CONCLUSIONS: S1PR1 overexpression, via EMT-induced vascular invasion and increased cancer stem cell properties, establishes a metastatic niche, enhances the capacity of hematogenous metastasis, and associates with poor outcomes in patients with HCC. Hence, S1PR1 may serve as a therapeutic target for patients with HCC with vascular invasion.

Successful salvage treatment with paclitaxel, ifosfamide, and cisplatin in a patient with methotrexate-resistant gestational trophoblastic neoplasia who developed hypersensitivity reaction to etoposide.

We report a 34-year-old woman with recurrent gestational trophoblastic neoplasia (GTN) who showed hypersensitivity to etoposide. Computed tomography (CT) revealed a 32-mm solid mass in the right lung and a 101-mm cystic mass with solid components in the left side of the liver. The patient's serum human chorionic gonadotropin (HCG) level was 689 439 mIU/mL. After eight cycles of combined paclitaxel 175 mg/m2 on day 1, ifosfamide 1 g/m2 on days 2-5, and cisplatin 20 mg/m2 on days 2-5 (TIP) every 3 weeks, the serum HCG level decreased to 2.4 mIU/mL. CT scan revealed disappearance of the lung tumor and significant reduction in the solid components of the liver tumor. Then, left hemihepatectomy was performed. After 3 months, there was no evidence of the disease, and the serum HCG level normalized. Thus, TIP chemotherapy, followed by residual mass resection, might be effective for methotrexate-resistant GTN.

Early detection of infectious complications using C-reactive protein and the procalcitonin levels after laparoscopic colorectal resection: a prospective cohort study.

PURPOSE: The predictive values of the C-reactive protein (CRP) and procalcitonin (PCT) levels for postoperative infectious complications were investigated in patients who underwent elective laparoscopic resection of colorectal cancer. METHODS: A total of 154 consecutive patients who underwent elective laparoscopic resection for colorectal cancer (CRC) were prospectively studied. The CRP and PCT levels on the first postoperative day (POD1) and the fourth postoperative day (POD4) were measured. Any correlations between the CRP and PCT levels on POD1 and POD4 with the occurrence of infectious complications were examined. RESULTS: Infectious complications occurred in 18 (11.7%) patients. CRP on POD1 and CRP and PCT on POD4 were significantly higher in patients who developed infectious complications than in those who did not. The areas under the receiver operating characteristic curves of CRP on POD1 and CRP and PCT on POD4 were 0.597, 0.763 and 0.768, respectively. The cut-off values of CRP and PCT levels on POD4 were 14.33 mg/dl and 0,264 ng/ml, respectively. Whereas the positive predictive value of an elevated CRP level was high, the negative predictive value of an elevated PCT was high. CONCLUSION: The CRP and PCT levels on POD4 are both considered to be useful for the early detection of infectious complications after laparoscopic resection of CRC.

High expression of Krüppel-like factor 5 is associated with poor prognosis in patients with colorectal cancer.

Krüppel-like factor 5 (KLF5) plays an oncogenic role and has diverse functions in cancer cells. However, correlation between KLF5 and clinical outcome has not been determined in patients with colorectal cancer and colorectal liver metastasis. Herein, we analyzed 65 patients with colorectal cancer who developed colorectal liver metastasis. Clinical effects were assessed through immunohistochemical analysis of primary colorectal cancer lesions and metastatic liver lesions. High expression of KLF5 in these tissues correlated with the presence of vascular invasion, elevated serum carbohydrate antigen 19-9 levels, large diameters of metastatic liver tumors, and poor prognosis following surgery. Multivariate analyses revealed that high expression of KLF5 was an independent prognostic factor. Increased expression of KLF5 in both colorectal cancer primaries and colorectal liver metastasis was significantly associated with shorter overall survival time and time to surgical failure. Krüppel-like factor 5 expression positively correlated with Ki-67 and c-Myc expression in colorectal cancer tissues. In vitro experiments with colon cancer cell lines showed that siRNA knockdown of KLF5 inhibited cell proliferation. Western blot analyses revealed that knockdown of KLF5 expression reduced cyclin D1 and c-Myc expression. It also impaired the stem cell-like properties of cancer cells in tumorsphere formation assays. Furthermore, anoikis assay indicated that KLF5 contributed to anoikis resistance. High KLF5 expression is associated with poor prognosis in patients with colorectal cancer and liver metastasis by promoting cell proliferation and cancer stem cell-like properties.

