Akihiko Nakaizumi

Development of ductal carcinoma of the pancreas during follow-up of branch duct intraductal papillary mucinous neoplasm of the pancreas

Background: Synchronous occurrence of intraductal papillary mucinous neoplasm (IPMN) and ductal carcinoma of the pancreas has been reported. Branch duct IPMNs with lower likelihood of malignancy are not submitted to resection but are followed-up, so ductal carcinoma may develop during the follow-up. The development of ductal carcinoma of the pancreas during follow-up of branch duct IPMNs was investigated. Methods: 60 patients with branch duct IPMN who had an intraductal tumour of <10 mm on imaging examinations and a negative result for malignancy on cytological examination of the pancreatic juice were investigated. They were followed-up mainly by ultrasonography (US), and additionally by endoscopic ultrasonography (EUS), CT, magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) with cytological examination of the pancreatic juice for an average period of 87 months. Results: Ductal carcinoma of the pancreas distinct from IPMN developed in 5 of 60 (8%) branch duct IPMNs during follow-up. The 5-year rate of development of ductal carcinoma was 6.9% (95% CI 0.4% to 13.4%), the incidence of ductal carcinoma was 1.1% (95% CI 0.1% to 2.2%) per year and the standardised incidence ratio of development of ductal carcinoma was 26 (95% CI 3 to 48). Patients >70 years old developed ductal carcinoma significantly more frequently than those under 69. Four of five ductal carcinomas identified during follow-up were resectable. Cancer developed in IPMN in 2 of 60 (3%) branch duct IPMNs during follow-up. Conclusions: During follow-up of branch duct IPMNs, ductal carcinoma of the pancreas not infrequently developed distinct from IPMN. In the follow-up of IPMN, special attention should be paid to the development of ductal carcinoma of the pancreas.

Pancreatic ductal adenocarcinoma derived from IPMN and pancreatic ductal adenocarcinoma concomitant with IPMN.

Objectives: Pancreatic ductal adenocarcinoma (PDAC) may derive from an intraductal papillary mucinous neoplasm (IPMN) of the pancreas or may develop in the pancreatic duct apart from IPMN. The purpose of this study was to define the clinicopathological features of these 2 entities and compare them with those of ordinary PDAC. Methods: Of 765 patients who had surgical resection for IPMN, 122 were diagnosed as having PDAC derived from IPMN and 31 with PDAC concomitant with IPMN. In addition, 7605 patients with PDAC who were registered in the Japan Pancreas Society pancreatic cancer registry were compared with the above patients. Results: Pancreatic ductal adenocarcinomas derived from IPMN and concomitant with IPMN were significantly smaller, less invasive, and less extensive than ordinary PDAC. The median survival of patients with the 2 conditions was significantly longer than for those with ordinary PDAC when compared overall or when limited to TS2 (2.0 cm < tumor size ≤ 4.0 cm) or TS3 (4.0 cm < tumor size ≤ 6.0 cm) cases. Conclusions: These findings suggest that PDAC concomitant with IPMN and PDAC derived from IPMN may have more favorable biological behaviors or be diagnosed earlier than ordinary PDAC.

Endoscopic ultrasonography in diagnosis and staging of pancreatic cancer

The accuracy of endoscopic ultrasonography (EUS) for diagnosis of pancreatic cancers was evaluated in consecutive 232 patients with possible pancreatic cancer, and that for assessment of their locoregional spread was evaluated in 28 patients with pancreatic cancer subjected to pancreatectomy, in comparison with the accuracies of transabdominal ultrasonography (US) and computed tomography (CT). EUS was found to be significantly more accurate than US or CT and was especially useful for detecting small pancreatic cancers of less than 2 cm in diameter. With EUS, pancreatic cancers could be detected as a hypoechoic mass with a relatively unclear margin and irregular internal echoes. EUS was also more sensitive than CT and US for detecting venous and gastric invasions: it was more useful for detecting direct invasion of pancreatic cancers when the tumors were less than 3 cm in diameter. These findings indicate that EUS is an accurate method for diagnosis of pancreatic cancer and assessment of their locoregional spread and is particularly useful for detecting small tumors.

