A nomogram to preoperatively predict 1-year disease-specific survival in resected pancreatic cancer following neoadjuvant chemoradiation therapy.

OBJECTIVE: This study aimed to develop a nomogram to predict the 1-year survival of patients with pancreatic cancer who underwent pancreatectomy following neoadjuvant treatment with preoperatively detectable clinical parameters. Extended pancreatectomy is necessary to achieve complete tumor removal in borderline resectable and locally advanced pancreatic cancer. However, it increases postoperative morbidity and mortality rates, and should be balanced with potential benefit of long-term survival. METHODS: The medical records of patients who underwent pancreatectomy following neoadjuvant treatment from January 2005 to December 2016 at Severance Hospital were retrospectively reviewed. Medical records were collected from five international institutions from Japan and Singapore for external validation. RESULTS: A total of 113 patients were enrolled. The nomogram for predicting 1-year disease-specific survival was created based on 5 clinically detectable preoperative parameters as follows: age (year), symptom (no/yes), tumor size at initial diagnostic stage (cm), preoperative serum carbohydrate antigen (CA) 19-9 level after neoadjuvant treatment (<34/≥34 U/mL), and planned surgery [pancreaticoduodenectomy (PD) (pylorus-preserving PD)/distal pancreatectomy (DP)/total pancreatectomy]. Model performance was assessed for discrimination and calibration. The calibration plot showed good agreement between actual and predicted survival probabilities; the the Greenwood-Nam-D'Agostino (GND) goodness-of-fit test showed that the model was well calibrated (χ2=8.24, P=0.5099). A total of 84 patients were used for external validation. When correlating actual disease-specific survival and calculated 1-year disease-specific survival, there were significance differences according to the calculated probability of 1-year survival among the three groups (P=0.044). CONCLUSIONS: The developed nomogram had quite acceptable accuracy and clinical feasibility in the decision-making process for the management of pancreatic cancer.

Blumgart method using LAPRA-TY clips facilitates pancreaticojejunostomy in laparoscopic pancreaticoduodenectomy.

The modified Blumgart method for pancreaticojejunostomy has been shown to reduce the rate of postoperative pancreatic fistula (POPF) in open surgery. We describe a modified Blumgart method using LAPRA-TY suture clips to facilitate laparoscopic pancreaticojejunostomy.We prepared a double-armed 4-0 nonabsorbable monofilament, which was ligated using the LAPRA-TY clip at the tail end, 12-cm in length. Next, the U-suture was placed through the pancreatic stump and the seromuscular layer of the jejunum. We performed duct-to-mucosa suturing with a 5-0 absorbable monofilament. After completing the duct-to-mucosa suturing, as a final step we placed the sutures through the seromuscular layer of the jejunum on the ventral side and tightly secured the thread with the LAPRA-TY clips. We performed laparoscopic Blumgart pancreaticojejunostomy during pancreaticoduodenectomy in 39 patients. We compared the surgical outcomes of 19 patients who underwent Blumgart pancreaticojejunostomy using the LAPRA-TY clips (LAPRA-TY group) with 20 patients undergoing surgery not using the LAPRA-TY clips (conventional group).The rate of clinically relevant postoperative pancreatic fistula in the LAPRA-TY group was 21.1%, which did not differ significantly from the rate of the conventional group. However, the mean time of pancreaticojejunostomy in the LAPRA-TY group was 56.2 min (range, 39-79 min), which was significantly shorter than that of the conventional group (69.7 min; range, 53-105 min, P < .001).Although the modified Blumgart pancreaticojejunostomy using LAPRA-TY suture clips did not improve the pancreatic fistula rate, it allowed for shorter operative times. Thus, this procedure lends itself to positive surgical and patient outcomes.

Clinical Impact of Neoadjuvant Chemotherapy and Chemoradiotherapy in Borderline Resectable Pancreatic Cancer: Analysis of 884 Patients at Facilities Specializing in Pancreatic Surgery.