The Expression of Yes-Associated Protein (YAP) Maintains Putative Cancer Stemness and Is Associated with Poor Prognosis in Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is resistant to most chemotherapeutic agents. Yes-associated protein (YAP) is related to tumor progression; however, its role in ICC remains unknown. We investigated the mechanism underlying YAP-mediated cancer progression by focusing on the property of cancer stem cells (CSCs) in ICC. Immunohistochemistry results revealed the positive YAP expression in 37 of 52 resected ICC cases. Those with positive YAP expression showed poor prognosis in Kaplan-Meier analysis (P = 0.023). YAP expression was associated with vimentin and the putative CSC marker, hepatic oval cell marker 6 (OV-6). The knockdown of YAP expression using specific siRNAs in ICC cells decreased octamer-binding transcription factor 4 (OCT4) expression in Western blot analyses and OV-6 and CD133 expression in flow cytometry analysis. Verteporfin, a YAP inhibitor, decreased N-cadherin and OCT4 expression in Western blot analyses. In vitro sphere formation and anoikis resistance assays revealed the impairment in CSC property and anoikis resistance in response to the decrease in YAP expression. Verteporfin treatment activated the protein kinase B/mechanistic target of rapamycin signaling pathway and dramatically impaired IL-6-stimulated STAT3 phosphorylation in ICC cells. The combination of verteporfin and rapamycin, an inhibitor of mechanistic target of rapamycin phosphorylation, inhibited cell proliferation and tumor growth. In conclusion, verteporfin regulates multiple signaling pathways and, in combination with rapamycin, might be a promising therapeutic strategy for ICC treatment.

Long-term outcomes and significance of preoperative lymphocyte-to-monocyte ratio as a prognostic indicator in patients with invasive pancreatic neoplasms after repeat pancreatectomy.

BACKGROUND: Invasive pancreatic neoplasms have a high propensity for recurrence even after curative resection. Recently, patients who underwent pancreatectomy have an opportunity of undergoing secondary pancreatic resection, so-called "repeat pancreatectomy" to achieve curative operation and prolong their survival. We evaluated the long-term clinical outcomes and identified the prognostic factors, including systemic inflammation markers and the lymphocyte-to-monocyte ratio (LMR) of patients who underwent repeat pancreatectomy for invasive pancreatic tumors. METHODS: Twenty-eight consecutive patients with invasive pancreatic neoplasms (22 pancreatic ductal adenocarcinomas, 2 pancreatic acinar cell carcinomas, and 4 invasive intra-papillary mucinous carcinomas) with isolated local recurrence only in the remnant pancreas were analyzed retrospectively. To identify factors for the selection of optimal patients who should undergo repeat pancreatectomy, perioperative clinical parameters were analyzed by Cox proportional regression models. RESULTS: Of 28 patients, 12 patients experienced recurrence within 3 years after repeat pancreatectomy. Kaplan-Meier analysis showed that the median cancer-specific overall survival time of patients with invasive pancreatic neoplasms was 61 months, showing favorable outcomes. High preoperative LMR (LMR ≥ 3.3) (p = 0.022), no portal vein resection (p = 0.021), no arterial resection (p = 0.037), and pathological lymph node negative (p = 0.0057) were identified as favorable prognostic parameters on univariate analysis, and LMR ≥ 3.3 (p = 0.0005), and pathological lymph node negative (p = 0.018) on multivariate analysis. CONCLUSIONS: Preoperative LMR is potentially a good indicator for selecting suitable patients to undergo repeat pancreatectomy in patients with isolated local recurrence of invasive pancreatic neoplasms.

Comparing prognostic factors of Glut-1 expression and maximum standardized uptake value by FDG-PET in patients with resectable pancreatic cancer.

