Biomedical subjects

G Giaccone

Publications and source records attributed to G Giaccone.

At least 19 recordsLinked to original sources

PubMed2000

Human natural killer T cells acquire a memory-activated phenotype before birth.

Natural killer T (NKT) cells have recently been shown to play an important role in the rejection of malignant tumors and in the regulation of autoimmune diseases. Potent antitumor effects of the marine sponge-derived NKT cell ligand KRN7000 were observed in mice. Therefore, the elucidation of the natural ligand of NKT cells, which is currently still unknown, might have important clinical consequences for the treatment of cancer and autoimmune diseases. Analysis of cord blood mononuclear cells from healthy term infants demonstrated that in sharp contrast with the vast majority of cord blood lymphocytes, human NKT cells have already acquired a memory-activated phenotype before birth. This observation indicates that NKT cells encounter a natural ligand during fetal life and that this ligand is unlikely to be of microbial origin.

Adult↗

PubMed2000

Synergistic effect of KRN7000 with interleukin-15, -7, and -2 on the expansion of human V alpha 24+V beta 11+ T cells in vitro.

KRN7000, (2S, 3S, 4R)-1-O-(alpha-D-galactopyranosyl)-2-(N-hexacosanoylamino)-1, 3, 4-octadecanetriol, has been shown to prevent tumor metastasis to the liver through the activation of natural killer (NK) T cells in mice. In this study, the proliferation of human NK T cells, which express an invariant T cell antigen receptor (TCR) consisting of a Valpha24 chain and a Vbeta11 chain, was investigated using KRN7000, interleukin (IL)-15, IL-7, and IL-2 in vitro. KRN7000 stimulated the expansion of Valpha24(+)Vbeta11(+) T cells derived from peripheral blood mononuclear cells in a dose-dependent fashion, with some fluctuation between donors. IL-15, IL-7, and IL-2 synergistically stimulated the expansion of Valpha24(+)Vbeta11(+) T cells when combined with KRN7000. Intracellular expression of interferon (IFN)-gamma and IL-4 in Valpha24(+)Vbeta11(+) T cells expanded in the presence of KRN7000 was identified using flow cytometry. Valpha24(+)Vbeta11(+) T cells, expanded in the presence of KRN7000, contained granzyme (Gr) B-positive granules and perforin-positive granules. The addition of IL-15 to the culture containing KRN7000 increased GrB expression in Valpha24(+)Vbeta11(+) T cells while IL-7 and IL-2 failed to do it. In conclusion, the antitumor effect of KRN7000 may depend, in part, on granule-mediated cell killing through the activation of NK T cells and IL-15 may potentiate this effect.

Adjuvants, Immunologic↗

PubMed2000

A phase I-II study of gemcitabine and paclitaxel in advanced non-small-cell lung cancer patients.

Thirty patients with chemotherapy-naïve advanced non-small-cell lung cancer (NSCLC) were given escalating doses of paclitaxel (150, 175, 200 mg/m2) on day 1 in three consecutive cycles, together with a fixed dose of gemcitabine 1000 mg/m2 on days 1 and 8; cycles were repeated every three weeks. The dose escalation of paclitaxel was feasible in the majority of patients. Subsequently, 30 other NSCLC patients received a dose of 200 mg/m2 paclitaxel with gemcitabine 1000 mg/m2 in a phase II study. The major side effect was mild myelosuppression. A response rate of 24% was achieved in 49 fully evaluable patients. This regimen proved to be safe and easy to administer on an out-patient setting, and constitutes now one of the arms of the current EORTC randomized study for advanced NSCLC.

Antimetabolites, Antineoplastic↗

PubMed2000

Creutzfeldt-Jakob disease: Carnoy's fixative improves the immunohistochemistry of the proteinase K-resistant prion protein.