BACKGROUND: The efficacy of neoadjuvant therapy (NAT), including neoadjuvant chemotherapy (NAC) and neoadjuvant chemo-radiotherapy (NACRT), for patients with borderline resectable pancreatic cancer (BRPC) has not been elucidated. This study aimed to clarify the efficacy of NAC and NACRT for patients with BRPC. METHODS: The study analyzed the treatment outcomes of 884 patients treated for BRPC from 2011 to 2013. Treatment results were compared between upfront surgery and NAT and between NAC and NACRT using propensity score-matching analysis. Overall survival (OS) was calculated via intention-to-treat analyses. RESULTS: The overall resection rates for the patients who underwent NAT were significantly lower than for the patients who underwent upfront surgery (75.1% vs 93.3%; p < 0.001). However, the R0 resection rate was significantly higher for NAT than for upfront surgery (p < 0.001). Additionally, the OS for the patients who received NAT was significantly longer than for those who underwent upfront surgery (median survival time [MST], 25.7 vs 19.0 months; p = 0.015). The lymph node rate for the patients with NACRT was significantly lower than for those who underwent NAC (p < 0.001). However, the resection rate for the NACRT cases was significantly lower than for the NAC cases (p = 0.041). The local recurrence rate for the NACRT cases was significantly lower than for the NAC cases (p = 0.002). However, OS did not differ significantly between NAC and NACRT (MST, 29.2 vs 22.5 months; p = 0.130). CONCLUSIONS: The study showed that NAT has potential benefit for patients with BRPC. Compared with NAC, NACRT decreased the rates for lymph node metastasis and local recurrence but did not improve the prognosis.

Why Does Postoperative Pancreatic Fistula Occur After Hand-sewn Parenchymal Closure and Staple Closure in Distal Pancreatectomy?

Hand-sewing (HS) and stapling are common parenchymal closure techniques after distal pancreatectomy. However, these methods cannot completely prevent postoperative pancreatic fistula (POPF). The mechanisms of POPF formation after closure are unknown. We performed distal pancreatectomy in mongrel dogs to identify the mechanisms of POPF formation after HS and staple closure. We measured the closed pancreatic duct burst pressures and examined the histology of the remnant pancreas. The after staple-closure burst pressures depended on stapler height; lower pressures were associated with greater stapler heights. Post-HS closure burst pressures were significantly higher than those at each stapler height (P<0.01). Post-HS closure pathologic findings showed extensive necrosis (day 3), and some regenerated pancreatic duct stumps (day 5). Necrosis was not observed around the stapled tissues. Although HS completely closes the pancreatic ducts, stump necrosis and blood flow disturbances may cause POPF. With stapler closure, pancreatic fluid leakage may occur even with appropriate stapler heights.

Surgical resection of neuroendocrine tumors of the pancreas (pNETs) by minimally invasive surgery: the laparoscopic approach.

Neuroendocrine tumors of the pancreas (pNETs) are a rare group of neoplasms that originate from the endocrine portion of the pancreas. Tumors that either secrete or do not secrete compounds, resulting in symptoms, can be classified as functioning and non-functioning pNETs, respectively. The prevalence of such tumors has recently increased due to the use of more sensitive imaging techniques, such as multidetector computed tomography, magnetic resonance imaging and endoscopic ultrasound. The biological behavior of pNETs varies widely from indolent, well-differentiated tumors to those that are far more aggressive. The most effective and radical treatment for pNETs is surgical resection. Over the last decade, minimally invasive surgery has been increasingly used in pancreatectomy, with laparoscopic pancreatic surgery (LPS) emerging as an alternative to open pancreatic surgery (OPS) in patients with pNETs. Non-comparative studies have shown that LPS is safe and effective. In well-selected groups of patients with pancreatic lesions, LPS was found to results in good perioperative outcomes, including reduced intraoperative blood loss, postoperative pain, time to recovery, and length of hospital stay. Despite the encouraging results of studies from highly specialized centers with extensive experience, no randomized trials to date have conclusively validated these findings. Indications for minimally invasive LPS for patients with pNETs remain unclear. This review presents the current state of LPS for pNETs.

