• Application of molecular biology studies to gene therapy treatment strategies.

• Evidence-based pancreatic head resection for pancreatic cancer and chronic pancreatitis.

• [Malignancy: treatment and prognosis of gastrointestinal and pancreatic endocrine neoplasia: retrospective study of a series of 16 cases]

• [Indications for chemotherapy in cancers of the esophagus, stomach and pancreas]

• Surgical and medical therapy for pancreatic carcinoma.

• Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma:

• Gemcitabine-radiotherapy in patients with locally advanced pancreatic cancer.

• [Pancreatic cancer]

• Adenovirus-mediated wild-type p53 tumor suppressor gene therapy induces apoptosis and suppresses growth of human pancreatic cancer [seecomments]

• Surgical experience with functioning pancreatic neuroendocrine tumors.

• The impact of pylorus-preserving pancreatoduodenectomy on surgical treatment for cancer of the pancreatic head.

• Antiproliferative activity induced by the somatostatin analogue, TT-232, in human pancreatic cancer cells.

• Blockade of the epidermal growth factor receptor tyrosine kinase activity by quercetin and luteolin leads to growth inhibition and

• A phase II study of gemcitabine and tamoxifen in advanced pancreatic cancer.

• Simultaneous analysis of quality of life and survival data.

• Gemcitabine and platinum combinations in pancreatic cancer.

• Gemcitabine in combination with 5-fluorouracil with or without folinic acid in the treatment of pancreatic cancer.

• Gemcitabine-based therapy in pancreas cancer: gemcitabine-docetaxel and other novel combinations.

• The pemetrexed/gemcitabine combination in pancreatic cancer.

• On the development of gemcitabine-based chemoradiotherapy regimens in pancreatic cancer.

• New applications of gemcitabine and future directions in the management of pancreatic cancer.

• Inhibition of NF-kappaB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin.

• Intraoperative hyperthermia and chemoradiotherapy for inoperable pancreatic carcinoma.

• [Total pancreatectomy for mucinous pancreatic tumor]

• [Natural history of the pancreatic stump after duodenopancreatectomy of the pancreatic head]

• Treatment of unresectable pancreatic carcinoma by intraluminal brachytherapy in the duct of Wirsung.

• [Surgical management of pancreatic metastasis from renal cell carcinoma]

• [Is total body hyperthermia plus chemotherapy useful in pancreas carcinoma?]

• Cytotoxic therapy of gastroenteropancreatic (GEP) tumors.

• Increased arylhydrocarbon receptor expression offers a potential therapeutic target for pancreatic cancer.

• Reevaluation of the indications for radical pancreatectomy to treat pancreatic carcinoma: is portal vein infiltration a contraindication?

• Gemcitabine, paclitaxel, and radiation for locally advanced pancreatic cancer: a Phase I trial.

• Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part

• Aspirin may lower risk of pancreatic cancer.

• Quality of life and outcomes after pancreaticoduodenectomy.

• Evaluation of quality of life (QOL) in pancreaticoduodenectomy survivors.

• [Pancreatic excisions for chronic pancreatitis and cancer: their rationale for "factual" surgery. Evidence-based medicine]

• [Pancreatic leakage after pancreas resection. An analysis of 345 operated patients]

• Weekly gemcitabine plus Epirubicin as effective chemotherapy for advanced pancreatic cancer: a multicenter phase II study.

1
UI - 11960211
AU - Gustin A; Pederson L; Miller R; Chan C; Vickers SM
TI - Application of molecular biology studies to gene therapy treatment strategies.
SO - World J Surg 2002 Jul;26(7):854-60
AD - Department of Surgery, University of Alabama at Birmingham, 1922 Seventh Avenue South, KB406, Birmingham, Alabama 35294, USA.
The diagnosis of pancreatic cancer continues to produce fear in both patients and practitioners in large part owing to the likely incurability in all for whom the diagnosis is made. It is this reality that continually motivates the surgical and medical oncologists who endeavor to treat these patients. Currently, the cure rate for pancreatic cancer has improved only minimally, and the overall survival of patients remains dismal, with fewer than 5% of patients alive at 5 years and 92% of these patients dead at 2 years. This current treatment status has stimulated numerous studies endeavoring to understand the diverse mechanisms of cell growth in this tumor. Intensive investigative efforts have produced the understanding of new tumor suppressor genes such as DPC4 and an increasing understanding of tyrosine kinase receptors and signal transduction and their regulation of programmed cell death (apoptosis). Detection of these numerous genetic defects may give new insights and understanding of the highly chemo- and radioresistant nature of pancreatic cancer. These same findings also provide the basis for the development of new potential therapies for pancreatic cancer through gene therapy. This paper reviews the significant molecular biologic findings and their influence on the development of gene therapy strategies in the treatment of pancreatic adenocarcinoma.

2
UI - 12170018
AU - Schafer M; Mullhaupt B; Clavien PA
TI - Evidence-based pancreatic head resection for pancreatic cancer and chronic pancreatitis.
SO - Ann Surg 2002 Aug;236(2):137-48
AD - Department of Surgery and Division of Gastroenterology, University of Zurich, Zurich, Switzerland.
OBJECTIVE: To review the current status of pancreatoduodenectomy for pancreatic cancer and chronic pancreatitis using evidence-based methodology. SUMMARY BACKGROUND DATA: Despite improved results of pancreatoduodenectomy over the recent years, the reputation of the Whipple procedure and its main modifications has remained poor. In addition, the current status of newer modifications of standard pancreatoduodenectomy is still under debate. METHODS: Medline search and manual cross-referencing were performed to identify all relevant articles for classification and analysis according to their quality of evidence. The search was limited to articles published between 1990 and 2001. RESULTS: The mortality rate of pancreatoduodenectomy has declined to less than 5% for chronic pancreatitis and 3% to 8% for pancreatic cancer. In contrast, overall morbidity rates remain high, ranging between 20% and 70%. Delayed gastric emptying represents almost half of all complications. The overall 5-year survival rate for patients with pancreatic cancer remains poor, ranging between 5% and 15%, with a median survival of 13 to 17 months. Mortality and morbidity are not related to the type of pancreatoduodenectomy; however, patients with pancreatic cancer tend to be at increased risk for complications. Extended lymph node dissection and portal vein resection can be performed with similar mortality and morbidity rates as standard procedures, but without apparent survival benefits in the long term. Major relief of pain is achieved in 70% to 100% of patients with chronic pancreatitis. CONCLUSIONS: Pancreatoduodenectomy and its main modifications are safe and effective treatment modalities, especially in experienced centers with a high patient volume. For chronic pancreatitis, surgical resection provides major relief of pain and thus increased quality of life. Overall survival for patients with pancreatic cancer is determined predominantly by the pathology within the resected specimen.