The neuropathological diagnosis of Creutzfeldt-Jakob disease relies on the immunohistochemical demonstration of the proteinase-K resistant form of the prion protein (PrPres) in the brain tissue. The antigenicity of PrPres is strongly reduced by the formalin solution widely used to fix the tissue, thus the PrPres immunoreactivity is inconsistently detectable in formalin-fixed tissue. A better PrPres immunostaining can be obtained by using Carnoy's fixing solution, which is composed of ethanol, chloroform and acetic acid (6:3:1). PrPres can easily be extracted from Carnoy's-fixed, paraplast-embedded tissue. Accordingly, Carnoy's-fixed tissue can prior to immunolabeling be subjected to proteinase K and guanidine thiocyanate, which respectively eliminate the normal cellular form of prion protein and promote protein denaturation. In comparison with the best protocols for formalin-fixed tissue (i.e.--hydrolytic autoclaving or autoclaving in distilled water followed by formic acid and guanidine thiocyanate), PrPres immunostaining carried out on sections cut from Carnoy's-fixed, paraplast-embedded tissue blocks and subjected to proteinase K and guanidine thiocyanate, proved more successful to detect and map both diffuse and focal PrPres immunoreactivity, and to correlate the immunoreactivity pattern with MV polymorphism at PRNP codon 129 and PrPres banding and glycosylation pattern revealed by Western blot.

Adult↗

PubMed2000

Drug-induced apoptosis in lung cnacer cells is not mediated by the Fas/FasL (CD95/APO1) signaling pathway.

Anticancer drugs exert at least part of their cytotoxic effect by triggering apoptosis. We previously identified chemotherapy-induced apoptosis in lung cancer cells and suggested a role for p53 alternative or complementary pathways in this process. Recently, a role for the Fas/FasL (CD95/Apo1) signaling system in chemotherapy-induced apoptosis was proposed in some cell types. In the present work, the involvement of the Fas/FasL system in drug-induced apoptosis in lung cancer cells was investigated upon exposure to four cytotoxic drugs (cisplatin, gemcitabine, topotecan, and paclitaxel). We assessed the expression of Fas and FasL and the function of the Fas pathway in six lung cancer cell lines (H460, H322, GLC4, GLC4/ADR, H187, and N417). All lung cancer cell lines expressed Fas and FasL at RNA and protein levels, and apoptosis could be induced in four of six cell lines upon exposure to the Fas agonistic monoclonal antibody (mAb) CLB-CD95/15. Nevertheless, after drug exposure, no significant FasL up-regulation was observed, whereas the Fas expression was increased in the wild-type p53 cell line H460, but not in the other lines, proved to be mutant p53 by direct gene sequencing. Moreover, no correlation was observed in lung cancer cell lines between sensitivity to drugs and to a Fas agonistic mAb, and preincubation of cells with either the Fas-antagonistic mAb CLB-CD95/2 or a FasL-neutralizing mAb did not protect from drug-induced apoptosis. Taken together, these observations strongly argue against a role of the Fas/FasL signaling pathway in drug-induced apoptosis in lung cancer cells. Interestingly, caspase-8 activation was observed upon drug exposure, independently from Fas/FasL signaling.

Antineoplastic Agents↗

PubMed1999

Sporadic Creutzfeldt-Jakob disease: co-occurrence of different types of PrP(Sc) in the same brain.

Phenotypic heterogeneity of sporadic Creutzfeldt-Jakob disease (CJD) has been linked to biochemically distinct types of the protease-resistant form of the prion protein (type 1 and type 2 PrP(Sc)). We investigated 14 cases of sporadic CJD and found that both type 1 and type 2 PrP(Sc) coexisted in 5 subjects. The distinct PrP(Sc) isoforms were associated with different patterns of PrP deposition and severity of spongiform changes, suggesting that the PrP(Sc) type plays a central role in determining the neuropathologic profile of CJD.

Aged↗

PubMed1999

Development of layer I of the human cerebral cortex after midgestation: architectonic findings, immunocytochemical identification of neurons and glia, and in situ labeling of apoptotic cells.

