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  • 1
    Keywords: SONIC HEDGEHOG ; pancreatic cancer ; SPARC ; GEMCITABINE ; extracellular matrix ; stem cells ; stellate cells ; stroma ; Nab-paclitaxel
    Abstract: Most patients with pancreatic cancer present with advanced/metastatic disease and have a dismal prognosis. Despite the proven albeit modest benefits of gemcitabine demonstrated over a decade ago, subsequent advances have been slow, suggesting it may be time to take a different approach. It is thought that some key characteristics of pancreatic cancer, such as the desmoplasia, restricted vasculature and hypoxic environment, may prevent the delivery of chemotherapy to the tumour thereby explaining the limited benefits observed to-date. Moreover, there is evidence to suggest that the stroma is not only a mechanical barrier but also constitutes a dynamic compartment of pancreatic tumours that is critically involved in tumour formation, progression and metastasis. Thus, targeting the stroma and the tumour represents a promising therapeutic strategy. Currently, several stroma-targeting agents are entering clinical development. Among these, nab-paclitaxel appears promising since it combines cytotoxic therapy with targeted delivery via its proposed ability to bind SPARC on tumour and stromal cells. Preclinical data indicate that co-treatment with nab-paclitaxel and gemcitabine results in stromal depletion, increased tumour vascularization and intratumoural gemcitabine concentration, and increased tumour regression compared with either agent alone. Phase I/II study data also suggest that a high level of antitumor activity can be achieved with this combination in pancreatic cancer. This was recently confirmed in a Phase III study which showed that nab-paclitaxel plus gemcitabine significantly improved overall survival (HR 0.72) and progression-free survival (HR 0.69) versus gemcitabine alone for the first-line treatment of patients with metastatic pancreatic cancer.
    Type of Publication: Journal article published
    PubMed ID: 23849556
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  • 2
    ISSN: 0168-583X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1569-8041
    Keywords: chemotherapy ; hepatocellular carcinoma ; raltitrexed ; ‘Tomudex’ ; treatment outcome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1569-8041
    Keywords: gemcitabine ; pancreatic cancer ; phase I ; vinorelbine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose:Gemcitabine and vinorelbine are active drugs with broadspectrum of activity and manageable toxicity in clinical trials. The aims ofthis study were to describe the toxicity, to determine the dose-limitingtoxicity, and to define the doses of gemcitabine and vinorelbine to berecommended for phase II studies in patients with advanced cancers. Patients and methods:Drugs were given as 30–min infusions on day1 and 8 (vinorelbine before gemcitabine) every 3 weeks. Thirty-six patients(male : female ratio 25 : 11; mean age 54, PS 〉60) were treated including1 retroperitoneal sarcoma, 7 head and neck, 10 lung, 4 thyroid, 6 pancreatic,1 bladder, 2 ovary, 2 gastric, 1 rectum, 1 unknown primary, and 1 renal cellcarcinoma. Doses of gemcitabine/vinorelbine ranged from 800/20mg/m2 to 1500/30 mg/m2. Results:The dose-limiting toxicity was neutropenia. A transientgrade 2–3 elevation of transaminases was frequently observed at severaldose-levels, although this toxicity did not appear to be dose dependant andwas reversible at day 21 before the next cycle. Other toxicities were mild andeasily manageable, consisting of fatigue and flu-like syndromes. Since the MTDwas not reach at the higher dose-level, the recommended dose level of thegemcitabine–vinorelbine combination was 1500/30 mg/m2. Onetoxic death due to hematologic toxicity was reported in a heavily pretreatedpatient who underwent prior chemotherapy and pelvic radiotherapy. A total of12 patients were treated at the recommended dose level which was associatedwith grade 3–4 neutropenia in 3 of 12 patients and in 22.9% ofcycles. Conclusions:This study estimates that the recommended dose forphase II studies of gemcitabine–vinorelbine is 1500/30 mg/m2at day 1 and 8 every three weeks. A careful monitoring of the hematologictoxicity is recommended in heavily pretreated patients and in patients whoreceived pelvic radiotherapy. Partial responses observed in a patient with anadvanced cisplatin–5–fluorouracil-resistant pancreatic adenocarcinomaand in a patient with mesothelioma support further evaluation of thiscombination in patients with tumors refractory to classical antitumor agents.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1534-4681
    Keywords: Cervical esophageal cancer ; Hypopharyngeal cancer ; Surgery ; Total esophagectomy ; Circumferential pharyngolaryngectomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Forty-nine cases of circumferential pharyngolaryngectomy with total esophagectomy (PLTE) done between 1982 and 1996 were studied retrospectively. These procedures were performed for advanced squamous cell tumors of the superior esophageal sphincter (n=23), for hypopharyngeal tumors with synchronous esophageal carcinoma (n=15), and for hypopharyngeal tumors extensively invading the cervical esophagus (n=11). Methods: Ninety-six percent of the patients had T3–4 lesions, and it was impossible to use a free jejunal graft reconstruction. Patients underwent primary surgery in 70% of the cases, and salvage surgery (after failure of chemoradiotherapy) in 30%. In most patients, esophagectomy was performed without thoractomy (n=45). Resection was curative (R0) in 70% of the cases, in spite of lymph node invasion in 94%. Reconstruction of the digestive tract was achieved with the stomach in 33 patients (67%) or with the