3
UI - 11865693
AU - Pansini GC; Lanzara S; Feo CV; Zamboni P; Liboni A; Ambrosio MR; Marzola
TI - A; Feggi L [Malignancy: treatment and prognosis of gastrointestinal and pancreatic endocrine neoplasia: retrospective study of a series of 16 cases]
SO - Ann Ital Chir 2001 Jul-Aug;72(4):413-21; discussion 422
AD - Dipartimenti di Scienze Chirurgiche, di Medicina Sperimentale Diagnostica, Anatomia e Istologia Patologica, di Scienze Biomediche e Terapie Avanzate ed Azienda Ospedaliera Universitaria di Ferrara.
The aim of this study was to review our experience with endocrine tumours of the gastrointestinal tract and pancreas (ETGIP). Between on at our institution. Of these patients we reviewed preoperative symptoms, diagnostic techniques (ultrasound, CT, MRI, radiolabelled octreotide scintigraphy, angiography, immunohistochemical study), treatment (surgical operation, neoadjuvant and adjuvant chemotherapy, and radiometabolic therapy) and survival. Nine patients (56%) had a carcinoid tumour, three (19%) an unspecified endocrine tumour, and four (25%) an endocrine tumour associated with a non-endocrine neoplasm. Only five patients (31%) had a preoperative diagnosis of endocrine tumour. Eight patients (50%) had metastatic disease at the time of the operation. All patients without preoperative metastasis (eight patients, 50%) are still alive without recurrent disease, with a mean postoperative survival of 36 months (12-60 months). Of eight patients with metastatic disease, six (75%) died after a mean of 20.5 months (3-60 months) and two (25%) are still alive with the disease after 3 and 6 months, respectively. These data show that presence of metastasis strongly influence survival. Furthermore, survival of patients with metastatic disease seems to be longer as compared to other gastrointestinal tract malignancies. ETGIP are more common and aggressive than previously believed and, therefore, early diagnosis is crucial for cure. Nowadays, however, new diagnostic tools such as radiolabelled octreotide scintigraphy are available for diagnosis and postoperative follow-up. The optimal treatment for ETGIP is a multimodal approach with surgical operation, chemoradiation, radiometabolic, and genetic therapies.

4
UI - 11930294
AU - Haag C; Ehninger G
TI - [Indications for chemotherapy in cancers of the esophagus, stomach and pancreas]
SO - Z Gastroenterol 2002 Apr;40 Suppl 1():S68-S70
AD - Medizinische Klinik I, Universitatsklinikum Carl-Gustav-Carus der Technischen Universitat Dresden, Germany. Haag@mkl.med.tu-dresden.de
During the last years the chemotherapy in osophageal, stomach and pancreatic cancer demonstrated some success. Radiochemotherapy for esophageal cancer is indicated as neoadjuvant therapy before surgery in locally advanced cancer or in patients with other diseases, which do not allow surgery. In stomach cancer patient there is a clear indication for chemotherapy in metastatic disease and within clinical trials as neoadjuvant chemotherapy in locally advanced cancer. In pancreatic cancer patient the chemotherapy shows less success comparing to other gastrointestinal cancer; it is part of the palliative concept with other therapeutic strategies.

5
UI - 12079268
AU - Magee CJ; Ghaneh P; Neoptolemos JP
TI - Surgical and medical therapy for pancreatic carcinoma.
SO - Best Pract Res Clin Gastroenterol 2002 Jun;16(3):435-55
AD - Department of Surgery, University of Liverpool, 5th Floor UCD Building, Royal Liverpool University Hospital, Daulby Street, Liverpool, L69 3GA, UK.
Progress on the treatment of pancreatic ductal adenocarcinoma has involved advances in medical and surgical care with important contributions from disciplines such as radiology and intensive care. In the last decade large randomized controlled trials have been undertaken that demonstrate the improved patient outcomes. There is an increased risk of pancreatic cancer in chronic pancreatitis, hereditary pancreatitis and a variety of familial cancer syndromes. The optimum outcome from pancreatic cancer needs management by multidisciplinary teams in regional specialist units. Endoscopic stenting, good pain relief and pancreatic enzyme supplementation are the basis of care in advanced pancreatic cancer. Chemotherapy prolongs survival in advanced pancreatic cancer with little to be gained using drugs other than 5FU. Resection, if possible, prolongs life and provides the best quality of life. Adjuvant chemoradiotherapy is of no benefit but chemotherapy may improve survival. Alongside the evolution in clinical management has been the elucidation of the molecular events that underlie pancreatic cancer and this knowledge has guided the introduction of targeted treatments for pancreatic cancer. Copyright 2002 Elsevier Science Ltd.