The development of layer I was studied in the human frontal cortex from 21 weeks of gestation (GW) to 2.5 postnatal months in series of adjacent sections processed for thionin staining, Bodian silver staining, and immunocytochemical labeling of neurons and glia. In addition, the terminal dUTP nick-end labeling (TUNEL) method was used to label in situ DNA fragmentation. A progressive decrease of cell density and the disappearance of the subpial granular layer (SGL) appeared as distinctive developmental features of human layer I, consistently with previous investigations. The neuronal antigen microtubule-associated protein2 was found to label preferentially Cajal-Retzius cells and dendritic processes extending from the cortical plate. At midgestation, the calcium binding protein calretinin stained in the marginal zone numerous neurons, including the Cajal-Retzius cells and their processes. Calretinin-immunoreactive neurons decreased during the subsequent maturation: such decline was abrupt in the SGL, whereas bipolar calretinin-immunopositive cells accumulated in the inner marginal zone to be presumably incorporated into the cortical plate. Cajal-Retzius cells expressed calretinin throughout the examined developmental stages. The glial antigen vimentin was already expressed at midgestation, and vimentin immunopositivity decreased progressively in cell bodies and fibers of layer I during development. Glial fibrillary acidic protein-positive elements gradually matured, and the positive cell bodies displayed the features of mature astrocytes at the end of gestation. Moreover, a decrease of free glial cells was observed in layer I, suggesting their progressive incorporation into the cortical plate. TUNEL-positive cells were detected at midgestation in the marginal zone, and they were concentrated in the SGL until its disappearance; their number decreased dramatically throughout layer I after 30 gestational weeks. TUNEL-positive nuclei or regressive changes were not detected in Cajal-Retzius cells throughout the examined developmental stages. Thus, our data point out that naturally occurring cell death is an active mechanism contributing to the disappearance of the SGL but not to the subsequent developmental reshaping of human layer I, in which, instead, migratory phenomena should play a major role. In addition, our findings argue against a disappearance of Cajal-Retzius cells due to regressive processes.

Apoptosis↗

PubMed1999

A Phase II study of gemcitabine in patients with malignant pleural mesothelioma. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.

BACKGROUND: Gemcitabine has shown activity in patients with less chemosensitive solid tumors. Phase II screening of novel drugs is an accepted method with which to investigate new therapies in malignant mesothelioma. The European Organization for Research and Treatment of Cancer-Lung Cancer Cooperative Group has performed several sequential Phase II trials of new agents for the treatment of mesothelioma over the last 10 years. METHODS: Twenty-seven chemotherapy-naive patients with histologically proven malignant mesothelioma were treated with gemcitabine as a 30-minute intravenous administration of 1250 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Therapy continued for up to ten cycles unless disease progression or excessive toxicity mandated discontinuation. RESULTS: With a median relative dose intensity of 96%, toxicity was mild and neutropenia of > or = Grade 3 (according to National Cancer Institute criteria) occurred in 30% of patients, without episodes of febrile neutropenia. One case of hemolytic-uremic syndrome, most likely related to gemcitabine use, was observed. Overall, 2 objective responses were observed (response rate of 7%; 95% confidence interval, 1-24%). The median survival was 8 months. CONCLUSIONS: At the prescribed dosage and schedule, single agent gemcitabine appears to have limited activity in chemotherapy-naive patients with malignant pleural mesothelioma.

Adult↗

PubMed1999

A betaPP peptide carboxyl-terminal to Abeta is neurotoxic.

Extracellular Abeta-amyloid and intraneuronal paired helical filaments (PHFs) composed of tau protein are the neuropathological hallmark of Alzheimer's disease. Abeta is a 39- to 43-residue peptide derived by cleavage of a 695- to 770-amino-acid membrane-associate glycoprotein (termed beta-protein precursor, betaPP). Following the observation that an antiserum to an epitope located between residues 713 and 723 of betaPP770 (ie, the transmembrane region of the betaPP distal to Abeta) labels PHFs and that a synthetic peptide homologous to residues 713 to 730 of betaPP770 (betaPP713-730) is highly fibrillogenic and interacts with tau in vitro, it has been hypothesized that betaPP fragments other than Abeta may feature in the pathogenesis of Alzheimer's disease concurring with neuronal degeneration. To investigate this issue, we have analyzed the effects of the exposure of primary neuronal cultures to the synthetic peptide betaPP713-730. Cultures were prepared from rat hippocampus on embryonic day 17 and incubated with the peptide at 2.5 to 30 micromol/L concentration for 1 to 4 days. Cell viability was compared with that of control cultures exposed to a scrambled sequence of the peptide. A 4-day exposure to 20 micromol/L betaPP713-730 resulted in almost complete neuronal loss, whereas no changes were observed with the scrambled peptide. Degenerating neurons showed DNA fragmentation by agarose gel electrophoresis and apoptotic changes by light and electron microscopy. These findings support the view that betaPP sequences other than Abeta may play a role in nerve cell degeneration in Alzheimer's disease.

Amyloid beta-Protein Precursor↗

PubMed1999

Cell cycle disturbances and apoptosis induced by topotecan and gemcitabine on human lung cancer cell lines.

