Although surgical resection is the only hope for cure in patients with pancreatic cancer, the prognosis of patients who undergo surgical resection still remains poor due to the aggressive biological behaviors. Recent advances in chemotherapy for pancreatic cancer led to the development of combination therapy including surgery and other adjuvant therapy. In this article, we introduce our three phase II trials for developing new multidisciplinary treatments for pancreatic cancer, CAP-001 (Adjuvant therapy; Gemcitabine (GEM) vs. GEM+UFT), CAP-002 (Adjuvant therapy; GEM vs. S-1 vs. GEM+S-1) and CAP-003 (Neoadjuvant and adjuvant therapy by GEM+S-1 for unresectable or borderline resectable locally advanced pancreatic cancer).

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Between April 2005 and October 2011, 67 patients with resected pancreatic cancer received adjuvant gemcitabine (G), 60 received gemcitabine and S-1 (GS), 20 received S-1 therapy, and 41 patients did not undergo any postoperative adjuvant chemotherapy. The 5-year survival rates for patients receiving adjuvant G, GS, S-1, and observation only were 25%, 20%, 31%, and 19%, respectively. There was no significant difference in survival among patients receiving G, GS, and S-1, however, there were significant differences in survival between patients with observation and those receiving G, GS, and S-1.
Forty-six patients with borderline resectable pancreatic cancers with suspected arterial involvement were retrospectively analyzed. Borderline resectable pancreatic cancers with only portal vein involvement were excluded from this study. Sixteen patients (35%) with borderline resectable cancer underwent pancreatic resection. R0 resection was performed in 6 patients. Thirty patients (65%) resulted in exploratory laparotomy or bypass procedures. The causes of unresectability were arterial involvement (n=25), peritoneal dissemination (n=3), and liver metastases (n=2). The 5-year survival rate for resected cases was 16%.

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Although the standard treatment for resected pancreatic cancer is adjuvant chemotherapy, the strategy cannot be indicated for all cases with planned resection because of delayed recovery and/or residual tumor. A Neoadjuvant strategy (N-group) was compared to the surgery-first approach (S-group) by intention-to-treat anlaysis.
Eligibility criteria for adjuvant therapy were defined by: distant lymph node involvement, peritoneal washing cytology, residual tumor, delayed recovery, and serum marker sustained elevation after surgery.
Resection rate of N- and S-groups were both more than 80%. The frequency of the case eligible for adjuvant therapy was similar, 47% in S-group and 53% in N-group. The median survival time (MST) of the whole cohort and subgroup receiving adjuvant therapy were 21.2 and 31.6 months in N-group and 17.1 and 21.4 months in S-group, respectively. In N-group, GS-neoadjuvant (NAC-GS) was compared with Gemcitabine-neoadjuvant (NAC-G) treatment. The MST of the whole cohort and subgroup receiving adjuvant therapy in NAC-GS were 25.2 and 35.8 months, respectively, which were both significantly longer than those in NAC-G.
These results suggest that neoadjuvant chemotherapy shows a survival benefit without reducing the resection rate.

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A total of 250 patients with T3・T4 (JPS) pancreatic cancer received preoperative gemcitabine-based CRT. Patients were classified into the following three groups based on the locoregional tumor extension: T3-R (n=64), tumors without extension to the adjacent vasculature systems; T4-R (n=125), tumors with extension to the adjacent vasculature system except SMA, CHA, and CA; T4-BR (n=61), tumors showing abutment to 180° of the circumference of the SMA and/or CHA and/or CA. We evaluated the followings in comparisons among patients with T3-R, T4-R and T4-BR: (1) resection rate, (2) rate of margin-negative resection, (3) survival, and (4) frequency of local recurrence. Resection rates of T3-R, T4-R, and T4-BR patients were 92%, 85%, and 74%, respectively. Pathological margin-negative resection was achieved in 98%, 100%, and 98% in those patients groups, respectively. The 5-year postoperative survival rates of T3-R, T4-R, and T4-BR patients were 70%, 52%, and 37%, respectively. The 5-year cumulative incidence of local recurrence was comparable in the three groups (10%, 17%, and 15%, respectively). In the resected cases, locoregional control was comparable regardless of the degree of locoregional tumor extension in the setting of preoperative CRT strategy. However, the resection rate and postoperative survival rate were lower in the patients with more locally advanced tumors.