6
UI - 12149301
AU - Berlin JD; Catalano P; Thomas JP; Kugler JW; Haller DG; Benson AB 3rd
TI - Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297.
SO - J Clin Oncol 2002 Aug 1;20(15):3270-5
AD - Vanderbilt University, 777 Preston Research Building, Nashville, TN 37232-6307, USA. jorden.berlin@mcmail.vanderbilt.edu
PURPOSE: Gemcitabine is generally considered to constitute first-line therapy for pancreatic cancer. To determine whether the addition of fluorouracil (5-FU) improves on the results from single-agent gemcitabine, the Eastern Cooperative Oncology Group (ECOG) compared gemcitabine plus bolus 5-FU with gemcitabine alone for patients with advanced pancreatic carcinoma. PATIENTS AND METHODS: This trial involved patients with biopsy-proven, advanced carcinoma of the pancreas not amenable to surgical resection. Patients were randomized to receive either gemcitabine alone (1,000 mg/m(2)/wk) weekly for 3 weeks of every 4 or to receive gemcitabine (1,000 mg/m(2)/wk) followed by 5-FU (600 mg/m(2)/wk) weekly on the same schedule. The primary end point of the trial was survival, with secondary end points of time to progression and response rate. RESULTS: Of 327 patients enrolled over 18 months, 322 were eligible. Overall, the median survival was 5.4 months for gemcitabine alone and 6.7 months for gemcitabine plus 5-FU (P =.09). Progression-free survival for gemcitabine alone was 2.2 months, compared with 3.4 months for gemcitabine plus 5-FU (P =.022). Objective responses were uncommon and were observed in only 5.6% of patients treated with gemcitabine and 6.9% of patients treated with gemcitabine plus 5-FU. Most toxicities were hematologic or gastrointestinal; no significant differences were noted between the two treatment arms. CONCLUSION: 5-FU, administered in conjunction with gemcitabine, did not improve the median survival of patients with advanced pancreatic carcinoma compared with single-agent gemcitabine. Further studies with other combinations of gemcitabine and 5-FU are not compelling, and clinical trial resources should address other combinations and novel agents.

7
UI - 12044508
AU - de Lange SM; van Groeningen CJ; Meijer OW; Cuesta MA; Langendijk JA; van
TI - Riel JM; Pinedo HM; Peters GJ; Meijer S; Slotman BJ; Giaccone G Gemcitabine-radiotherapy in patients with locally advanced pancreatic cancer.
SO - Eur J Cancer 2002 Jun;38(9):1212-7
AD - Department of Medical Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands. sm.delange@vumc.nl
A feasibility study was performed to assess the toxicity and efficacy of a combination of gemcitabine-radiotherapy in patients with locally advanced pancreatic cancer (LAPC). 24 patients (15 females and 9 males) with measurable LAPC were included; the median age of the patients was 63 years (range 39-74 years). The performance status ranged from 0 to 2. Gemcitabine was administered at a dose of 300 mg/m(2), concurrent with radiotherapy, three fractions of 8 Gy, on days 1, 8 and 15. When compliance allowed, gemcitabine alone was continued thereafter, at 1000 mg/m(2), weekly times 3, every 4 weeks, depending on the response and toxicity. All patients were evaluable for toxicity and response. The objective response rate was 29.2% (1 complete remission+6 partial remissions); 12 patients had stable disease. However, 2 of the radiological partial remissions were shown to be complete remissions by pathology assessment. Median duration of response was 3 months (range 1-35+months). Median time to progression was 7 months (range 2-37+months). Median survival was 10 months (range 3-37+months). Dose reduction or omission of gemcitabine was necessary in 10 patients. Non-haematological toxicity consisted of 87.5% nausea and vomiting grade I-II, diarrhoea 54%, ulceration in stomach and duodenum 37.5% (20.8% ulceration with bleeding); 1 patient developed a fistula between the duodenum and aorta, 5 months after treatment. Anaemia grade III-IV was observed in 8.3% of the patients. Neutropenia grade III-IV was observed in 8.3%, thrombocytopenia grades III-IV in 16.7%. In 1 patient who underwent resection postchemoradiation, no viable tumour cells were found. In addition, in the patient who suddenly died of a fistula between the duodenum and aorta, no viable tumour cells were detectable at autopsy. Although the toxicity of this treatment was occasionally severe, the response and survival are encouraging and warrant further studies of this combination.

8
UI - 12082856
AU - Hovendal CP; Jensen TS
TI - [Pancreatic cancer]
SO - Ugeskr Laeger 2002 Jun 3;164(23):3040-2
AD - Odense Universitetshospital, kirurgisk afdeling A. cph@dadlnet.dk

9
UI - 9869513
AU - Bouvet M; Bold RJ; Lee J; Evans DB; Abbruzzese JL; Chiao PJ; McConkey
TI - DJ; Chandra J; Chada S; Fang B; Roth JA Adenovirus-mediated wild-type p53 tumor suppressor gene therapy induces apoptosis and suppresses growth of human pancreatic cancer [seecomments]
SO - Ann Surg Oncol 1998 Dec;5(8):681-8
AD - Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
BACKGROUND: The p53 tumor suppressor gene is mutated in up to 70% of pancreatic adenocarcinomas. We determined the effect of reintroduction of the wild-type p53 gene on proliferation and apoptosis in human pancreatic cancer cells using an adenoviral vector containing the wild-type p53 tumor suppressor gene. METHODS: Transduction efficiencies of six p53-mutant pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-1, CFPAC-1, MIA PaCa-2, and PANC-1) were determined using the reporter gene construct Ad5/CMV/beta-gal. Cell proliferation was monitored using a 3H-thymidine incorporation assay, Western blot analysis for p53 expression was performed, and DNA laddering and fluorescence-activated cell sorter analysis were used to assess apoptosis. p53 gene therapy was tested in vivo in a subcutaneous tumor model. RESULTS: The cell lines varied in transduction efficiency. The MIA PaCa-2 cells had the highest transduction efficiency, with 65% of pancreatic tumor cells staining positive for beta-galactosidase (beta-gal) at a multiplicity of infection (MOI) of 50. At the same MOI, only 15% of the CFPAC-1 cells expressed the beta-gal gene. Adenovirus-mediated p53 gene transfer suppressed growth of all human pancreatic cancer cell lines in a dose-dependent manner. Western blot analysis confirmed the presence of the p53 protein product at 48 hours after infection. DNA ladders demonstrated increased chromatin degradation, and fluorescence-activated cell sorter analysis demonstrated a four-fold increase in apoptotic cells at 48 and 72 hours following infection with Ad5/CMV/p53 in the MIA PaCa-2 and PANC-1 cells. Suppression of tumor growth mediated by induction of apoptosis was observed in vivo in an established nude mouse subcutaneous tumor model following intratumoral injections of Ad5/CMV/p53. CONCLUSIONS: Introduction of the wild-type p53 gene using an adenoviral vector in pancreatic cancer with p53 mutations induces apoptosis and inhibits cell growth. These data provide preliminary support for adenoviral mediated p53 tumor suppressor gene therapy of human pancreatic cancer.