BACKGROUND: This study aimed to assess the prognostic values of preoperative maximum standardized uptake value (SUVmax) of primary pancreatic tumors and Glut-1 expression in patients with resectable pancreatic ductal adenocarcinoma (R-PDAC), and to investigate whether Glut-1 expression is more effective than SUVmax in predicting survival in patients with R-PDAC. METHODS: We investigated 101 R-PDAC patients who underwent pancreatectomy for pancreatic cancer treatment. SUVmax analyzed through 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT), and Glut-1 expression, were assessed for predicting the prognosis of patients with R-PDAC. RESULTS: In patients with R-PDAC, the high SUVmax group (≥4.25) had significantly shorter overall survival (OS) and disease-free survival (DFS) than the low SUVmax group (＜4.25). Surprisingly, Glut-1 expression was not significantly correlated with SUVmax. Moreover, the high Glut-1 expression group, which was related to higher levels of CA 19-9, had significantly shorter OS and DFS than the low Glut-1 expression group. Furthermore, among the high SUVmax group, OS and DFS were significantly shorter in the high Glut-1 expression group. Multivariate analyses revealed that Glut-1 overexpression was an independent prognostic factor in patients with R-PDAC. Glut-1 knockdown also induced cell cycle arrest in PDAC cells in vitro. CONCLUSIONS: The study determined that Glut-1 overexpression is a more powerful prognostic factor than SUVmax for predicting OS and higher risk of recurrence in R-PDAC patients. Glut-1 overexpression is also more likely to be associated with malignant activity in PDAC patients.

Pancreatic neuroendocrine carcinoma G3 may be heterogeneous and could be classified into two distinct groups.

BACKGROUND/OBJECTIVES: Pancreatic neuroendocrine carcinoma (PanNEC)-G3 often presents along with genetic abnormalities such as KRAS, RB1, and TP53 mutations. However, the association between these genetic findings and response to chemotherapy and prognosis has not been clarified. This study aimed to clarify the clinicopathological features of PanNEC-G3. METHODS: We performed a subgroup analysis of the Japanese PanNEN-G3 study (multicenter, retrospective study), which revealed that Rb loss and KRAS mutation were predictors of the response to platinum-based regimen in PanNEN-G3. We re-classified WHO grades of PanNENs using the 2017 WHO classification and then analyzed the clinicopathological features and prognostic factors in 49 patients with PanNEC-G3. RESULTS: The rates of Rb loss and KRAS mutation in PanNEC-G3 were 54.5% and 48.7%, respectively. Patients with Rb loss and/or KRAS mutation showed a higher response rate to first-line platinum-based regimen than those without Rb loss or KRAS mutation (object response rate 70.0% vs 33.3%, odds ratio 9.22; 95% CI 1.26-67.3, P = 0.029), but tended to have shorter overall survival rates than those without Rb loss or KRAS mutation (median 239 vs 473 days, hazard ratio 2.11; 95% CI 0.92-4.86, P = 0.077). CONCLUSIONS: Patients with PanNEC-G3 have varied clinical outcomes for platinum-based regimen. When grouped based on Rb loss and KRAS mutation, there seemed to be two groups with distinct prognoses and responses to the platinum-based regimen. PanNEC-G3 could, therefore, be classified into two distinct groups based on immunohistochemical and genetic findings.

Needle tract seeding recurrence of pancreatic cancer in the gastric wall with paragastric lymph node metastasis after endoscopic ultrasound-guided fine needle aspiration followed by pancreatectomy: a case report and literature review.

BACKGROUND: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has high accuracy and a low complication rate; therefore, it has been widely used as a useful tool for diagnosis of and to determine treatment strategies for pancreatic tumors. Recently, reports of the recurrence of needle tract seeding after EUS-FNA are emerging. CASE PRESENTATION: An 83-year-old woman was referred to our hospital to undergo further examination of her pancreatic tumor. Multidetector computed tomography (MDCT) revealed a 25-mm-diameter mass in the pancreatic body. She underwent EUS-FNA (transgastric, 22-G needle, 2 passes) and was subsequently diagnosed with adenocarcinoma. Distal pancreatosplenectomy followed by adjuvant chemotherapy with S-1 for 6 months was performed. The level of carbohydrate antigen 19-9 gradually increased 22 months after surgery, and MDCT, which was performed 3 months later, revealed a 23-mm low-density mass in the stomach and paragastric lymph node swelling. Gastroendoscopy revealed a submucosal tumor, and endoscopic ultrasound revealed a hypoechoic mass in the submucosa of the gastric wall. Partial gastrectomy with lymph node resection was performed. The pathological findings showed adenocarcinoma extending from the subserosa to the submucosa and lymph node metastasis, consistent with a tumor recurrence from the resected pancreatic tumor. She received adjuvant chemotherapy with S-1; recurrence was not observed for 5 months, at the time of this writing. CONCLUSION: It is important to pay careful attention to the development of needle tract seeding in patients with pancreatic cancer diagnosed by EUS-FNA. This is the first case of needle tract seeding with lymph node metastasis, highlighting the need for caution and providing novel insight in the postoperative follow-up of patients with pancreatic body/tail cancer.