Feasibility and Efficacy of Combination Therapy With Preoperative Full-Dose Gemcitabine, Concurrent Three-Dimensional Conformal Radiation, Surgery, and Postoperative Liver Perfusion Chemotherapy for T3-Pancreatic Cancer

Objective:To evaluate both the feasibility and efficacy of our combined therapy, which consisted of preoperative chemoradiation, surgery, and postoperative liver perfusion chemotherapy (LPC) for patients with T3 (extended beyond the pancreatic confines) cancer of the pancreas. Summary Background Data:Because of the high incidence of local recurrence and liver metastasis, long-term outcomes for patients after resection of T3-pancreatic cancer are extremely poor. Methods:During the period from 2002 to 2007, 38 patients with T3-pancreatic cancers consented to receive a combination of preoperative chemoradiation, surgery, and postoperative LPC. With the aid of 3D radiation planning, irradiation fields were constructed that included both the primary pancreatic tumor and retropancreatic tissues while taking care to exclude any section of the gastrointestinal tract. The total dose of radiation was 50 Gy (2 Gy × 25 fractions/5 weeks) and was administered in combination with gemcitabine treatments (1000 mg/m2/week × 9/3 months). Preoperative restaging via computerized tomography and intraoperative inspection were used to determine if pancreatectomy was indicated. For respected cases, one catheter was placed into the gastroduodenal artery and another one into the superior mesenteric vein. Postoperatively, 5-FU (125 mg/day × 28 days) was infused via each of these 2 routes. Results:Preoperative chemoradiation was completed for all 38 patients, including 3 patients who required gemcitabine-dose reduction. Seven patients (18%) did not undergo surgical resection because either distant metastases or progressive local tumors had been detected after chemoradiation. The remaining 31 patients (82%) underwent pancreatectomy plus postoperative LPC, without postoperative or in-hospital mortality. The 5-year survival rate after pancreatectomy was 53%, with low incidences of both local recurrence (9%) and liver metastasis (7%). Postoperative histopathologic study revealed a marked degenerative change in cancer tissue, showing negative surgical margins (R0) for 30 patients (96%) and negative nodal involvement for 28 patients (90%). Conclusion:Results of this trial suggest that a combination of preoperative full-dose gemcitabine, concurrent 3D-conformal radiation, surgery, and postoperative LPC is feasible for the treatment of T3-pancreatic cancer. Using the method described in this article, we were able to effectively reduce the incidence of both local and liver recurrence. Therefore, this type of combination therapy seems promising for improving long-term outcomes for patients with T3-cancers of the pancreas. This study is registered with University hospital Medical information Network clinical trials Registry number, UMIN000001804.

Diagnosis of pancreatic cancer by detecting telomerase activity in pancreatic juice: comparison with K-ras mutations

OBJECTIVE:Telomerase activity is reported to be specific and very frequent in human malignancy. K-ras mutations are also very frequently detected in pancreatic cancer, but their specificity for pancreatic cancer is controversial. We examined the telomerase activity and K-ras mutations in pancreatic juice from patients with pancreatic disease.METHODS:Pancreatic juice was obtained endoscopically at endoscopic retrograde pancreatography from 10 patients with pancreatic cancer, three with chronic pancreatitis, and three with a normal pancreas. The telomerase activity in pancreatic juice was assayed by telomeric repeat amplification protocol. K-ras mutations in exon 1 codon 12 were examined by the two-step polymerase chain reaction combined with restriction enzyme digestion, followed by single-strand conformation polymorphism analysis and direct sequencing.RESULTS:Telomerase activity of >5.0 was detected in eight of 10 (80%) subjects with pancreatic cancer, but in none with chronic pancreatitis or normal pancreas. K-ras mutations were detected not only in eight of 10 (80%) subjects with pancreatic cancer but also in two of three with chronic pancreatitis and in one of three with a normal pancreas.CONCLUSIONS:It was shown that the detection of telomerase activity in pancreatic juice is a more useful diagnostic tool for pancreatic cancer than that of K-ras mutations.