Apoptosis is a major mode of cell death in response to cytotoxic drug treatment. A correlation between induction of apoptosis and chemosensitivity has been documented in some preclinical models. Topotecan (a topoisomerase I inhibitor) and gemcitabine (a deoxycytidine analogue), two active new drugs for the treatment of lung cancer, were evaluated for their growth inhibitory effect on human lung cancer cell lines and their effect on cell cycle perturbation, apoptosis and apoptosis-related genes. The cytotoxicities of topotecan and gemcitabine on the human lung cancer cell lines H460 (wild-type-p53) and H322 (mutant p53 were determined after 72 h drug exposure employing the MTT assay. The apoptotic index (AI) was assessed by three methods: analysis of morphological changes using May-Grünwald-Giemsa (MGG) staining, the TUNEL assay and FACS analysis. Cell cycle disturbances were studied by FACS and the number of cells expressing p53 and p21 were determined by immunohistochemistry. Both gemcitabine and topotecan had potent growth inhibitory effects in human lung cancer cell lines; combination treatment with these two drugs showed some additivity but no synergism. Induction of apoptosis after treatment was concentration- and time-dependent with both drugs and IC80 concentrations induced the highest values. The DNA histograms at 4, 24, 48 and 72 h indicate that topotecan at IC80 concentrations causes accumulation of cells in S and G2/M phases, whereas gemcitabine at IC80 concentrations causes, accumulation of cells in G1 phase. Both compounds induced p53 and p21 expression in the H460 cell line but not in the H322 cell line; the percentage of cells expressing p53 was highest at IC80 values, whereas the highest percentage of p21 positive cells could be induced with IC50 values. This could suggest that p53 induces cell cycle arrest at low drug concentrations, whereas p53 induces apoptosis at higher concentrations. In conclusion, p53-dependent and independent pathways of apoptosis exist in lung cancer cell lines. Activation of the p53 pathway depends on the induced cellular damage. Understanding the cell cycle disturbances induced by these drugs may help in the design of more rational treatment schedules.

Antineoplastic Agents↗

PubMed1999

p53 and chemosensitivity.

BACKGROUND: Although hematologic malignancies and some solid tumors such as germ cell tumors and pediatric malignancies can be cured by cytotoxic treatment, the most prevalent solid tumors are relatively resistant to these interventions. Apoptosis is involved in the cell kill of anticancer drugs and p53 is believed to be of principal importance in this process. However p53 also plays a role in cell cycle arrest and DNA repair, cellular processes that can decrease the sensitivity to chemotherapy. Therefore, p53 may play a dual role after exposure to cytotoxic treatment, activating either mechanisms that lead to apoptosis or launching processes directing to DNA repair and survival of the cell. DESIGN: In this article, we review in details the p53 functions involved in the mediation of chemosensitivity. The preclinical and clinical data published in the recent years about the relation between p53 and chemosensitivity are discussed and the potential pitfalls associated to most of these studies, and that may account for the contradictory results produced so far are also mentioned.

Apoptosis↗

PubMed1999

Effects of alpha-galactosylceramide (KRN7000), interleukin-12 and interleukin-7 on phenotype and cytokine profile of human Valpha24+ Vbeta11+ T cells.

The alpha-galactosylceramide KRN7000 was reported to be presented by CD1d to natural killer (NK) T cells, cells that are thought to play an important role in the rejection of malignant tumours and in the regulation of several autoimmune diseases. Here we analysed human peripheral blood (PB) NK T cells (Valpha24+ Vbeta11+ T cells) before and after a short-term culture in the presence of KRN7000. KRN7000 strongly activated PB Valpha24+ Vbeta11+ T cells and, when stimulated, the vast majority of these cells expressed interferon-gamma (IFN-gamma). Exposure of these KRN7000-cultured Valpha24+ Vbeta11+ T cells to interleukin-12 (IL-12), but not to IL-7, resulted in a relative increase in IFN-gamma-expressing Valpha24+ Vbeta11+ T cells, compared with IL-4-expressing Valpha24+ Vbeta11+ T cells, indicating a shift towards a T-helper type 1 (Th1) phenotype. KRN7000 strongly up-regulated the expression of the cytotoxic molecule granzyme B (GrB) in Valpha24+ Vbeta11+ T cells. Although IL-7 resulted in a decrease in GrB levels in KRN7000-cultured Valpha24+ Vbeta11+ T cells, IL-12 increased GrB levels in both Valpha24+ Vbeta11+ T cells and in Valpha24+ Vbeta11+ T-cell clones and increased cytotoxicity against hCD1d-transfected HeLa cells. Our data provide further insight into the characteristics of human Valpha24+ Vbeta11+ T cells and indicate that KRN7000 is a potent activator of Valpha24+ Vbeta11+ T cells. Combined with the established anti-tumour effects of KRN7000 in mouse models, these results may support the use of KRN7000 as an anti-tumour agent in man.

