The feasibility of dose escalation using concurrent radiation and 5-fluorouracil therapy following pancreaticoduodenectomy for pancreatic carcinoma

We evaluated the feasibility of dose escalation using external beam radiation therapy (RT) and 5-fluorouracil (5-FU) following pancreaticoduodenectomy for pancreatic carcinoma. Fourteen patients who underwent pancreaticoduodenectomy for stage I–III adenocarcinoma of the pancreas received postoperative high-dose chemoradiation. RT was given at 1.8-Gy daily fractions to total doses of 54 Gy for patients with negative surgical margins (n = 12), and 64.8 Gy for those with gross residual disease (n = 2). Concurrent 5-FU was given as a continuous infusion (CI) at 225 mg/m² per day (n = 9) beginning or day 1 and continuing until the completion of RT, or by bolus injection at 500 mg/m² per day (n = 5) during weeks 1 and 4 of RT. Follow-up ranged from 32 to 36 months (median, 35 months). All patients were able to complete the planned high-dose postoperative chemoradiation and none required a treatment break. No grade 4 acute toxicity was observed. Grade 3 acute toxicity was limited to 2 patients. Two patients developed grade 3 (n = 1) or 4 (n = 1) subacute toxicity, all gastrointestinal-related. There have been no fatal toxicities and no grade 3 or 4 late toxicity has been observed. The 3-year survival is 21%. Dose escalation of postoperative 5-FU chemoradiation following pancreaticoduodenectomy for pancreatic carcinoma is well tolerated. Further dose-intensification of postoperative adjuvant therapy in these patients appears feasible and is being evaluated in a recently activated national trial. Received for publication on Feb. 16, 1999; accepted on June 10, 1999     

A new in-vitro drug sensitivity test (collagen-gel droplet embedded-culture drug sensitivity test) in carcinomas of pancreas and biliary tract: possible clinical utility

The collagen-gel droplet embedded-culture drug sensitivity test (CD-DST), a chemosensitivity test, evaluate the efficacy of anticancer drugs and to was used clinically to thus plan rational postoperative chemotherapy for patients with pancreatic and biliary tract carcinomas. The CD-DST solves some problems inherent in other conventional assays. This method: (1) allows evaluation of four chemotherapeutic agents, using small quantities of cells (1 × 10⁵ cells), (2) shows high primary culture success rates, (3) maintains the original growth characteristics of the cultured cells, (4) eliminates the effects of fibroblasts by employing image analysis, and (5) permits evaluation using physiologic drug concentrations. Primary cultures of tumor cell samples from all 25 patients with pancreatic or biliary tract carcinomas studied were successful. Against pancreatic carcinomas, the efficacy rates, assessed by CD-DST, of four anticancer drugs evaluated were: 25.0% for mitomycin (MMC), followed by 23.5% for adriamycin, 18.8% for 5-fluorouracil (5-FU), and 11.8% for cisplatin (CDDP). Against biliary tract carcinomas, the rates were highest for 5-FU and MMC (50.0%) and lowest for CDDP (25.0%). The efficacy rates for all four anticancer drugs evaluated were higher against biliary tract carcinomas than against pancreatic carcinomas. Tumor cultures from 10 of 17 patients with pancreatic cancer and 3 of 8 patients with biliary tract cancer showed no sensitivity to any of the drugs tested. The in-vitro results with CD-DST suggest the risk of administering non-selective postoperative chemotherapy to patients with pancreatic and biliary tract carcinomas, and emphasize the importance of carefully selecting effective chemotherapeutic agents based on adequate chemosensitivity testing. Received for publication on July 29, 1998; accepted on Aug. 13, 1998     

Resection of locally advanced pancreatic cancer after downstaging-wth continuous-infusion 5-fluorouracil,mitomycin-C,leucovorin, and dipyridamole