10
UI - 12206598
AU - Matthews BD; Smith TI; Kercher KW; Holder WD Jr; Heniford BT
TI - Surgical experience with functioning pancreatic neuroendocrine tumors.
SO - Am Surg 2002 Aug;68(8):660-5; discussion 665-6
AD - Department of General Surgery, Carolinas Medical Center, Charlotte, North Carolina 28203, USA.
Pancreatic islet-cell tumors (ICTs) are rare malignancies usually recognized by specific clinical endocrinopathies. The purpose of this study is to evaluate our surgical experience with functioning pancreatic ICT in an academic referral center. Twenty patients (male:female 12:8) with a mean age of 53 years (range 26-82) underwent surgery for a functioning pancreatic ICT [gastrinoma (eight), multiple endocrine neoplasia (three), insulinoma (seven), glucagonoma (four), and VI-Poma Signs and symptoms of hormonal excess were present in 95 per cent (19 of 20). One patient (glucagonoma) presented with obstructive jaundice and mild glucose intolerance. Elevated peptide levels were detected preoperatively in 65 per cent, including all patients with an insulinoma. Curative resections were attempted in 80 per cent including three procedures for insulinoma. Palliative procedures were performed in 20 per cent--all gastrinomas. One patient with an insulinoma had diffuse nesidioblastosis. Three patients (with gastrinoma, insulinoma, and glucagonoma) had lymph node-positive disease and three patients with gastrinoma had liver metastasis. The overall 30-day morbidity rate was 30 per cent and mortality rate 0 per cent. Symptomatic improvement was achieved in 90 per cent at a mean follow-up of 44 months. Two patients developed diabetes after a subtotal and a total pancreatectomy, respectively. Sixty-three per cent of patients who underwent an attempted curative resection are alive at a mean follow-up of 47 months (range 3-231) and all patients who underwent a palliative procedure are alive at a mean follow-up of 31 months (range 27-36). Functioning pancreatic ICTs are fascinating tumors that produce distinct clinical syndromes. Symptomatic improvement is accomplished in the majority of patients after surgery and short-term palliation is achieved in patients with nonresectable disease.

11
UI - 12140611
AU - Ogata Y; Hishinuma S
TI - The impact of pylorus-preserving pancreatoduodenectomy on surgical treatment for cancer of the pancreatic head.
SO - J Hepatobiliary Pancreat Surg 2002;9(2):223-32
AD - Department of Surgery, Tochigi Cancer Center, 4-9-13, Yohnan, Utsunomiya, Tochigi 320-0834, Japan.
Pylorus-preserving pancreatoduodenectomy (PPPD) was reintroduced in 1978. This pylorus-preserving modification was designed to minimize complications related to gastric resection, such as early satiety, marginal ulceration, and bile reflux gastritis, as well as diarrhea and dumping. Since 1978, PPPD has been performed preferentially for benign and malignant diseases of the periampullary region and pancreatic head. Some groups have argued against PPPD for cancer of the pancreatic head, because the pylorus-preserving procedure is likely to compromise the field of resection and does not allow lymph node dissection of the peripyloric and perigastric groups. However, comparative survival rates after PPPD have been the same as, or better than, those with classic pancreatoduodenectomy, showing the rationale for PPPD as a radical resection procedure for cancer of the pancreatic head. PPPD can be performed with low mortality. Delayed gastric emptying, which is the most common complication in the immediate postoperative period after PPPD, is always transient. Many investigators have shown that body weight and the majority of nutritional parameters are better than after PD. PPPD does not appear to cause any negative outcomes. We conclude that PPPD is the surgical procedure of choice for cancer of the head of the pancreas.

12
UI - 12110500
AU - Lee JU; Hosotani R; Wada M; Doi R; Koshiba T; Fujimoto K; Miyamoto Y;
TI - Tsuji S; Nakajima S; Hirohashi M; Uehara T; Arano Y; Fujii N; Imamura M Antiproliferative activity induced by the somatostatin analogue, TT-232, in human pancreatic cancer cells.
SO - Eur J Cancer 2002 Jul;38(11):1526-34
AD - Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto, University, 54 Shogoin-Kawaracho, Sakyo, 606-8507, Kyoto, Japan.
Somatostatin analogues have been developed as antiproliferative agents, but their administration as general antitumour agents is limited, mainly because of the wide distribution of somatostatin receptors throughout the human body. TT-232, a new somatostatin structural analogue, was reported to have tumour-selective antiproliferative activity without an antisecretory action. We examined whether TT-232 had antiproliferative activity in human pancreatic cancer cell lines, and compared its antiproliferative activity with that of RC-160 and other TT-232 derivatives. TT-232 inhibited the growth of all of the cell lines used in this study and induced apoptotic cell death. RC-160 showed no such growth inhibition. TT-232 also inhibited tumour formation in a xenograft model. A competitive binding assay was performed using the cell membrane fraction and 111In-DTPA-TT-232 in order to show the existence of a specific binding site on the cells. A specific binding site was detected in MIAPaCa-2 cells. It has been shown that the activation of protein tyrosine phosphatase (PTPase) is one of the main intracellular pathways responsible for somatostatinergic inhibition of cell growth. We found a significant PTPase stimulation after TT-232 administration using an immunoblot analysis assessing the level of protein tyrosine phosphorylation, and also a direct measurement of the PTPase activity. We also demonstrated that PTPase stimulation by TT-232 was involved in its antiproliferative activity as this activity was reversed by the addition of sodium orthovanadate, a PTPase inhibitor. Our results indicate that TT-232 could be a potentially useful therapeutic agent if these data are translated into clinical practice.