Adult↗

PubMed1999

Second-line chemotherapy and its evaluation in small cell lung cancer.

The literature on second-line chemotherapy for small cell lung cancer between 1989-1999 is reviewed. The reports consisted mainly of phase II studies and included a total of 1749 patients. The information was frequently incomplete with respect to duration of response on first-line chemotherapy and the length of treatment free interval. The overall second-line response rate was 20%. Obviously, new chemotherapy regimens are needed for relapsed small cell lung cancer. We propose a methodology for future trials based on the distinction between sensitive and refractory patients. The latter group of patients who progress on or within a short time of induction of treatment are candidates for single arm phase II trials with agents with unknown or new mechanisms of action or new combination regimens. The sole endpoint of this type of phase II studies is response rate. For sensitive patients we propose re-induction chemotherapy as the standard against which investigational agents or combination regimens should be tested. Major end-points include response rate, toxicity and quality of life. Regimens with demonstrated therapeutic activity in this setting could be tested as first-line chemotherapy in phase II trials.

Antineoplastic Agents↗

PubMed1999

Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau.

The tau gene has been found to be the locus of dementia with rigidity linked to chromosome 17. Exonic and intronic mutations have been described in a number of families. Here we describe a P301S mutation in exon 10 of the tau gene in a new family. Two members of this family were affected. One individual presented with frontotemporal dementia, whereas his son has corticobasal degeneration, demonstrating that the same primary gene defect in tau can lead to 2 distinct clinical phenotypes. Both individuals developed rapidly progressive disease in the third decade. Neuropathologically, the father presented with an extensive filamentous pathology made of hyperphosphorylated tau protein. Biochemically, recombinant tau protein with the P301S mutation showed a greatly reduced ability to promote microtubule assembly.

Adult↗

PubMed1999

Gemcitabine and paclitaxel: pharmacokinetic and pharmacodynamic interactions in patients with non-small-cell lung cancer.

PURPOSE: To assess possible pharmacokinetic and pharmacodynamic interactions between gemcitabine and paclitaxel in a phase I/II study in non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Eighteen patients with advanced NSCLC received the following in a 3-week schedule: gemcitabine 1,000 mg/m(2) (30 minutes, days 1 and 8) and paclitaxel 150 (n = 9) or 200 mg/m(2) (n = 9) before gemcitabine (3 hours, day 1). Plasma pharmacokinetics and pharmacodynamics in mononuclear cells were studied. RESULTS: Gemcitabine did not influence paclitaxel pharmacokinetics at 150 and 200 mg/m(2) (area under the concentration-time curve [AUC], 7.7 and 8.8 micromol/ L. h, respectively; maximum plasma concentration [C(max)], 3.2 and 4.0 micromol/L, respectively), and paclitaxel did not influence that of gemcitabine (C(max), 30 +/- 3 micromol/L) and 2',2'-difluorodeoxyuridine. Paclitaxel, however, dose-dependently increased the C(max) of gemcitabine triphosphate (dFdCTP), the active metabolite of gemcitabine, from 55 +/- 10 to 106 +/- 16 pmol/10(6) cells.( )No significant difference in the AUC of dFdCTP was observed. Moreover, the gemcitabine-paclitaxel combination significantly increased ribonucleotide levels, most pronounced for adenosine triphosphate (six- to seven-fold). Postinfusion paclitaxel AUC was related to pretreatment hepatic function (bilirubin: r = 0. 79; P <.001) and to the percentage decrease in platelets (r = 0.61; P =.009). The latter was also related to the duration of paclitaxel concentration above 0.1 micromol/L (r = 0.62; P =.007). Gemcitabine C(max )was related to the percentage decrease in platelets (r = 0. 58; P =.01), pretreatment hepatic function (bilirubin: r = 0.77; P <. 001), and to plasma creatinine (r = 0.5; P =.03). The pharmacokinetics and pharmacodynamics were not related to response or survival. CONCLUSION: Gemcitabine and paclitaxel pharmacokinetics were related to the percentage decrease in platelets. Paclitaxel did not affect the pharmacokinetics of gemcitabine, nor did gemcitabine affect the pharmacokinetics of paclitaxel, but paclitaxel increased dFdCTP accumulation. This might enhance the antitumor activity of gemcitabine.