Outcome of interventional radiology for delayed postoperative hemorrhage in hepatobiliary and pancreatic surgery.

BACKGROUND AND AIM: Postoperative hemorrhage is a rare but potentially lethal complication of hepatobiliary and pancreatic surgeries. This study aimed to retrospectively evaluate the clinical outcome of patients with delayed postoperative hemorrhage and compare the results according to the surgical procedure. METHODS: Overall, 4220 patients underwent surgery for hepatobiliary and pancreatic diseases. Delayed postoperative hemorrhage (observed more than 24 h postoperatively) occurred in 62 patients. Of these, 61 underwent interventional radiology to achieve hemostasis. Patients' clinical data were analyzed retrospectively. The chi-squared or Fisher's exact test was used in data analysis. RESULTS: A total of 62 patients (1.5%) developed delayed postoperative hemorrhage; 61 (1.4%) of them underwent interventional radiology to achieve hemostasis. Median duration from surgery to interventional radiology was 19 days (range: 5-252 days). Sentinel bleeding was detected in 31 patients; Clinical success was achieved in 54 patients (88.5%) by interventional radiology. Overall mortality rate was 26.2%. Causes of 16 in-hospital deaths were uncontrollable hemorrhage (n = 4) and worsening of general condition after hemostasis (n = 12). Mortality rates were 50.0% (11/22) and 12.8% (5/39) after hepatobiliary surgery and pancreatic resection, respectively. Mortality rate was significantly higher after hepatobiliary surgery than after pancreatic surgery (P = 0.002). CONCLUSIONS: Interventional radiology can be successfully performed to achieve hemostasis for delayed hemorrhage after hepatobiliary and pancreatic surgeries. Because successful interventional radiology does not necessarily lead to survival, particularly after hepatobiliary surgery, meticulous attention to prevent surgical complications and intensive treatments before and after interventional radiology are required to improve outcomes.

Diverse transitions in diabetes status during the clinical course of patients with resectable pancreatic cancer.

OBJECTIVE: Pancreatic cancer and diabetes status have complex bilateral interactions; therefore, understanding their clinical features is essential for the clinical management of pancreatic cancer patients. We aimed to evaluate the diabetes status before diagnosis, after resection and until the time of recurrence in patients with resectable pancreatic cancer and to clarify the correlations among the clinical course of pancreatic cancer, operative procedure and diabetes status. METHODS: Between 2011 and 2016, we retrospectively identified 189 pancreatic cancer patients who underwent pancreatoduodenectomy or distal pancreatectomy at our institution. The entire clinical course of each patient was retrieved from the medical records, and the diabetes status in the longest possible duration was assessed. RESULTS: Among 115 pancreatic cancer patients who had normal glucose tolerance at the time of resection, 22 (19.1%) developed type 2 diabetes after resection. In a multivariate analysis, distal pancreatectomy was strongly associated with the development of postoperative diabetes. On the other hand, 74 pancreatic cancer patients had already been diagnosed with type 2 diabetes at the time of resection. During the follow-up period, 15 patients were noted to have diabetes resolution after resection; interestingly, the majority of these patients had newly diagnosed diabetes, which was defined as the diagnosis of diabetes within 3 months before resection. Moreover, newly diagnosed diabetes was an independent factor for diabetes resolution after resection. CONCLUSIONS: In pancreatic cancer patients who underwent pancreatectomy, distal pancreatectomy was correlated with postoperative diabetes, and newly diagnosed diabetes had a high probability of resolution after resection.

Splenic enlargement induced by preoperative chemotherapy is a useful indicator for predicting liver regeneration after resection for colorectal liver metastases.