13
UI - 12168845
AU - Lee LT; Huang YT; Hwang JJ; Lee PP; Ke FC; Nair MP; Kanadaswam C; Lee MT
TI - Blockade of the epidermal growth factor receptor tyrosine kinase activity by quercetin and luteolin leads to growth inhibition and apoptosis of pancreatic tumor cells.
SO - Anticancer Res 2002 May-Jun;22(3):1615-27
AD - Institute of Biological Chemistry Academia Sinica, Taipei, Taiwan.
To glean insights into the mechanism of their action, we assessed the effects of two flavonoids, quercetin (Qu) and luteolin (Lu), on the growth and epidermal growth factor receptor (EGFR) tyrosine kinase activity of MiaPaCa-2 cancer cells. Exposure of these EGFR-expressing cells to 20 microM Qu or Lu resulted in concomitant decreases in cellular protein phosphorylation and growth. On the cellular level, Qu and Lu sensitivity correlated with EGFR levels and rapid cell proliferation, indicating the possibility of targeting those cells most prone to neoplastic progression. Cell treatment with the flavonoids markedly diminished the extent of cellular protein phosphorylation, by effectively modulating protein tyrosine kinase (PTK) activities, including that of EGFR. Immunocomplex kinase assay revealed that both Qu and Lu inhibited the PTK activities responsible for the autophosphorylation of EGFR as well as for the transphosphorylation of enolase. Treatment of the cells with Qu or Lu also reduced the phosphotyrosyl levels of 170-, 125-, 110-, 65-, 60-, 44-, 30- and 25-kDa proteins. We identified the 170-kDa phosphotyrosylprotein as EGFR. Qu and Lu exhibited a specific action in hampering the levels of phosphorylation of this and the aforementioned proteins, while having no discernible effect on their synthesis. A time-dependent attenuation of the phosphorylation of the above proteins was demonstrable. Treatment of the cells with Qu or Lu for 6 hours showed little inhibition, but prolonging the cell treatment for 24 hours caused the suppression of phosphorylation. Further continuation of the cell treatment culminated in the induction of apoptosis, characteristically exhibiting shrinkage of the cell morphology, DNA fragmentation and poly(ADP-ribose)polymerase (PARP) degradation. The onset of apoptosis and associated events occurred in a time-dependent fashion. The data clearly demonstrate that MiaPaCa-2 cells respond to Qu and Lu by a parallel reduction in cellular protein phosphorylation and cellular proliferation. The flavonoid-evoked attenuation of the phosphorylation of EFGR and of other proteins appeared to be transient, since removal of the flavonoid from the cell growth medium after 24 hours of incubation followed by exposure to 10 nm EGF, restored protein phosphorylation and cellular proliferation. Such an addition of EGF was also able to reverse Qu- or Lu-induced cell growth inhibition and diminish nuclear digestion evoked by 20 microM Qu or Lu. Both Qu and Lu were able to reverse the effect of EGF biochemically as well as functionally. Based on the evidence accrued, the above proteins could be implicated in growth signal transduction and the subtle changes in their phosphorylation, as effected by flavonoids, utilized as a reliable guide to predict growth response. The antiproliferative effect of flavonoids might result, at least in part, from the modulation of the EGF-mediated signaling pathway. The results indicate that the blockade of the EGFR-signaling pathway by the PTK inhibitors Qu and Lu significantly inhibits the growth of MiaPaCa-2 cells and induces apoptosis. The modulation of EGFR kinase appears to be a critically important, intrinsic component of Qu- and Lu-induced growth suppression, even though other mechanisms could also have contributed to the net effect.

14
UI - 12174927
AU - Tomao S; Romiti A; Massidda B; Ionta MT; Farris A; Zullo A; Brescia A;
TI - Santuari L; Frati L A phase II study of gemcitabine and tamoxifen in advanced pancreatic cancer.
SO - Anticancer Res 2002 Jul-Aug;22(4):2361-4
AD - National Institutefor Cancer Research of Genoa, Unit of Rome and Department of Experimental Medicine and Pathology, University of Rome La Sapienza, Italy.
BACKGROUND: Advanced pancreatic cancer (APC) constitutes a poor-prognosis disease with few and disappointing therapeutic options. In recent years chemotherapy has demonstrated a positive effect on disease-related symptoms with the introduction of a novel pyrimidine analogue, gemcitabine. Moreover there is experimental and clinical evidence that endocrine therapy may play a small but unexplored role in the management of APC. Therefore we performed a phase II study to assess whether the combination of gemcitabine and tamoxifen could be an active and safe schedule for the treatment of APC in terms of response rate and clinical benefits. MATERIALS AND METHODS: Twenty-seven evaluable consecutive patients with locally advanced, unresectable or metastatic adenocarcinoma of the pancreas were treated with gemcitabine (1000 mg/mq given as a short infusion once weekly for 3 consecutive weeks out of every 4 weeks) and tamoxifen (20 mg daily starting the second day after gemcitabine). The treatment was continued until progression or unacceptable toxicity. Evaluation of efficacy included response rate, time to progression, survival and clinical benefit, an integrated measurement of pain parameters, weight and performance status. RESULTS: A partial response was achieved in 11% of patients while 48% experienced stable disease, lasting at least 8 weeks; disease progression was documented in 41% of patients. The median time of progression was 4.5 months; the median survival-time was 8 months and one-year survival was 31%. Clinical benefit was documented in 59% of patients with a median duration of 13 weeks. No gastrointestinal or haematological grade 4 toxicity was observed. In general the treatment showed a satisfactory safety profile and tamoxifen-related toxicity was not documented. CONCLUSION: The combination of gemcitabine and tamoxifen appears to be an innovative therapeutic approach in the management of APC with interesting clinical activity and a good profile of toxicity. This novel schedule of treatment deserves further investigation in large randomized trials to assess if the addition of tamoxifen could improve the therapeutic results of gemcitabine in APC, mostly in term of quality of lfe.