Aged↗

PubMed1999

Gemcitabine plus taxane combinations in non-small cell lung cancer.

Among the relatively new cytotoxic agents that are active in non-small cell lung cancer, gemcitabine and the taxanes (paclitaxel and docetaxel) are certainly of particular interest due to their essentially nonoverlapping toxicities and single-agent activities, which compare favorably with single-agent cisplatin. For these reasons, new combinations including these agents are being tested in dose-finding studies in phase II and III trials. Combinations of gemcitabine with a taxane, with or without a platinum compound, represent new and promising regimens for the treatment of non-small cell lung cancer and other tumor types.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

Prolonged neoadjuvant chemotherapy with GM-CSF in locally advanced breast cancer.

BACKGROUND: Neoadjuvant chemotherapy improves survival in patients with locally advanced breast cancer (LABC). Usually three to four cycles of conventional-dose neoadjuvant chemotherapy are administered prior to local therapy, and another three cycles thereafter. In an attempt to improve results, we increased the dosages and applied GM-CSF, which, besides being a hematopoietic growth factor, has become increasingly known for its immunostimulatory effects, which might enhance the antitumor effect. METHODS: Forty-two patients with stage IIIA or IIIB breast cancer were treated with doxorubicin (A) (90 mg/m2) and cyclophosphamide (C) (1,000 mg/m2) at three-weekly intervals. In the second and fourth cycle a 10% dose reduction of both agents was applied. On the second day GM-CSF 250 micrograms/m2/day was started and given for 10 days. Initially, some patients were treated with < or = four cycles, but as the study progressed and toxicity appeared tolerable, six cycles were given whenever possible. After the chemotherapy, patients underwent surgery and postoperative radiotherapy. RESULTS: The response rate for the whole group to AC was 98% (95% confidence interval 94%-100%), with a clinical complete response rate of 50% (95% confidence interval 35%-65%). Six patients had a pathological complete response. Median follow-up from the start of chemotherapy is 49 months (range 10-100). The disease-free survival (DFS) at three years is 57% and the overall survival (OS) at three years is 79%. There is a significant trend for improved DFS (p = 0.0000) and OS (p = 0.0002) with increasing number of cycles. CONCLUSION: The results of the present study with neoadjuvant dose-intensive AC chemotherapy and GM-CSF compare favorably with previous studies in patients with LABC. This is most apparent in patients who received six cycles of neoadjuvant chemotherapy. We hypothesize that these encouraging results are probably related to the prolonged presence of the primary tumor, and to the long-term administration of GM-CSF with the primary tumor and axillary lymph nodes in situ. Therefore, a randomized study is warranted. We already initiated an international randomized trial in patients with LABC in order to answer two questions. First, does prolonged neoadjuvant chemotherapy result in an improved DFS and OS in comparison with the conventional approach, and secondly, what is the effect of GM-CSF in this approach in comparison with G-CSF?

Adult↗

PubMed1999

Current chemotherapeutic possibilities in pancreaticobiliary cancer.

At time of presentation the majority of patients with pancreaticobiliary cancer have locally advanced or metastatic disease which makes them unamenable for curative surgery. In these patients chemotherapy is an option which has gained more support over the past few years. Special problems faced in chemotherapeutic treatment are the patient's poor condition and the difficulties faced in evaluating response. 5-FU has been the only drug with some efficacy for a long time, but more recently gemcitabine appeared to be more efficient. In locally advanced pancreatic cancer the combination of chemotherapy with radiotherapy has not gained much support. However, studies are implicating better local control with combined treatment and recurrences appear more often at distant sides. In some cases irresectable tumors became resectable. Because of the poor survival after surgery with curative intent, adjuvant and neoadjuvant therapy are becoming important issues. Although studies of adjuvant therapy suggest benefit, research is seriously hampered by poor patient accrual due to the morbidity of pancreaticoduodenectomy. Neoadjuvant treatment may overcome this problem. Until now there has been only modest improvement in the treatment of pancreatic cancer. Hopefully, new treatment modalities such as immunotherapy, gene therapy and antiangiogenic therapy will alter this dismal picture. In biliary cancer the role of chemotherapy is less well defined, since only few studies with low patients numbers have been performed.

Biliary Tract Neoplasms↗