BACKGROUND: Conversion chemotherapy may downsize unresectable colorectal liver metastases (CRLMs), but may cause liver injury and splenic enlargement. The effect of preoperative chemotherapy on liver regeneration after liver resection remains undetermined. The aim of this study was to examine whether splenic enlargement induced by preoperative chemotherapy is an indicator to identify high-risk patients for impaired liver regeneration and liver dysfunction after resection. METHODS: We retrospectively reviewed 118 Japanese patients with CRLMs. Fifty-one patients had conversion chemotherapy. The other 67 patients underwent up-front liver resection. We clarified effects of conversion chemotherapy on splenic volume, liver function, and postoperative liver regeneration. Perioperative outcome was also analyzed. RESULTS: A ratio of the splenic volume before and after chemotherapy (SP index) in the oxaliplatin-based chemotherapy group was significantly greater than other chemotherapy groups after 9 or more chemotherapy cycles. Patients whose SP index was 1.2 or more had significantly higher indocyanine green retention rate at 15 min (ICG-R15) than patients without chemotherapy. Analyses of covariance showed liver regeneration rate after resection was decreased in patients whose SP index was 1.2 or more. The incidence of postoperative liver dysfunction in patients whose SP index was 1.2 or more was significantly greater than patients without chemotherapy. Multivariate analysis showed SP index was a significant predictive factor of impaired liver regeneration. CONCLUSIONS: Splenic enlargement induced by preoperative chemotherapy was a useful indicator for impaired liver regeneration after resection and a decision-making tool of treatment strategy for unresectable CRLMs.

[A Case of Anaplastic Carcinoma with Osteoclastlike Giant Cells of the Pancreas Concomitant with Lung Recurrence of Solitary Fibrous Tumor].

A 32-year-old woman presented with epigastric pain and an abdominal mass. Abdominal CT showed a 130mm pancreatic tail mass with an enhanced rim, central necrosis, and small calcification. A 6mm lung tumor was also found via chest CT. Her medical history included surgical resection of cerebral solitary fibrous tumor when she was 24 years old. When she was 31 years old, it had recurred but was cured by gamma knife radiosurgery. We performed distal pancreatectomy and splenectomy with lymph node dissection. According to pathological and immunohistochemical findings, it was diagnosed as an anaplastic carcinoma with osteoclast-like giant cells. She underwent surgical resection of the lung tumor 2 months after pancreatic resection and was diagnosed with metastasis from the solitary fibrous tumor. Fourteen months since undergoing pancreatectomy, the patient experienced no recurrence from both diseases. We report a rare resected case of anaplastic carcinoma of pancreas concomitant with recurrent solitary fibrous tumor.

Benchmarks in Pancreatic Surgery: A Novel Tool for Unbiased Outcome Comparisons.

OBJECTIVE: To use the concept of benchmarking to establish robust and standardized outcome references after pancreatico-duodenectomy (PD). BACKGROUND: Best achievable results after PD are unknown. Consequently, outcome comparisons among different cohorts, centers or with novel surgical techniques remain speculative. METHODS: This multicenter study analyzes consecutive patients (2012-2015) undergoing PD in 23 international expert centers in pancreas surgery. Outcomes in patients without significant comorbidities and major vascular resection (benchmark cases) were analyzed to establish 20 outcome benchmarks for PD. These benchmarks were tested in a cohort with a poorer preoperative physical status (ASA class ≥3) and a cohort treated by minimally invasive approaches. RESULTS: Two thousand three hundred seventy-five (38%) low-risk cases out of a total of 6186 PDs were analyzed, disclosing low in-hospital mortality (≤1.6%) but high morbidity, with a 73% benchmark morbidity rate cumulated within 6 months following surgery. Benchmark cutoffs for pancreatic fistulas (B-C), severe complications (≥ grade 3), and failure-to-rescue rate were 19%, 30%, and 9%, respectively. The ASA ≥3 cohort showed comparable morbidity but a higher in hospital-mortality (3% vs 1.6%) and failure-to-rescue rate (16% vs 9%) than the benchmarks. The proportion of benchmark cases performed varied greatly across centers and continents for both open (9%-93%) and minimally invasive (11%-62%) PD. Centers operating mostly on complex PD cases disclosed better results than those with a majority of low-risk cases. CONCLUSION: The proposed outcome benchmarks for PD, established in a large-scale international patient cohort and tested in 2 different cohorts, may allow for meaningful comparisons between different patient cohorts, centers, countries, and surgical techniques.