Patients with locally advanced pancreatic adenocarcinoma who receive conventional therapy with radiation with S-fluorouracil(5-FU) have median survivals ranging from 8 to 12 months. Here we report our experience with a four-drug chemotherapeutic regimen that resulted in sufficient downstaging of tumor in some patients to justify surgical reexploration and resection. From April 1991 through April 1994,38 patients received 5-FU as a continuous infusion (200 mg/m²/day), calcium leucovorin weekly by imravenous bolus injection (30 mg/m²), mitomycin-C every 6 weeks (10 mg/m² intravenously), and dipyridamole daily orally (75 mg) for locally advanced unresected pancreatic cancer. All of these patients were evaluable for response, toxicity, and survival. There were 14 partial responses and one complete response—a 39% response rate. The median survival for all patients was 15.5 months; the l-year survival rate from time of initial diagnosis was 70%. Six of 15 responding patients had sufficient tumor regression to meet clinical criteria for resectability and reexploration, four of whom underwent a curative resection. The median survival of these six patients was 28 months from the time of original diagnosis. The l-year survival was 83 %, with one patient still alive and free of disease at 53 months. We believe this unique experience from a single institution justifies a prospective multi-institutional trial to evaluate the efficacy of this approach iu a larger number of patients. Presented at the Thirty-Eighth Annual Meeting of The Society for Surgery of the Alimentary Tract, Washington, D.C., May 11–14, 1997.     

Intravenously administered human epidermal growth factor in the rat. Biliary excretion and influences on pancreatic secretion

BACKGROUND/AIM: Epidermal growth factor (EGF) is known to exert mitogenic effects in different tissues, including the digestive tract and pancreas. EGF is also found in high concentrations in pancreas. Infusion of human EGF has been shown to induce proliferation of cells in exocrine pancreas, and to increase the thickness of the small intestine. The aim of this study was to investigate the influence of intravenously administered human EGF on pancreatic and biliary secretions in the rat. MATERIALS AND METHODS: Rats were fasted overnight and were given human EGF intravenously, either as a bolus dose of 5 microg or as a continuous infusion in increasing doses from 0.5 to 10 microg/h. Bile and pancreatic juice were either collected together or separately. The concentration of human EGF in bile and pancreatic juice was measured. RESULTS: After a bolus dose of EGF increased bile/pancreatic secretion was seen after 60 and 90 min when the bile and pancreatic secretions were not separated. Continuous infusion of EGF increased the joint secretion rate of bile and pancreatic juice in a dose-dependent manner. No effect on secretion rate was seen when bile and pancreatic juice were collected separately. After intravenous infusion of human EGF a 1,000-fold increase of human EGF excretion was found in bile but not in pancreatic juice. CONCLUSION: Intravenously administered human EGF was excreted in high concentrations in bile and increased the secretion rate of pancreatic juice when collected together with bile. The results suggest that EGF, at least partly, exerts its effect on the pancreas and the proximal gastrointestinal tract after excretion with bile and stimulates pancreatic secretion via this route.     

Treatment perspectives in locally advanced unresectable pancreatic cancer.

Locally advanced unresectable pancreatic cancer is sometimes encountered without manifest distant metastases. Twenty patients with histologically proven unresectable pancreatic cancer without distant metastases were treated with radiotherapy and 5-fluorouracil (5-FU). Radiotherapy consisted of 50 Gy external upper abdomen radiation in two courses, concomitant with intravenous 5-FU 375 mg/m2 given as a bolus injection 4-6h before radiation on the first 4 days of each treatment course. The treatment protocol was completed in 18 patients without complications. The median survival time was 10 months which compares favourably with a 3-5 months median survival time when treatment is withheld. Nine patients (45 per cent) were alive at 1 year, two patients at 2, 3 and 4 years. A second-look operation was performed in four patients 6, 11, 12 and 22 months after completion of radiotherapy. In two patients the tumour could be resected. It appears that treatment with radiotherapy and 5-FU may benefit patients with locally advanced unresectable pancreatic cancer.     