Inhibition by ginsenoside Rg3 of bombesin-enhanced peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane in Wistar rats

The effects of concomitant use of bombesin and ginsenoside Rg3 on the incidence of peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane were investigated in male inbred Wistar rats. From the start of the experiment, rats were given weekly s.c. injections of azoxymethane (7.4mg/kg body weight) for 10 weeks and s.c. injection of bombesin (40μg/kg body weight) every other day, and from week 20, s.c. injections of ginsenoside Rg3 (2.5 or 5.0mg/kg body weight) every other day until the end of the experiment in week 45. Bombesin significantly increased the incidence of intestinal tumors and cancer metastasis to the peritoneum in week 45. It also significantly increased the labeling index of intestinal cancers. Although administration of a higher dose of ginsenoside Rg3 with bombesin had little or no effect on the enhancement of intestinal carcinogenesis by bombesin, the location, histologic type, depth of involvement, infiltrating growth pattern, labeling and apoptotic indices and tumor vascularity of intestinal cancers, it significantly decreased the incidence of cancer metastasis. These findings indicate that ginsenoside Rg3 inhibits cancer metastasis through activities that do not affect the growth or vascularity of intestinal cancers.

Attenuation by genistein of sodium‐chloride‐enhanced gastric carcinogenesis induced by N‐methyl‐N′‐nitro‐N‐nitrosoguanidine in Wistar rats

The effects of prolonged administration of genistein, a tyrosine‐kinase inhibitor, on sodium‐chloride‐enhanced induction of gastric carcinogenesis induced by N‐methyl‐N′‐nitro‐N‐nitrosoguanidine, and the labeling and apoptotic indices and vessel counts in the gastric mucosa and gastric cancers, were investigated in Wistar rats. After 25 weeks of the carcinogen treatment, rats were fed chow pellets containing 10% sodium chloride and were given s.c. injections of genistein at dosages of 15 mg/kg or 30 mg/kg body weight every other day. In week 52, the incidence of gastric cancers was significantly greater in rats fed sodium chloride than in untreated control rats. Prolonged administration of genistein at a dosage of 30 mg/kg, but not 15 mg/kg, body weight significantly reduced the incidence of gastric cancers, which was increased by oral treatment with sodium chloride. Genistein at the higher dose significantly decreased the labeling index and vessel counts of the antral mucosa and the gastric cancers (which were increased by treatment with sodium chloride) and significantly increased the apoptotic index of the antral mucosa and the cancers (which was lowered by the treatment with sodium chloride). These findings suggest that genistein attenuates gastric carcinogenesis promoted by sodium chloride, by inducing increased apoptosis and lower cell proliferation and angiogenesis of antral mucosa and gastric cancers. Int. J. Cancer 80:396–399, 1999.

Serum CA19-9 Alterations During Preoperative Gemcitabine-Based Chemoradiation Therapy for Resectable Invasive Ductal Carcinoma of the Pancreas as an Indicator for Therapeutic Selection and Survival