Surgical Outcomes of Pancreaticoduodenectomy for Pancreatic Cancer with Proximal Dorsal Jejunal Vein Involvement.

BACKGROUND/PURPOSE: The proximal jejunal vein which branches from the dorsal side of the superior mesenteric vein (SMV) usually drains the inferior pancreatoduodenal veins (IPDVs) and contacts the uncinate process of the pancreas. We focused on this vein, termed the proximal dorsal jejunal vein (PDJV), and evaluated the anatomical classification of the PDJV and surgical outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) with PDJV involvement (PDJVI). METHODS: The jejunal veins that branch from the dorsal side of the SMV above the inferior border of the duodenum are defined as PDJVs. We investigated 121 patients who underwent upfront pancreaticoduodenectomy for PDAC between 2011 and 2017; PDJVs were resected in all patients. The anatomical classification of PDJV was evaluated using multidetector computed tomography. Surgical and prognostic outcomes of pancreticoduodenectomy for PDAC with PDJVI were evaluated. RESULTS: The PDJVs were classified into seven types depending on the position of the first and second jejunal veins relative to the superior mesenteric artery. In all patients, the morbidity and mortality rates were 15.7 and 0.8%, respectively. The rates for parameters including SMV resection, presence of pathological T3-4, R0 resection, and 3-year survival were 46.2, 92.3, 92.3, and 61.1%, respectively, when there was PDJVI (n = 13). When there was no PDJVI (n = 108), the rates were 60.2, 93.5, 86.1, and 58.3%, respectively. Overall, there were no significant differences. CONCLUSIONS: Pancreaticoduodenectomy with PDJV resection is feasible for PDAC with PDJVI and satisfactory overall survival rates are achievable. It may be necessary to reconsider the resectability of PDAC with PDJVI.

Approaching the superior mesenteric artery from the right side using the proximal-dorsal jejunal vein preisolation method during laparoscopic pancreaticoduodenectomy.

BACKGROUND: Although the artery-first approach is widely used in open pancreaticoduodenectomy, it is difficult to laparoscopically expose the origin of the inferior pancreaticoduodenal artery (IPDA) from the left side of the superior mesenteric artery (SMA). By contrast, damaging the inferior pancreaticoduodenal veins (IPDVs) is possible when approaching the IPDA from the right side of the SMA. To facilitate the artery-first approach in laparoscopic pancreaticoduodenectomy (LPD), we focused on the proximal-dorsal jejunal vein (PDJV) that branched from the superior mesenteric vein (SMV) dorsal side and drained the IPDVs. This study aimed to clarify the usefulness of the right SMA approach using the PDJV preisolation method. METHODS: The PDJV was first isolated, and the IPDVs were divided along the PDJV on the right side of the SMA. Then, the IPDA was divided at the root without first separating the pancreatic head from the portal vein and the SMV. Overall, 21 patients underwent this approach, and the results were retrospectively compared with those of 21 patients who underwent the artery-first approach, which was performed on the left side of the SMA. Anatomical characteristics of the PDJV were evaluated using multidetector computed tomography for the two groups. RESULTS: Operative times and resection times were significantly lower for the PDJV preisolation group than for the conventional LPD group (489.3 vs. 541.7 min, respectively; p = 0.002). During anatomical evaluation, 41 patients (97.6%) had a PDJV that drained from the SMV dorsally and was in contact with the anterior aspect of the uncinate process. The PDJV was confirmed as the first jejunal vein in 31 patients (73.8%) and as the second jejunal vein in 10 patients (23.8%). CONCLUSIONS: This approach facilitates dissection of the IPDA on the right side of the SMA, thereby reducing operative times.

Liver metastasis is established by metastasis of micro cell aggregates but not single cells.