5-氟尿嘧啶缓释剂瘤内注射治疗胰腺癌的实验研究和临床研究

目的 观察5-氟尿嘧啶(5-Fu)缓释剂对荷胰腺癌裸鼠肿瘤细胞及胰腺癌患者血清肿瘤标记物和细胞免疫的影响。方法 (1)5-Fu缓释剂的体外释放实验和体外抑瘤实验：测定浸出液药物的浓度，计算释放量；检测其浸出液对人胰腺癌细胞株PC3的抑制作用：(2)将荷胰腺癌细胞株Pc3裸鼠60只，随机分成静脉对照组(A组)、5-Fu静注组(B组)、基质植入组(C组)、大剂量5-Fu缓释剂植入组(D组)和小剂量5-FU缓释利植入组(E组)：治疗前及治疗后l4d测肿瘤大小。治疗2周后观察肿瘤组织学变化：免疫组化法测定bcl-2和Bax的蛋白表达水平；TUNEL法检测凋亡指数(Al)。(3)手术探查不能切除之胰腺癌69例随机分成3组：将5-FU缓释剂瘤内植入治疗组(治疗组)、术后行5-FU静脉化疗组(化疗组)和对照组。分别于术前1d和术后第14天采血，测定各组血清中NK细胞，T细胞亚群和CEA，CA50，CA19-9，CA125，CA242血清肿瘤标记物水平。结果 (1)5mg 5-FU缓释剂第1天释放量最大，为0．85mg，第3天为0．45mg，其后在0．25mg水平维持稳定的缓慢释放；释放时间长达l4d以上。(2)5-Fu缓释剂第1天的浸出液对人胰腺癌细胞株PC-3的抑制率达60．27％，第3天为34．25％，以后稳定在25．00％左右。5-Fu缓释剂瘤内注射治疗组裸鼠移植瘤生长速度减慢，bcl-2基因表达明显低于其他各组，而Bax基因表达明显高于其他各组，肿瘤细胞的Al明显高于其他各组。D组和E组肿瘤组织中炎症反应和血管内膜增厚程度明显高于其他各组。术后治疗组CD4 ／CD8 和NK细胞水平高于化疗组，而血清中E述5种肿瘤标记物低于对照组和化疗组。结论 5-Fu缓释剂能在2周内在体外较稳定地持续释放，对人胰腺癌细胞株PC3有持续抑制作用。该剂瘤内注射可明显抑制荷胰腺癌瘤裸鼠瘤体的生长，其作用机制与药物在肿瘤组织中引起的炎症反应和血管内膜增厚等因素有关；并可能与诱导肿瘤细胞的凋亡有关。该剂植入患者胰腺癌实体内，能明显降低5种血清肿瘤标记物水平，同时对患者的细胞免疫功能影响较小，5-Fu缓释剂可望成为治疗不能切除之胰腺癌的较好的制剂。     

Phase II trial of 5-fluorouracil and low-dose cisplatin in patients with squamous cell carcinoma of the esophagus

A phase II study was conducted to determine the clinical efficacy and toxicity of 5-fluorouracil (5-FU) and low-dose cisplatin (CDDP) in patients with squamous cell carcinoma of the esophagus. Chemotherapy consisted of 5-FU at a dose of 330 mg/m² per day, given as a 24-h infusion on days 1–7, and CDDP at a dose of 6 mg/m² per day, given as a 2-h infusion on days 1–5. Either two or four cycles of chemotherapy were administered to 20 patients with stage III advanced esophageal carcinoma. All 20 patients were then assessed for response and toxicity. An objective response was demonstrated by 11 of the 20 patients, with one complete response (CR) and ten partial responses (PR), bringing the response rate to 55%, with a 95% confidence interval of 27% to 83%. Surgical resection of the tumor was performed in all 20 patients. One patient was found to have a grade 3 histological CR. The median survival of all the patients was 20.5 months, with a range of 4.5 to 48.0 months. Neutropenia and thrombocytopenia developed in five (25%) and two (10%) patients, respectively, and the nonhematologic toxicities were insignificant. The findings of this phase II study indicate that preoperative treatment using 5-FU and low-dose CDDP chemotherapy for patients with advanced esophageal carcinoma appears to achieve a high response rate after shortterm administration without affecting the quality of sophisticated lymph node dissection.     