Roles of Pin1 as a Key Molecule for EMT Induction by Activation of STAT3 and NF-κB in Human Gallbladder Cancer.

BACKGROUND: Despite developments in multidisciplinary treatment, the prognosis for advanced gallbladder cancer (GBC) still is poor because of its rapid progression. Epithelial-mesenchymal transition (EMT) plays a central role in promoting tumor invasion and metastasis in malignancies thorough signal transducer and activator of transcription-3 (STAT3) and nuclear factor κB (NF-κB) activation. Whereas Pin1 mediates STAT3 and NF-κB activation, the involvement of Pin1 in GBC progression is unclear. METHODS: Factors regulating Pin1-related STAT3 and NF-κB activation were evaluated using surgical specimens collected from 76 GBC patients, GBC cells, and orthotopic GBC xenograft mice. RESULTS: In the patients with GBC, high Pin1 expression in GBC was associated with aggressive tumor invasion and increased tumor metastasis, and was an independent factor for a poor prognosis. Pin1 expression was correlated with phosphorylation of STAT3(Ser727) and NF-κB-p65(Ser276), thereby activating STAT3 and NF-κB in GBC. Pin1-mediated STAT3 and NF-κB activation induced EMT in GBC. When Pin1 knockdown was performed in GBC cells, the phosphorylation of STAT3(Ser727) and NF-κB-p65(Ser276) was inhibited, and STAT3 and NF-κB activation was suppressed. Inactivation of STAT3 and NF-κB in Pin1-depleted cells decreased snail and zeb-2 expression, thereby reducing the rate of mesenchymal-like cells, suggesting that EMT was inhibited in GBC cells. PiB, a Pin1-specific inhibitor, inhibited EMT and reduced tumor cell invasion by inactivating STAT3 and NF-κB in vitro. Moreover, PiB treatment inhibited lymph node metastasis and intrahepatic metastasis in orthotopic GBC xenograft tumor in vivo. CONCLUSIONS: Pin1 accelerates GBC invasion and metastasis by activating STAT3 and NF-κB. Therefore, Pin1 inhibition by PiB is an excellent therapy for GBC by safely inhibiting its metastasis.

Surgery for Pancreatic Neuroendocrine Tumor G3 and Carcinoma G3 Should be Considered Separately.

BACKGROUND: The role of surgery in pancreatic neuroendocrine neoplasm grade 3 (pNEN-G3) treatment remains unclear. We aimed to clarify the role of surgery for pNEN-G3, which has recently been reclassified as pancreatic neuroendocrine tumor-G3 (pNET-G3) and pancreatic neuroendocrine carcinoma-G3 (pNEC-G3), with and without metastases, respectively. METHODS: We analyzed a subgroup of patients from the Japanese pancreatic NEC study, a Japanese multicenter case-series study of pNEN-G3. Pathologists subclassified 67 patients as having pNET-G3 or pNEC-G3 based on morphological features. We compared the overall survival (OS) rates among patients who were grouped according to whether they had undergone tumor-targeted surgery for tumors without (SwoM) or with (SwM) metastases, or non-surgical procedures (NS). RESULTS: Data from 21 patients with pNET-G3 (SwoM, n = 6; SwM, n = 5; NS, n = 10) and 46 patients with pNEC-G3 (SwoM, n = 8; SwM, n = 5; NS, n = 33) were analyzed. OS of patients with pNET-G3 was significantly longer after SwoM and SwM than with NS (p = 0.018 and p = 0.022). In contrast, OS did not significantly differ between either SwoM or SwM and NS (p = 0.093 and p = 0.489) among patients with pNEC-G3. CONCLUSION: The role of surgery should be considered separately for pNET-G3 and pNEC-G3. Although SwoM and SwM can be considered for pNET-G3, caution is advised before considering SwM and SwoM for pNEC-G3.

Feasibility and safety of distal pancreatectomy with en bloc celiac axis resection (DP-CAR) combined with neoadjuvant therapy for borderline resectable and unresectable pancreatic body/tail cancer.