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Unresectable locally advanced pancreatic cancer (LAPC) is defined as surgically unresectable cancer with no evidence of distant metastases. Several studies have compared chemoradiotherapy with chemotherapy in unresectable LAPC, however, the benefit of chemoradiotherapy is still controversial. The purpose of this study was to compare the prognosis of unresectable LAPC between chemoradiotherapy and chemotherapy. We retrospectively evaluated the clinical records of unresectable LAPC patients treated between 2001 and 2011 in our institution. All unresectable LAPC cases were diagnosed pathologically. One hundred three patients were treated by chemotherapy and 51 patients were treated by chemoradiotherapy. There was no significant difference in overall survival (OS) between chemotherapy and chemoradiotherapy (median OS, 13.8 months vs. 12.7 months;p=0.825). In a Cox proportional hazard model adjusting for age and lymph node metastasis, the hazard ratio for death was 0.94 (95% confidence interval, 0.60-1.50;p=0.997). Our analysis demonstrated that chemoradiotherapy is not superior to chemotherapy in patients with unresectable LAPC.

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Inhibition of the renin angiotensin system (RAS) is reported to be a possible target for cancer treatment. We investigated the role of RAS in the treatment of advanced pancreatic cancer. In our retrospective analysis of 155 patients receiving gemcitabine, the use of ACE inhibitors or angiotensin receptor blockers were associated with better progression free survival and overall survival. Subsequently, we conducted phase I and II trials of combination therapy of gemcitabine and candesartan, an angiotensin receptor blocker. In the phase I trial, a recommended dose of 16mg was confirmed and the results of progression free survival and overall survival were promising, but in phase II trial, though gemcitabine and candesartan combination therapy was safe, progression free survival did not demonstrate additional effects of candesartan. Given the supportive data in basic research and clinical data in other cancers, we are planning to conduct another clinical trial in selected patients who are likely to respond to the inhibition of RAS.

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To investigate whether additional chemotherapy for patients with unresectable pancreatic cancer who acquired resistance against both gemcitabine (GEM) and S-1 would be effective or not, we retrospectively compared the median survival from the date of progression for both treatments (PD) between two cohorts. One group is the additional chemotherapy group which consists of cases with best supportive care (BSC) plus any additional chemotherapy after PD and the other group is BSC group which consists of cases without any chemotherapy. The median survival of the former group was significantly longer than that of the latter group (120 vs. 39 days; p<0.0001, respectively). Similarly, in patients with good general condition (ECOG: PS≤2), the median survival of the additional chemotherapy group was significantly longer than that of the BSC group (143 vs. 47.5 days; p<0.0001, respectively). Interestingly, dividing patients with PS ≤2 into three groups: the group with the different regimen from GEM or/and S-1; the group with GEM or/and S-1; and the BSC group, the median survival of the first group was the longest (225 vs. 113 vs. 47.5 days; p<0.0001, respectively). Even after PD for both gemcitabine and S-1 treatment, if the general condition of the patients is relatively good, the continuation of chemotherapy could prolong overall survival. Therefore, we expect that the use of additional therapeutic regimens would improve overall survival for patients with unresectable pancreatic cancer who acquired resistance against both gemcitabine (GEM) and S-1.

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To evaluate indications for gastroenteric bypass surgery in pancreas cancer patients (pts) with duodenal obstruction, we reviewed 39 pts who underwent bypass surgery at our hospital. Pts were classified into three groups, i.e. pts with adequate calorie intake (≥1000kcal/day) who were discharged without tube feeding (good group; 14 pts), pts who could not take more than 500kcal/day and were not discharged after surgery (poor group; 10 pts), and pts with an intake ≥1000kcal/day temporarily or those discharged with tube feeding (fair group; 15 pts). The median survival time (good, fair, and poor) was 167, 172, and 46 days, respectively, and was statistically different between stage IVa (without metastases) and IVb (with metastases) (p=0.028). We conclude that for pancreatic cancer pts without metastases, gastroenteric bypass surgery can be useful. For pts with metastatic cancer, however, gastroenteric bypass is not necessarily effective, and non-surgical treatment such as duodenal stenting should be considered.

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A 23-year-old male visited our hospital complaining of epigastric pain. Ultrasonography identified a solid, round tumor, including cyst, measuring 13cm in diameter in the pancreatic head. A solid pseudopapillary neoplasm (SPN) was confirmed by computed tomography and magnetic resonance imaging. A pancreatoduodenectomy was therefore performed. During surgery, infiltration of the mesentery in the transverse colon was detected and a resection was performed accordingly. The tumor was encapsulated. Solid and cystic lesions with hemorrhage and necrosis were observed. Histological examination revealed solid hyperplasia of small tumor cells with eosinophilic cytoplasm and partly-formed pseudopapillary structures. Immunohistochemistry staining revealed positive reactions for CD10 and β-catenin in the nuclei. SPN with malignant potential was diagnosed on the basis of the findings, including cellular atypia, mitotic figures, and infiltration to the mesocolon.