Interferon-based adjuvant chemoradiation therapy improves survival after pancreaticoduodenectomy for pancreatic adenocarcinoma

BACKGROUND: Based on a 2-year survival of 43%, the Gastrointestinal Tumor Study Group (GITSG) recommended adjuvant 5-FU-based chemoradiation for resected patients with adenocarcinoma of the pancreatic head. Here we report improved survival over the GITSG protocol with a novel adjuvant chemoradiotherapy based on interferon-alpha (IFNalpha). METHODS: From July 1993 to September 1998, 33 patients with adenocarcinoma of the pancreatic head underwent pancreaticoduodenectomy (PD) and subsequently went on to adjuvant therapy (GITSG-type, n = 16) or IFNalpha-based (n = 17) typically given between 6 and 8 weeks after surgery. The latter protocol consisted of external-beam irradiation at a dose of 4,500 to 5,400 cGy (25 fractions per 5 weeks) and simultaneous three-drug chemotherapy consisting of (1) continuous infusion 5-FU (200 mg/m2 per day); (2) weekly intravenous bolus cisplatin (30 mg/m2 per day); and (3) IFNalpha (3 million units subcutaneously every other day) during the 5 weeks of radiation. This was then followed by two 6-week courses of continuous infusion 5-FU (200 mg/m2 per day, given weeks 9 to 14 and 17 to 22). Risk factors for recurrence and survival were compared for the two groups. RESULTS: A more advanced tumor stage was observed in the IFNalpha-treated patients (positive nodes and American Joint Committee on Cancer [AJCC] stage III = 76%) than the GITSG group (positive nodes and stage III = 44%, P = 0.052). The 2-year overall survival was superior in the IFNalpha cohort (84%) versus the GITSG group (54%). With a mean follow-up of 26 months in both cohorts, actuarial survival curves significantly favored the IFNalpha group (P = 0.04). CONCLUSIONS: With a limited number of patients, this phase II type trial suggests better survival in the interferon group as compared with the GITSG group even though the interferon group was associated with a more extensive tumor stage. The 2-year survival rate in the interferon group is the best published to date for resected pancreatic cancer. The interferon/cisplatin/5-FU-based adjuvant chemoradiation protocol appears to be a promising treatment for patients who have undergone PD for adenocarcinoma of the pancreatic head.     

Significance of K-ras mutation and CEA level in pancreatic juice in the diagnosis of pancreatic cancer

The early diagnosis of pancreatic carcinoma is essential for increasing patient survival rates. In this study, 52 patients with suspected pancreatic diseases were examined to investigate the value of K-ras codon 12 point mutation, levels of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19-9), and cytology of pancreatic juice in the diagnosis of pancreatic carcinoma. Pancreatic juice was taken without secretin stimulation. K-ras mutation was detected by enriched polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP). K-ras mutation in pancreatic juice was more frequent in carcinoma than in benign diseases (P = 0.0448). The positive predictive value of K-ras mutation for the diagnosis of neoplastic disease was 83%. The CEA level in pancreatic juice in carcinoma was significantly greater than that in benign disease (P < 0.0001). When the cutoff level of CEA was set at 50 ng/ml, its accuracy for the diagnosis of carcinoma was 85%. A multivariate analysis showed that K-ras mutation and CEA level in pancreatic juice, as well as serum CA19-9 level and age of the patient were independent variables for the diagnosis of carcinoma, and the accuracy of diagnosis by this analysis was increased to 90%. In conclusion, both K-ras mutation and CEA level in pancreatic juice may be valuable for the diagnosis of carcinoma. Better discrimination was possible with a multivariate analysis. Received for publication on Dec. 12, 1998; accepted on July 19, 1999     

化疗药物在血液和胰液中的动态分布及其相关性研究

化疗目前仍然是胰腺癌辅助治疗的重要手段之一，但常用的化疗药物５－氟尿嘧啶（５－ＦＵ），丝裂霉素（ＭＭＣ）是否能够通过胰腺组织，并达到有效治疗浓度，尚不清楚。作者以狗为实验对象，于测定多种抗生素在血液和胰液中浓度比的工作基础上，研究了快速静脉推注５－ＦＵ及ＭＭＣ后血液和胰液中药物分布及相关性，同时对术后有胰支架管的部分胰十二肠切除患者进行了上述观察。结果显示血中５－ＦＵ及ＭＭＣ能够穿透胰腺组织，通过血－胰屏障。作者认为５－ＦＵ和ＭＭＣ可适用于胰腺癌的辅助化疗。     