Cancer cell engraftment in the target organ is necessary to establish metastasis. Clinically, lymph node metastasis of single cells has been confirmed using cytokeratin staining. In the current study, a LacZ-labeled cancer cell line was used to visualize intrahepatic metastasis of single cells or liver micrometastasis. KM12SM-lacZ stably expressing LacZ was prepared with a highly metastatic colon cancer cell line, KM12SM. KM12SM-lacZ was injected into the spleen of nude mice and following 1 week the spleen was excised. The liver was then examined for metastasis following 1, 2 or 3 weeks. Confirmation of liver metastasis was completed by observing the grade of metastasis. Grade-1 metastasis (DNA level), human DNA in liver tissue was detected; Grade-2 metastasis (metastasis of single cells), confirmed by X-gal staining; Grade-3 metastasis (histopathological micrometastasis), diagnosed by light microscopy and Grade-4 metastasis (typical metastasis), easily detected macroscopically or by hematoxylin and eosin staining. The Grade-1 metastasis detection rates 1, 2 and 3 weeks following splenectomy were 50, 100 and 100%, respectively. Grade-2 metastasis was not detected by microscopy. The Grade-3 metastasis detection rates for 1, 2 and 3 weeks were 75, 100 and 100%, respectively. Micrometastasis was observed in the portal vein lumen and wall. The Grade-4 metastasis detection rates were 50, 100 and 100% for 1, 2 and 3 weeks respectively. Cancer cells were present in vessels surrounding the main tumor. In conclusion, a specific number of cancer cell aggregates may be necessary to establish hematogenous metastasis.

RhoA activity increases due to hypermethylation of ARHGAP28 in a highly liver-metastatic colon cancer cell line.

Certain cell lines exhibit metastatic ability (highly metastatic cell lines) while their parent cell lines have no metastatic ability. Differences in methylation, which are not derived from differences in the gene sequence between cell lines, were extensively analyzed. Using an established highly metastatic cell line, KM12SM, and its parent cell line, KM12C, differences in the frequency of methylation were analyzed in the promoter regions of ~480,000 gene sites using Infinium HumanMethylation450. The promoter region of the Rho GTPase-activating protein 28 (ARHGAP28) gene was the most markedly methylated region in KM12SM compared with KM12C. ARHGAP28 is a GTPase-activating protein (GAP), and it converts activated RhoA to inactivated RhoA via GTPase. RhoA activity was compared between these two cell lines. The activated RhoA level was compared using western blot analysis and G-LISA. The activated RhoA level was higher in KM12SM compared to KM12C for western blot analysis and G-LISA analysis. RhoA is a protein involved in cytoskeleton formation and cell motility. RhoA, for which ARHGAP28 acts as a GAP, is possibly a factor involved in the metastatic ability of cancer.

A Novel "Artery First" Approach Allowing Safe Resection in Laparoscopic Pancreaticoduodenectomy: The Uncinate Process First Approach.

BACKGROUND/AIMS: Laparoscopic pancreaticoduodenectomy (LPD) is still a challenging operation, particularly because the dissection around the superior mesenteric artery (SMA) and bleeding control are difficult. Although it has been reported that early ligation of the origin of the inferior pancreaticoduodenal artery (IPDA) reduces blood loss, it is difficult to laparoscopically expose the origin of the IPDA. We sought to develop a novel approach to simplify the dissection of the IPDA and reduce bleeding. METHODOLOGY: The uncinate process was exposed at the left posterior side of the SMA, and the branches of the IPDA were divided at positions where they enter and exit the uncinate process before isolating the pancreatic head from the right aspect of the SMA. Ten patients were operated using this new approach, and the results were retrospectively compared to those of 22 patients treated with conventional LPD. RESULTS: The operation times did not differ significantly between the two groups. However, the intraoperative blood loss was significantly lower in the "uncinate process first" group than in the conventional LPD group. (162.7 ml vs. 463.8 ml, respectively; P = 0.023). CONCLUSIONS: The new approach facilitates the initial dissection of the IPDA at the right side of the SMA, reducing intraopera- tive blood loss.