15
UI - 11923992
AU - Billingham LJ; Abrams KR
TI - Simultaneous analysis of quality of life and survival data.
SO - Stat Methods Med Res 2002 Feb;11(1):25-48
AD - Cancer Research Campaign Trials Unit, Institute for Cancer Studies, Medical School, University of Birmingham, Birmingham B15 2TT, UK.
In many phase III clinical trials, particularly in the field of cancer, the comparison of treatments is based on both length of survival and quality of life. Subjects are followed over time until death and during this period, quality of life is assessed on a number of occasions. Simultaneous analysis of these two outcomes supplements the comparison of treatments in terms of each outcome independently with an assessment of the net effect. In addition, it provides a means of accounting for the informative dropout due to death of patients within the time frame of the quality of life study. The methods also have the potential to be extended to allow for informative dropout from the quality of life study prior to death. There are a number of broad approaches for the simultaneous analysis of quality of life and survival data. The most widely used approach in clinical research is quality-adjusted survival analysis, where treatments are compared in terms of a composite measure of quality and quantity of life. The paper reviews the different techniques for quality-adjusted survival analysis, illustrating the methodology by application to data from a phase III clinical trial in pancreatic cancer. In addition, alternative approaches using multistate survival analysis and joint modelling methods are also discussed.

16
UI - 12209670
AU - Philip PA
TI - Gemcitabine and platinum combinations in pancreatic cancer.
SO - Cancer 2002 Aug 15;95(4 Suppl):908-11
AD - Division of Hematology and Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA. philipp@karmanos.org
Progress in the treatment of pancreatic cancer in the past several decades has been very modest. Several new agents with activity against this disease have been identified. Of these, gemcitabine appears to be the most promising when used in combination with other drugs. Gemcitabine and cisplatin combinations have been tested in several studies. The major toxicity reported to occur with the gemcitabine-cisplatin combination is myelosuppression, which is greater than that encountered with single-agent gemcitabine. However, episodes of neutropenic fever or spontaneous bleeding are reported to be very infrequent. Pilot Phase II studies combining gemcitabine with cisplatin have shown improved outcomes in objective response rates and survival; however, these findings must be confirmed in larger randomized studies. Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10757

17
UI - 12209671
AU - Oettle H; Riess H
TI - Gemcitabine in combination with 5-fluorouracil with or without folinic acid in the treatment of pancreatic cancer.
SO - Cancer 2002 Aug 15;95(4 Suppl):912-22
AD - Medizinische Klinik und Poliklinik m.S. Hamatologie und Onkologie, Medizinische Fakultat der Humboldt Universitat zu Berlin, Berlin, Germany. pankreas@charite.de
Pancreatic cancer is one of the most frequently reported gastrointestinal tumors and has been reported to have a 5-year survival rate of < 5%. It is most commonly diagnosed at an advanced stage and until recently, the most frequently administered treatment for patients with advanced disease has been palliative 5-fluorouracil (5-FU)-based chemotherapy. However, in clinical trials, the novel antinucleoside gemcitabine is currently considered the standard of care and has demonstrated both a survival benefit over 5-FU and an improvement in disease-related symptoms in those patients with advanced disease. The current review presents an overview of recently completed and ongoing clinical trials of gemcitabine/5-FU combination therapy for pancreatic cancer. In these trials, the administration of 5-FU varied widely from bolus injection to 24-hour infusion to protracted infusion over several weeks. These variations make a definitive judgment of this combination difficult, especially because the majority of the data represent only Phase I and Phase II study results. Although a recently completed randomized Phase III trial of gemcitabine plus bolus 5-FU versus gemcitabine failed to show a clinically meaningful survival benefit for the combination arm, current data indicate that other gemcitabine/5-FU combinations might provide a therapeutic advantage over gemcitabine alone. However, the results of ongoing Phase III studies must be reviewed before a definitive statement can be made regarding the value of this combination in the treatment of pancreatic cancer. Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10758

18
UI - 12209672
AU - Jacobs AD
TI - Gemcitabine-based therapy in pancreas cancer: gemcitabine-docetaxel and other novel combinations.
SO - Cancer 2002 Aug 15;95(4 Suppl):923-7
AD - Department of Cancer Care Services, Virginia Mason Medical Center, Seattle, Washington 98111, USA. andrew.jacobs@vmmc.org
Since its approval in 1998 by the Food and Drug Administration, gemcitabine has rapidly become accepted as a standard part of palliative therapy for patients with advanced pancreatic cancer. It has modest activity when used as a single agent, and this has led to numerous studies combining it with other active agents, including cytotoxic as well as biologic and targeted therapies. Numerous Phase II studies suggest that the combinations may have greater activity than single agent therapy. However, randomized trials concerning this are still in progress. In the current article, a variety of gemcitabine-based novel combinations showing promising activity are reviewed. Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10756