胰头癌的外科手术综合治疗143例临床分析

目的 探讨胰十二指肠切除术治疗胰头癌的外科临床价值。方法 回顾性分析我院2005年3月至2009年3月外科治疗的143例胰头癌患者的临床资料,分为非手术治疗组（27例）、姑息性手术组（88例）、手术切除组（28例）。结果 本组外科治疗胰头癌143例,随访率97.4%（140/143）,中位生存时间11.3个月,1、3及5年术后生存率分别49.1%、10.3%、4.3%。其中,外科手术治疗的胰头癌患者的根治性切除率为24.1%（28/116）,手术切除组1、3及5年术后生存率（85.7%、42.9%、17.9%,中位生存时间25.5个月）较非手术治疗组（0、0、0,中位生存时间6.6个月）或姑息性手术组（37.5%、0、0,中位生存时间8.3个月）明显提高（P＜0.01）,但其围手术期并发症发生率也明显升高（P＜0.05）。三组围手术期病死率差异无统计学意义（P＞0.05）。术前减黄组与术前未减黄组在围手术期并发症发生率、死亡率及1、3、5年生存率方面比较,其差异无统计学意义（P＞0.05）。结论 外科手术切除是治疗胰头癌的重要手段,尤其根治性胰十二指肠切除术是治愈胰头癌的唯一有效的方法,联合门静脉或肠系膜上静脉切除术、半肝切除的胰十二指肠扩大切除术提高了胰头癌的根治性切除率、临床治愈的机会以及改善了患者的生存质量。     

Biochemical modulation therapy for pancreatic cancer

It is well known that the clinical course in most patients with advanced pancreatic cancer is not influenced substantially by chemotherapy and/or radiotherapy. However, new chemotherapy, based on the synergistic antitumor activities of 5-fluorouracil (5-FU) and cisplatin (CDDP) producing biochemical modulation in solid cancers diagnosed as adenocarcinoma, has recently been reported to be effective. In gastrointestinal cancers, the optimal concentrations of each drug and the duration of the anticancer effects, as well as adverse effects have been confirmed in pharmacodynamic studies. Our experience of this treatment for advanced pancreatic cancer (stage IV) indicates the usefulness of the antitumor effect in terms of both effect on the tumor size in unresectable patients and prognosis in resectable patients. These results were remarkable in patients diagnosed as stage IV b and/or curability C. Although there were adverse effects, none were severe. However, anything compromising the patient's quality of life must be prevented. Randomized prospective studies of the combination of 5-FU and CDDP are expected in the near future. Received for publication on July 29, 1998; accepted on July 31, 1998     

Mitogen-activated protein kinases and chemoresistance in pancreatic cancer cells

BACKGROUND: Chemoresistance is an important clinical problem in pancreatic cancer. As the mitogen-activated protein kinases (MAPKs) have been found to be involved in the development of chemoresistance in a variety of cancer cell lines, the aim of the current study was to assess the role and mechanism of MAPK signaling in mediating chemoresistance in pancreatic cancer cells. MATERIALS AND METHODS: The effects of pharmacological inhibition of MAPKs on resistance of pancreatic cancer cells to apoptosis induced by treatment with chemotherapeutic drugs were analyzed. RESULTS: Compared with parental cells, the activity of extracellular signal-regulated kinase (ERK) was elevated in all of the three chemoresistant sublines at basal conditions. Inhibition of the ERK pathway by PD98059 sensitized cells to 5-fluorouracil (5-FU), whereas cells became more resistant to Adriamycin (ADM; Meiji Seika, Tokyo, Japan) and gemcitabine (GEM). 5-FU induced apoptosis primarily via a caspase-8-dependent pathway, and ADM and GEM via caspase-9. PD98059 enhanced the activity of caspase-8 and inhibited the activation of caspase-9. In addition, PD98059 regulated the level of phospho-Bcl-2. CONCLUSIONS: These data suggest that although constitutive activation of the ERK pathway might be a marker of chemoresistance, the effects of this pathway on chemoresistance of pancreatic cancer cells are drug dependent. This study also provides evidence for a possible link between the ERK pathway and activation of the caspases and Bcl-2.     