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A 49-year-old man, an alcohol abuser, was referred to our institute due to a growing splenic cyst after he recovered from acute pancreatitis. Although was asymptomatic, the abdominal ultrasonography, computed tomography and magnetic resonance imaging depicted a cyst of 7cm diameter growing in the spleen. He underwent a splenectomy and distal pancreatectomy. Pathological examination revealed that the splenic cyst had no epithelium, namely a pseudocyst and pancreas tissue existed adjacent to the cyst in the spleen. Considering the pathology and his history, the splenic pseudocyst might be an intrasplenic pancreatic pseudocyst induced by acute pancreatitis through the direct rupture of the pancreatic pseudocyst of the pancreatic tail into the spleen. This is a rare case because it followed acute pancreatitis, but not chronic pancreatitis, and was asymptomatic in spite of diameter of 7cm.

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A 50-year-old man presented to our department because of abdominal pain. He had alcoholic chronic pancreatitis with pancreatic stones and diabetes mellitus, and was being treated by a nearby doctor. The level of tumor marker CA19-9 rose to 3228U/ml. Abdominal enhanced CT showed a 20×14mm hypovascular tumor, in the pancreatic head near a 20×10mm pancreatic stone. Caudal pancreatic duct dilation was noticed. An FDG-PET hot spot corresponded with the tumor location shown by the CT scan. We diagnosed this patient as having pancreatic cancer and performed surgery. The final diagnosis was pancreatic cancer (f Stage III). When a pancreatic cancer occurs near a pancreatic stone, as in this case, it would be easy to overlook the pancreatic duct dilation caused by the cancer, obtained as indirect findings for dilation by the pancreatic stone, and thus an early diagnosis of pancreatic cancer would be difficult. During follow-up in patients with pancreatic stones, it is important to pay particular attention to the possibility of pancreatic cancer in the vicinity of pancreatic stones.

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We here report two cases of pancreas head cancer associated with celiac axis (CA) stenosis due to compression by the median arcuate ligament (MAL). Case 1: A 75-year-old man with epigastralgia was diagnosed as having a tumor of the pancreatic head. Abdominal CT and angiography showed CA stenosis. We diagnosed pancreatic head cancer with celiac axis stenosis due to MAL compression. During the operation, since CA was not fully revascularized only by excising the MAL, we performed vascular reconstruction following pancreaticoduodenectomy by end-to-end anastomosis of the gastroduodenal and inferior pancreatoduodenal arteries. Case 2: A 47-year-old woman with epigastralgia and back pain was diagnosed pancreatic head cancer with CA stenosis with MAL compression. CA was successfully revascularized only by excising the MAL. CA stenosis or occlusion is not rare condition. The most often cause of CA stenosis reported in Japan is compression by MAL. The precise preoperative evaluation and intraoperative examination to save hepatic blood flow are critical to perform pancreatoduodenectomy in such cases.

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We report a case of resectable metachronous pancreatic metastasis from colorectal cancer in a 45-year-old man who underwent a Miles' operation for rectal cancer, diagnosed as moderately differentiated adenocarcinoma, stage IIIa, A, N1, M0, followed by adjuvant chemotherapy using UFT/UZEL. One year after primary surgery, he was underwent right upper lobectomy of lung for metastatic lung cancer and was followed by mFOLFOX6 for half a year.
Four years after a Miles' operation, follow-up CT showed a tumor in the pancreatic body. We diagnosed it as primary pancreatic cancer and performed distal pancreatectomy. The pancreatic tumor was diagnosed histologically as moderately differentiated adenocarcinoma, which was identical to the primary rectal cancer. Immunohistochemistry showed an antigen expression profile of the tumor as negative for cytokeratin 7 and positive for cytokeratin 20, indicating metachronous metastasis from rectal cancer to the pancreas. Resectable cases of pancreatic metastasis from colorectal cancer have been rarely reported. Concerning the acceptable prognosis of reported cases including our case, the surgical resection for pancreatic metastasis from colorectal cancer should contribute to long-term survival in combination with systemic chemotherapy.

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Mediastinal pancreatic pseudocyst is a rare complication of pancreatitis. A 42-year-old-man with a medical history of alcoholic pancreatitis was admitted to our surgical unit with a high fever and dry cough. Blood examination revealed an increased white blood cell count of 157×10²/mm³ and C-reactive protein level of 19.5mg/dl. CT and MRI demonstrated an internal pancreatic fistula through the esophageal hiatus from the pancreatic pseudocyst in the pancreatic tail to cystic lesions in the mediastinum. We diagnosed the patient with mediastinal pancreatic pseudocyst with mediastinitis. In an emergency operation we drained the pancreatic pseudocyst in the mediastinum, which showed markedly elevated amylase activity of 4895IU/l.
The mechanism of mediastinal pancreatic pseudocyst is actually unknown in this case, but is probably due to acute migration of the pancreatic pseudocyst in the pancreatic tail through the esophageal hiatus. The postoperative course has been uneventful for the 2 years since the operation.

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