19
UI - 12209673
AU - Kindler HL
TI - The pemetrexed/gemcitabine combination in pancreatic cancer.
SO - Cancer 2002 Aug 15;95(4 Suppl):928-32
AD - Director of Gastrointestinal Oncology, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois 60637, USA. hkindler@medicine.bsd.uchicago.edu
Gemcitabine has modest antitumor activity in advanced pancreatic cancer. New agents are clearly needed. Pemetrexed (ALIMTA) is a novel antifolate that inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed has shown in vitro activity against pancreatic cancer cell lines. In a Phase I trial of pemetrexed, two patients with pancreatic cancer achieved partial responses on the once every 21 days schedule. A Phase II trial of pemetrexed in patients with advanced pancreatic cancer showed an objective response rate of 6%, a one year survival of 28%, and a mild toxicity profile. The combination of pemetrexed and gemcitabine is synergistic in vitro and was broadly active in a Phase I trial. The pemetrexed/gemcitabine combination was evaluated in a Phase II trial in 42 patients with advanced pancreatic cancer. The promising activity observed in this study has led to an ongoing international, randomized, Phase III trial in 520 patients comparing the pemetrexed/gemcitabine combination with gemcitabine alone. Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10755

20
UI - 12209674
AU - McGinn CJ; Lawrence TS; Zalupski MM
TI - On the development of gemcitabine-based chemoradiotherapy regimens in pancreatic cancer.
SO - Cancer 2002 Aug 15;95(4 Suppl):933-40
AD - Department of Radiation Oncology, University of Michigan Health Systems, Ann Arbor, Michigan 48109-0010, USA. mcginn@umich.edu
The use of chemotherapy with concurrent radiation therapy remains a standard treatment option for patients with unresectable or resected adenocarcinoma of the pancreas. This treatment strategy is based in large part on data from serial Gastrointestinal Tumor Study Group trials that have included 5-fluorouracil. Unfortunately, the majority of patients continue to succumb to the disease process. Recently, there has been a resurgence in clinical trials utilizing gemcitabine as a single agent, in combination chemotherapy regimens, and with concurrent radiation therapy. Use with concurrent radiation therapy is based in part on laboratory studies investigating mechanisms of radiosensitization and strategies that might increase the therapeutic index. In the current review, the authors summarize the preclinical data that support the use of gemcitabine as a radiosensitizing agent and the clinical trials that have been conducted to date. Issues regarding the use of gemcitabine in concurrent radiotherapy regimens need to be viewed in the context of both local and distant disease control, given the radiosensitizing and systemic activity of this agent. Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10754

21
UI - 12209675
AU - Abbruzzese JL
TI - New applications of gemcitabine and future directions in the management of pancreatic cancer.
SO - Cancer 2002 Aug 15;95(4 Suppl):941-5
AD - Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA. jabbruzz@mdanderson.org
Gemcitabine has been reported to be an active agent in pancreatic cancer. Recent applications have included the use of a fixed-dose rate regimen in patients with advanced pancreatic cancer based on the observation that deoxycytidine kinase is saturated at the plasma gemcitabine concentrations achieved with standard infusion, thereby limiting the accumulation of intracellular gemcitabine triphosphate. In a Phase II study, this regimen was associated with survival rates better than those typically observed in patients with advanced disease. Gemcitabine also has been assessed as a radiosensitizer in locally advanced cancer and although toxicity was significant, objective responses were observed and included tumor response, which permitted curative resection. Future directions in therapy for pancreatic cancer include the development of agents targeting signal transduction pathways and nuclear transcription factors based on the continually improving understanding of the role of molecular events in carcinogenesis. Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10753

22
UI - 11314019
AU - Arlt A; Vorndamm J; Breitenbroich M; Folsch UR; Kalthoff H; Schmidt WE;
TI - Schafer H Inhibition of NF-kappaB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin.
SO - Oncogene 2001 Feb 15;20(7):859-68
AD - Laboratory of Molecular Gastroenterology, 1st Department of Medicine, University of Kiel, Germany.
The transcription factor NF-kappaB has anti-apoptotic properties and may confer chemoresistance to cancer cells. Here, we describe human pancreatic carcinoma cell lines that differ in the responsiveness to the topoisomerase-2 inhibitors VP16 (20 microM) and doxorubicin (0.3 microM): Highly sensitive T3M4 [corrected] and PT45-P1 cells, and Capan-1 and A818-4 cells that were almost resistant to both anti cancer drugs. VP16, but not doxorubicin, transiently induced NF-kappaB activity in all cell lines, whereas basal NF-kappaB binding was nearly undetectable in T3M4 [corrected] and PT45-P1 cells, but rather high in Capan-1 and A818-4 cells, as demonstrated by gel-shift and luciferase assays. Treatment with various NF-kappaB inhibitors (Gliotoxin, MG132 and Sulfasalazine), or transfection with the IkappaBalpha super-repressor, strongly enhanced the apoptotic effects of VP16 or doxorubicin on resistant Capan-1 and 818-4 cells. Our results indicate that under certain conditions the resistance of pancreatic carcinoma cells to chemotherapy is due to their constitutive NF-kappaB activity rather than the transient induction of NF-kappaB by some anti-cancer drugs. Blockade of basal NF-kappaB activity by well established drugs efficiently reduces chemoresistance of pancreatic cancer cells and offers the potential for improved therapeutic strategies.