Marginal effects of regional intra-arterial chemotherapy as an alternative treatment option in advanced pancreatic carcinoma

Background Locoregional intra-arterial (i.a.) chemotherapy may provide high levels of cytostatic concentrations within the tumour and, simultaneously, a low rate of systemic side effects compared with systemic administration of anti-neoplastic drugs. In addition, this may lead to an increase of tumour response rate and prolongation of survival time. The aim of the study was (1) to evaluate the benefit of an i.a. infusion of cytostatic drugs via the coeliac trunk on tumour response rate and survival time, (2) to elucidate problems and risks, and finally (3) to achieve an improvement of overall therapeutic management in pancreatic carcinoma.Patients and methods In 22 patients (12 female; 10 male; mean age 57.1 years) with locally advanced pancreatic carcinoma, which was confirmed by histopathology, i.a. chemotherapy was administered. Through a catheter, which was inserted via the femoral artery by the Seldinger technique and placed with the tip in the coeliac trunk, two different drug combinations were given. Group A (n=12) were given a bolus injection of a mixture (chemo-occlusion) consisting of amilomer (Spherex) and epirubicin (Farmorubicin) followed by short-time infusion of folic acid and 24-h infusion of 5-FU. Group B (n=10) were given treatment over 5 days: mitoxantrone (Novantrone, day [d] 1), 5-FU and folic acid (Haemato-folin, d 2–4), and cisplatin (d 5). Treatment was repeated in both groups every 4 weeks. Tumour response was assessed by computed tomography every 8 weeks.Results In group A, there was one complete and one partial remission, resulting in a remission rate of 16.6%. Two patients showed stable disease, while in two-thirds of the patients (n=8), progressive disease was found. Median survival time was 3 months; 1-year survival rate was 33.3% (4 of 12 patients). In group B, again, one complete and one partial remission were observed (remission rate 20%). In three cases, stable disease, and in 50% of patients (n=5), progressive disease, were documented. Median survival was 7.0 months; 1-year survival rate was 20% (2 of 10 patients). If both groups were compared, there was no difference in survival. In addition, no prolongation of survival time was found in comparison with patients of a historical study group treated with established systemic chemotherapy using gemcitabine monotherapy (n=28; median survival time 9 months). Though a tendency for poorer outcome of i.a. chemotherapy was seen when the Kaplan–Meier curves of survival were compared, this difference was not statistically significant (log rank test, P=0.08).Conclusion Despite conceptual and pharmacokinetic advantages of locoregional i.a. chemotherapy, better outcome with regard to tumour response rate and survival time could not be found. I.a. chemotherapy is, therefore, still an experimental treatment option in pancreatic carcinoma and can, currently, not be recommended for routine use.     

氟尿嘧啶与生长抑素受体基因联合治疗鼠 胰腺癌移植瘤的研究

目的 ： 观察生长抑素二型受体(SSTR2)基因体内转染后裸鼠胰腺癌移植瘤对5-氟尿嘧啶（5-FU）的反应，并探讨其可能机制。方法 ：将人胰腺癌细胞株panc-1种植于裸鼠背部皮下形成胰腺癌移植瘤模型。成模后动物随机分成4组（每组6只）;I组为对照组;II组为腹腔注射5-FU治疗组;III组为瘤内注射pCMV-6C-SSTR2-脂质体转染SSTR2基因治疗组;IV组为基因治疗+5-FU治疗组。观察肿瘤生长速度，测量瘤体大小及重量。用免疫组织化学方法和免疫印迹技术(Westernblot)检测转染效率;用凋亡原位检测方法(Tunel)检测胰腺癌细胞的凋亡率。结果 ：体内转染后SSTR2可重新表达。5-FU和SSTR2基因联合治疗(IV)组肿瘤生长速度显著慢于单独基因治疗(III)组及单独5-FU治疗(II)组和空白对照(I)组（ P <0.01）;最终肿瘤大小，重量也显著小于其他3组（均 P <0.01），而癌细胞凋亡率显著高于其他3组（均 P <0.01）。结论 ：SSTR2重新表达后可增强胰腺癌细胞对化疗药物5-FU的敏感性，联合5-FU 和SSTR2基因治疗可望成为治疗胰腺癌新的途径。     