PURPOSE: Pancreatic body/tail cancer commonly invades the hepatic artery or celiac artery, making surgical resection difficult. Distal pancreatectomy with celiac axis resection (DP-CAR) has recently been performed to achieve curative resection of these tumors. However, the safety and efficacy remain unclear. This study aimed to clarify the efficacy and safety of DP-CAR, mainly focusing on the combination with neoadjuvant therapy (NAT). METHODS: We retrospectively reviewed 31 consecutive patients with pancreatic ductal adenocarcinoma who underwent DP-CAR between 2010 and 2016. Data from 7 patients who underwent DP-CAR without NAT were used as a reference (upfront surgery, US). RESULTS: Gemcitabine + S-1 (GS) (n = 17) and gemcitabine + albumin-bound paclitaxel (GnP) (n = 8) were frequently used as NAT. DP-CAR following NAT was performed safely with 1 death, resulting in a mortality rate of 3%. The median survival time (MST) in the NAT group was 38.6 months, while that in the US group was 15.6 months. The NAT group had a high R0 resection rate (74%), while only 1 of 7 cases in the US group achieved R0 resection. Within the NAT group, patients treated with GS showed favorable overall survival with 39.5 months of MST, while that of patients treated with GnP was 19.8 months. CONCLUSION: The combination of NAT and DP-CAR was feasible and safe for pancreatic body/tail cancer invading the celiac artery and/or hepatic artery. This strategy should be further assessed for the optimal regimen and duration of NAT in prospective studies.

Is hepatic artery coil embolization useful in distal pancreatectomy with en bloc celiac axis resection for locally advanced pancreatic cancer?

BACKGROUND: The exact contribution of preoperative coil embolization in distal pancreatectomy with en bloc celiac axis resection (DP-CAR) for the prevention of ischemic liver complication is not fully elucidated. METHODS: From January 2004 to July 2015, 31 patients underwent DP-CAR for the pancreatic body-tail cancer. Twenty-three patients received preoperative coil embolization. The characteristics and operative outcomes were analyzed retrospectively. RESULTS: The median survival time and 1- and 3-year overall survival rates were 23.7 months and 74.2% and 34.4%, respectively. No 30-day mortality occurred in any of the patients. Postoperative liver infarction developed only in 8 patients (25.8%) even though 7 of 8 patients had undergone preoperative coil embolization. Tumor contact with the gastroduodenal artery (GDA)/proper hepatic artery (PHA) on preoperative multi-detector computed tomography (MDCT), tumor size, operative time, portal vein resection, and stenosis of the GDA/PHA after DP-CAR are related to liver infarction. Among them, postoperative stenosis of the GDA/PHA on MDCT, which was observed in all 8 patients with liver infarction, was the most closely related factor to postoperative liver infarction. Tumor contact with the GDA/PHA did not worsen the R0 resection rate or overall survival rate. CONCLUSION: Our data indicate that preoperative coil embolization of the common hepatic artery is not useful in DP-CAR as long as GDA is completely preserved during surgery.

Conversion surgery for initially unresectable pancreatic cancer: current status and unresolved issues.

Pancreatic cancer is one of the most lethal of all malignancies. One of the reasons for the dismal prognosis is that most diagnoses are made when the disease is either locally advanced or metastatic. Recent advances in chemotherapy and chemoradiotherapy (CRT) enable "conversion surgery" to be performed for selected patients with initially unresectable pancreatic cancer following favorable responses to preoperative treatment. Using FOLFIRINOX as preoperative treatment, the resection rate was reported as 6-44% of patients with locally advanced cancer and the prognosis of these patients was favorable. Even for metastasized cancer, recent reports show the effectiveness of conversion surgery, which has achieved 27-56 months of median overall survival. However, there are many unanswered questions about conversion surgery. The optimal regimen and duration of preoperative treatment remain unclear and there is still debate regarding the safety and effectiveness of vascular resection, which is often required for curative resection of locally advanced cancer. Accumulation of more data on conversion surgery is required to establish the safety and effectiveness of this treatment. In this review, we summarize the current status and unresolved issues about conversion surgery for initially unresectable pancreatic cancer.