Objective:To evaluate serum CA19–9 alterations during preoperative gemcitabine-based chemoradiation therapy (CRT) for resectable pancreatic cancer (PC) in the earlier identification of patients who are likely to benefit from subsequent resection. Summary Background Data:One of the advantages of the preoperative CRT strategy for patients with advanced PC is that undetectable systemic disease may be revealed during preoperative CRT, thus avoiding unnecessary surgery. Serum CA19–9 has been evaluated as a predictive indicator of the treatment efficacy and outcome in various clinical settings. Methods:We retrospectively reviewed 64 consecutive patients with resectable PC (at diagnosis) who received preoperative CRT at our hospital between 2002 and 2008. Patients were divided into 2 groups (efficacy grouping) to evaluate the efficacy of preoperative CRT according to the clinical course. Group A included patients who were unable to receive the subsequent resection due to the development of unresectable factors during preoperative CRT and those who received the subsequent resection but developed recurrent disease within 6 months after surgery; group B included patients who received the subsequent resection and survived without recurrences for more than 6 months after surgery. We developed a new classification utilizing pretreatment CA19–9 and proportional alteration of CA19–9 2 months after the initiation of treatment. The categories were defined as: I (increased), MD (modestly decreased), and SD (substantially decreased). Clinicopathological variables and CA19–9 alteration status were correlated with the efficacy grouping and overall survival. Results:All of the category I patients were included in group A, 93.5% of the category SD patients in group B, and approximately half of the category MD patients in group A. CA19–9 alteration status was a single independent variable associated with efficacy grouping and overall patient survival, with the 1-year survival rate of category I patients, and the 4-year survival rate of category MD and SD patients being 22.2%, 34.1%, and 58.9%, respectively. Conclusions:CA19–9 alteration status is useful in identifying those who will benefit from the preoperative CRT and subsequent resection and those who will not; it was a significant predictor for patient prognosis in the setting of the preoperative CRT strategy for resectable PC.

Role of intraoperative cytology combined with histology in detecting continuous and skip type intraductal cancer existence for intraductal papillary mucinous carcinoma of the pancreas.

Intraductal papillary mucinous neoplasm (IPMN) is a recently discovered pancreatic tumor that has continuous or discontinuous (skip) lesions. Recent reports suggest a higher frequency of cancer recurrence in the remnant pancreas after surgical resection of IPMN. It is therefore important to precisely detect intraductal cancer extension and skip lesions when resecting IPMN.

Postoperative Cytology for Drained Fluid from the Pancreatic Bed After “Curative” Resection of Pancreatic Cancers: Does It Predict Both the Patient’s Prognosis and the Site of Cancer Recurrence?

Objective To evaluate the postoperative cytology of drained fluid from the pancreatic bed as a predictive indicator of local recurrence after curative (R0) resection of pancreatic cancer. Summary Background Data The pancreatic bed offers a common site of cancer recurrence (local recurrence), even after curative (R0) resection is performed for pancreatic cancer. If local recurrence is thereby predicted precisely, soon after surgery, we have a chance to treat it by adding radiation or some other locoregional therapy before it can grow or spread beyond the pancreatic bed. However, there have been no previous reports of cytology performed on the drained fluid after pancreatectomy. Methods This study includes 94 patients who had shown negative results in the peritoneal washing cytology before resection and subsequently received pancreatectomies for pancreatic tumors. They consisted of 12 benign tumors, 17 noninvasive or minimally invasive carcinomas and 65 invasive ductal carcinomas (R0 = 58; R1/2 = 7). Postoperatively, the drained fluid from the pancreatic bed was collected for 24 hours and used for cytologic examination. The cytologic results were examined in association with the histopathology of the resected tumor, patients survival, and mode of cancer recurrence, including local recurrence. Results Patients with benign tumors or noninvasive/minimally invasive carcinomas had negative result in cytology, and none of them have died of local recurrence (limited to the pancreatic bed) to date. However, patients with invasive ductal carcinoma revealed higher cytology-positive rates: 28% (16/58) in curative (R0) resection; and 71% (5/7) in noncurative (R1/2) resection. Among 58 patients with R0 resection, the 3-year survival rate was 14% in 16 cytology-positive patients and 55% in 42 cytology-negative patients (P < 0.05). The 3-year cumulative rate of local recurrence was 85% and 23%, respectively (P < 0.05). Compared with other histopathologic parameters obtained from the resected specimens, the drain cytology was more specific in predicting the subsequent development of local recurrence. Conclusions Drain-cytology was a quick examination that enabled us to specifically indicate both minute residual cancer and subsequent development of local recurrence even after R0 resection of pancreatic cancer.