Basaloid-Squamous Carcinoma of the Esophagus Treated by Preoperative Chemotherapy: Report of Two Cases

Basaloid squamous carcinoma (BSC) of the esophagus has been associated with a poor outcome after surgery. We herein report two patients with esophageal BSC treated by preoperative chemotherapy. Patient 1 was a 55-year-old man who presented with a tumor of the middle esophagus diagnosed as BSC. He was treated by chemotherapy using a combination of 5-fluorouracil (5-FU: 750 mg/m², 1st–5th day, 24-h continuous infusion) and cisplatin (CDDP: 75 mg/m², 1st day, drip infusion per 2 h) before surgery, because of lymph node metastases of the mediastinum and around the left gastric artery. Even though the metastatic nodes were reduced and an esophagectomy was performed, the patient died of recurrence 12 months after chemotherapy. Patient 2 was a 57-year-old man who demonstrated BSC of the esophagus with direct invasion to the discending aorta, who was treated by preoperative chemotherapy using the same regimen as that of patient 1. The esophageal tumor was reduced, and a curative esophagectomy was performed. The patient is now alive without recurrence 38 months after chemotherapy. In conclusion, preoperative chemotherapy using a combination of 5-FU and CDDP may thus be an effective treatment for patients with advanced BSC of the esophagus. Received: September 19, 2001 / Accepted: May 7, 2002 RID="*" ID="*" Reprint requests to: N. Koide     

A modified version of Herrera's method for creating a pancreatic fistula in dogs

Various cannulae have been devised to serve in experiments for collecting pancreatic juice. In this study we created a pancreatic fistula in dogs through a modification of Herrera's method. Since it is advisable to make as small a duodenal pouch as possible to collect almost all the secreted pancreatic juice, both ends of the pouch were closed by an inverted continuous all-layer suture. The lateral flange of the cannula was then introduced into the pouch to sample the pancreatic juice. Duodenoduodenostomy was performed to restore continuity of the alimentary tract, and the other end was inserted into the duodenum 3 cm distal to the anastomosis on the anal side. The exocrine pancreatic secretion of these dogs responded well to food ingestion, with a peak level of 14.5±5.4 ml/15 min appearing after 30 to 45 min in a postprandial state. Moreover, the animals were able to survive and be utilized for experiments for a period of 3 to 5 months. This experimental model is therefore considered to be of great value for the investigation of exocrine pancreatic secretion.     

Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience.

OBJECTIVE: This study was designed to evaluate prospectively survival after pancreaticoduodenectomy for pancreatic adenocarcinoma, comparing two different postoperative adjuvant chemoradiation protocol to those of no adjuvant therapy. SUMMARY BACKGROUND DATA: Based on limited data from the Gastrointestinal Tumor Study Group, adjuvant chemoradiation therapy has been recommended after pancreaticoduodenectomy for adenocarcinoma of the head, neck, or uncinate process of the pancrease. However, many patients continue to receive no such therapy. METHODS: From October 1991 through September 1995, all patients with resected, pathologically confirmed adenocarcinoma of the head, neck, or uncinate process of the pancreas were reviewed by a multidisciplinary group (surgery, radiation oncology, medical oncology, and pathology) and were offered three options for postoperative treatment after pancreaticoduodenectomy: 1) standard therapy: external beam radiation therapy to the pancreatic bed (4000-4500 cGy) given with two 3-day fluorouracil (5-FU) courses and followed by weekly bolus 5-FU (500 mg/m2 per day) for 4 months; 2) intensive therapy: external beam radiation therapy to the pancreatic bed (5040-5760 cGy) with prophylactic hepatic irradiation (2340-2700 cGy) given with and followed by infusional 5-FU (200 mg/m2 per day) plus leucovorin (5 mg/m2 per day) for 5 of 7 days for 4 months; or 3) no therapy: no postoperative radiation therapy or chemotherapy. RESULTS: Pancreaticoduodenectomy was performed in 174 patients, with 1 in-hospital death (0.6%). Ninety-nine patients elected standard therapy, 21 elected intensive therapy, and 53 patients declined therapy. The three groups were comparable with respect to race, gender, intraoperative blood loss, tumor differentiation, lymph node status, tumor diameter, and resection margin status. Univariate analyses indicated that tumor diameter < 3 cm, intraoperative blood loss < 700 mL, absence of intraoperative blood transfusions, and use of adjuvant chemoradiation therapy were associated with significantly longer survival (p < 0.05). By Cox proportional hazards survival analysis, the most powerful predictors of outcome were tumor diameter, intraoperative blood loss, status of resection margins, and use of postoperative adjuvant therapy. The use of postoperative adjuvant chemoradiation therapy was a predictor of improved survival (median survival, 19.5 months compared to 13.5 months without therapy; p = 0.003). The intensive therapy group had no survival advantage when compared to that of the standard therapy group (median survival, 17.5 months vs. 21 months, p = not significant). CONCLUSIONS: Adjuvant chemoradiation therapy significantly improves survival after pancreaticoduodenectomy for adenocarcinoma of the head, neck, or uncinate process of the pancreas. Based on these survival data, standard adjuvant chemoradiation therapy appears to be indicated for patients treated by pancreaticoduodenectomy for adenocarcinoma of the head, neck, or uncinate process of the pancreas. Intensive therapy conferred no survival advantage over standard therapy in this analysis.     