23
UI - 12099945
AU - Kouloulias VE; Nikita KS; Kouvaris JR; Golematis BC; Uzunoglu NK;
TI - Mystakidou K; Vlahos LJ Intraoperative hyperthermia and chemoradiotherapy for inoperable pancreatic carcinoma.
SO - Eur J Cancer Care (Engl) 2002 Jun;11(2):100-7
AD - University of Athens, Medical School, Aretaieion Hospital, Department of Radiotherapy, Athens, Greece. vkouloul@cc.ece.ntua.gr
The aim of this study was to evaluate the tolerability and the possible clinical benefit of intraoperative hyperthermia combined with multischedule chemotherapy and bypass surgery for the palliative treatment of inoperable pancreatic cancer. Ten patients with unresectable adenocarcinoma of the pancreas received preoperative chemotherapy [5-fluorouracil (5-FU)], bypass surgery and postoperative chemotherapy (5-FU, doxorubicin and cisplatin) plus sandostatin and radiotherapy (45 Gy, 25 fractions, 5 days a week). A single session of intraoperative hyperthermia was performed, by using a waveguide-type applicator (433 MHz). The tumour region was heated to 43-45 degrees C for up to 60 min, while 500 mg 5-FU was infused simultaneously through the gastroduodenal into the splenic artery. Postoperative recovery was uneventful for all patients. A brief instrument was developed for evaluating patients' quality of life. Chemotherapy-related toxicity included myelosuppression, vomiting, alopecia and increase in blood urea nitrogen (BUN), creatinine, SGOT and SGPT. Glucose and amylase determinations remained within normal limits throughout the whole treatment. There was a significant improvement before and 1 month after combined treatment in Eastern Cooperative Oncology Group (ECOG) status (1.8 +/- 0.4), Scott-Huskinsson pain scale (3.2 +/- 0.8) and quality of life score (30.5 +/- 6.7). No progressive disease was noticed and the median overall survival was 11 (SE = 2.4) months. There was also a significant (P = 0.002, Wilcoxon test) decrease in values of both serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19-9), from 7.6 +/- 1.3 ng/mL and 875.7 +/- 104.8 U/mL to 3.5 +/- 0.7 ng/mL and 65.3 +/- 14.1 U/mL respectively. The first clinical results suggest a potential advantage of using combined intraoperative hyperthermia, chemotherapy and postoperative radiotherapy in the palliative treatment of the adenocarcinoma of the pancreas. The whole procedure seems to be free of perioperative morbidity, while the chemotherapy toxicity was rather moderate. However, the preliminary nature limits the general applicability of our results.

24
UI - 12122717
AU - Blanchet MC; Andreelli F; Scoazec JY; Le Borgne J; Ozoux P; De Calan L;
TI - Partensky C [Total pancreatectomy for mucinous pancreatic tumor]
SO - Ann Chir 2002 Jun;127(6):439-48
AD - Service de chirurgie digestive, pavillon D, hopital Edouard-Herriot, 5, place d'Arsonval, 69437 Lyon, France.
AIM OF THE STUDY: To report our experience of total pancreatectomy (TP) in ten patients with mucinous pancreatic tumors (MPT), to discuss pre and peroperative investigations in the management of MPT, and operative, functional and carcinologic results after TP. PATIENTS AND METHODS: This patients, 5 men and 5 women (mean aged: 64 years). Six patients underwent one step TP for intraductal papillary mucinous tumor of the pancreas (IPMT) in 5 cases, and multifocal mucinous cystadenoma in one case. Four patients underwent a second step TP for tumor recurrence (2 IPMT, and 2 cystadenocarcinomas) which occurred 12 to 121 months post operatively (mean: 49 months). RESULTS: Post TP diabetes was controlled by insulinotherapy (3 injections a day), except in one patient who needed insulin administration through a pump. One patient, with cystadenocarcinoma, died from cancer recurrence 18 months after TP and 140 months after the initial pancreaticoduodenectomy. One patient died from heart disease 34 months postoperatively. The 8 other patients were alive with a mean follow-up of 33 months (range 11-61 months). CONCLUSION: Curative surgery for mucinous tumors of the pancreas may require TP, which is indicated preoperatively according to imaging, or intraoperatively following surgical findings and frozen section of the pancreatic margin. Totalization of a previous partial pancreatectomy is mandatory in case of tumoral persistence or recurrence in the pancreatic remnant. Postoperative diabetes can be managed successfully by a specialized team.

25
UI - 12122721
AU - Gouillat C; Faucheron JL; Balique JG; Gayet B; Saric J; Partensky C;
TI - Baulieux J; Chipponi J [Natural history of the pancreatic stump after duodenopancreatectomy of the pancreatic head]
SO - Ann Chir 2002 Jun;127(6):467-76
AD - Services de chirurgie, Hotel-Dieu, 1, place de l'hopital, 69288 Lyon, France. christian.gouillat@chu-lyon.fr
Major complications following pancreaticoduodenectomy are thought to be chiefly associated with exocrine secretion of the pancreatic remnant which is not well known. This work aims to assess the exocrine secretion of the pancreatic remnant within the early post-operative period. PATIENTS AND METHODS: Seventy-five patients undergoing pancreaticoduodenectomy for presumed tumour were included in a prospective multicentre study. A tube was inserted in the pancreatic duct at the time of construction of the pancreatic anastomosis. Peripancreatic drainage was routinely used. Pancreatic juice and peripancreatic drainage fluid were collected and measured and pancreatic enzyme monitored. For 7 days patients received total parenteral nutrition and continuous infusion of randomly Somatostatin 14 (S-14) at a dose of 6 mg/24 h (days 1-6) and 3 mg/24 h (day 7) or matching placebo. Pancreatic fistula was defined as a daily drainage of more than 100 cc of amylase-rich fluid after day 3, persisting after day 12 or associated with symptoms or needing specific treatment. RESULTS: Daily output of pancreatic juice was low during the first postoperative day and then increased gradually until day 5. A high enzyme concentration was observed in pancreatic juice on the first post-operative day. S-14 infusion resulted in a significant decrease of both pancreatic fistula rate and enzyme concentration in peripancreatic fluid. CONCLUSIONS: During the first postoperative days, the outflow of the exocrine secretion of the pancreatic remnant is low but contains a high enzyme concentration with significant leaks within the peripancreatic area. S-14 infusion results in a decrease of pancreatic juice leaks from the pancreatic remnant.

26
UI - 12170409
AU - Mutignani M; Shah SK; Morganti AG; Perri V; Macchia G; Costamagna G
TI - Treatment of unresectable pancreatic carcinoma by intraluminal brachytherapy in the duct of Wirsung.
SO - Endoscopy 2002 Jul;34(7):555-9
AD - Digestive Endoscopy Unit, Universita Cattolica del Sacro Cu

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