Pancreatic juice cytology for monitoring pancreatic grafts in the early postoperative period

Thirty-one pancreas transplant recipients were monitored by pancreatic juice cytology in the early post-operative period. An increase in the total amount of cells and, in particular, signs of immunoactivation with the appearance of two or more blast-transformed cells per specimen were taken as evidence of acute rejection. According to these criteria a total of 38 rejection episodes were diagnosed. The first positive cytology appeared after 9 days (mean) and lasted for 2 days (mean). Immunocytochemical analysis of the juice showed increased amounts of CD3+ cells during rejection. When rejection occurred during prophylaxis with antithymocyte globulin, neutrophils were preponderant in the pancreatic juice while during OKT-3 prophylaxis a high percentage of monocytes was a characteristic finding. Antirejection treatment was started when the cytology became positive and all rejection episodes except one were reversed. A decrease in the pancreatic juice amylase activity occurred in 66% of the rejection episodes, but in only 5 of the 38 episodes was the decrease highly significant. No correlation was found between graft rejection and volume excretion of pancreatic juice. There were no persistent or characteristic changes in serum amylase or peripheral white blood cell count at the time of rejection. Graft pancreatitis was diagnosed cytologically in 7 patients, in 5 of whom the grafts were eventually lost.     

Minute pancreatic carcinoma with initial symptom of acute pancreatitis

We experienced a case of minute pancreatic carcinoma in a 59-year-old man who complained of upper abdominal pain after drinking alcohol. Abdominal ultrasonography (US) revealed dilatation of the main pancreatic duct (MPD). Abdominal computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) showed slight dilatation of the MPD and its obstruction near the portal vein. Endoscopic retrograde cholangiopancreatography (ERCP) demonstrated occlusion of the MPD, and cytology of aspirated pancreatic juice was negative for malignancy. With the diagnosis of benign localized obstruction of the MPD, the patient underwent surgery. There was a clear demarcation of hardness and color of the pancreas on the left margin of the superior mesenteric vein, and the caudal pancreas was hard and fibrotic. Intraoperative US revealed slight dilatation of the MPD, and the aspiration cytology result was class IV. First, segmental resection of the pancreas was performed, but pathological examination of frozen section showed neither malignancy nor stenotic lesion. An additional small portion of the proximal pancreas was resected. The specimen included a ductal carcinoma, 5 mm in diameter. Accordingly, a pylorus-preserving pancreatoduodenectomy was performed. Microscopically, the minute carcinoma had already penetrated the duct wall and infiltrated lymph vessels and veins. The patient has been under close observation at our outpatient clinic, and so far there have been no signs of recurrence. To improve the poor prognosis of pancreatic cancer, we should be alert to the occurrence of acute pancreatitis as an initial symptom. Received: December 31, 2001 / Accepted: June 10, 2002 Offprint requests to: M. Imamura