colon in 16 patients (33%). Results: Before 1989, postoperative mortality was high, was correlated with the high frequency of palliative surgery, and resulted in unsatisfactory survival results (overall 5-year survival rate of 7%). After 1989, as a result of better selection of patients and appropriate training of our team, postoperative mortality decreased from 33% to 10%, R1–2 resections decreased from 39% to 26%, and a 3-year overall survival rate of 28% was obtained for the last 25 patients, all of whom were able to eat without difficulty. These results are superior to the survival rates and functional results obtained with radiochemotherapy alone for such advanced tumors, even though the voice is preserved with radiochemotherapy alone. Conclusions: PLTE for advanced pharyngeal or cervical esophageal tumors is the best treatment currently available, but it is indicated only in very selected cases: when it is technically impossible to perform reconstruction with a free jejunal graft after circumferential pharyngolaryngectomy; as primary surgery, rather than as salvage surgery following chemoradiotherapy; after careful preoperative morphologic and endoscopic assessment of the extent of the tumor; and in patients able to tolerate a thoracotomy for an esophagectomy with lymphadenectomy. Selection according to these guidelines should improve results.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1569-8041
    Keywords: 5-fluorouracil ; efficacy ; oxaliplatin ; platinum compounds ; salvage chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: To provide evidence for the therapeutic efficacy of oxaliplatin (Eloxatin®) when given as a 2–6-hour i.v. infusion, alone or in combination with 5-fluorouracil/folinic acid (5-FU ± FA) in patients with advanced colorectal carcinoma (ACRC) who have failed 5-FU-based therapy. To confirm the safety of the drug and its combination in an extended-access context. Patients and methods: Prescribing physicians were supplied oxaliplatin on a nominative compassionate-use basis, after obtaining informed consent. Europe-wide, 206 ACRC patients in 44 centers received 1168 cycles of chemotherapy with oxaliplatin (80–100 mg/m2 q 2 weeks or 100–135 mg/m2 q 3 weeks) delivered as a short (2–6 hours) i.v. infusion, 177 of them (1026 cycles) receiving oxaliplatin + 5-FU ± FA. Results: Oxaliplatin added to the 5-FU ± FA regimens of 111 verified 5-FU-refractory patients (imaging and/or clinical proof of progression under prior 5-FU-based regimen), elicited objective responses in 25 of 98 evaluable patients, (ORR: 25.5%, 95% confidence interval (95% CI: 17–35). The median time to progression was 4.1 months (95% CI: 3.3–5.0) and the median overall survival was 9.6 months (95% CI: 8.2–10.9). Differences in the toxicity profile of the oxaliplatin + 5-FU ± FA combination appear related to administration modality, dose and schedule of the 5-FU-based regimen. Conclusions: The addition of oxaliplatin (2–6-hour i.v. infusion) to 5-FU ± FA regimens is active in ACRC patients with clinical resistance to fluoropyrimidines. The therapeutic index of oxaliplatin + 5-FU ± FA combinations administered as salvage therapy compares favorably with those reported in recent phase II–III trials involving other new agents or combinations active in 5-FU-refractory ACRC patients.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1569-8041
    Keywords: anal cancer ; cisplatin ; 5-fluorouracil ; phase II study ; radiation therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Chemotherapy (5-fluorouracil–mitomycin C) concomitant withradiotherapy (RT) increases local control and colostomy-free survival inadvanced anal canalcarcinomas (ACC). The purpose of this prospective trial was to analyse thetoxicity of and response to an induction chemotherapy combining 5-fluorouracil(5-FU) and CDDP administered concomitantly with irradiation. Patients and methods: Thirty patients (24 F/6 M, mean age 60, range38–74) with an advanced ACC 〉40 mm and/or with node involvement wereprospectively treated (1 T1, 16 T2, 8 T3, 5 T4, 10 N1, 1 N2, 8 N3) fromNovember 1994 to January 1996. Two induction and two concomitant cycles of5-FU(800 mg/m2 D1–4 infusion) and CDDP (80mg/i.v./m2 at D1) were delivered. RT consisted of 45 Gy (1.8Gy/fr, 5 fr/w) on pelvis ± inguinal nodes or 30 Gy (3 Gy/fr, 4 fr/w)by direct perineal field. A boost (15–20 Gy) was delivered six weekslater. Results: Toxicity: one patient died of a pulmonary embolism on D4.The remaining 29 received the entire treatment, with reduced 5-FU doses in 11patients because of acute toxicity. The RT boost was delayed for one patient(aplasia). In 109 cycles, 3 grade 4 and 17 grade 3 toxicities were observed;there were no toxic deaths. Tumor response: the complete response (CR)and partial response (PR) rates were, respectively, 11% and 61%after induction chemotherapy, 59% and 31% after concomitantradiochemotherapy and 96% and 0% two months after completion ofthe treatment. No tumor progression was observed. Conclusion: the treatment was well tolerated and there was good compliance.After induction chemotherapy, most of the patients were in PR, with some evenin CR. After completion of the treatment all but one were in CR. The tumorresponse and the long term results of 50 patients will be analysed beforeinitiation of a randomised trial is considered.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1569-8041
    Keywords: biliary tract cancer ; chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: The combination of 5-fluorouracil (5-FU) and cisplatin hasshown great activity in many different types of tumour with an in vitrosynergistic effect between 5-FU and cisplatin. A phase II study of 5-FU pluscisplatin was performed in 25 previously untreated patients with inoperablelocally advanced or metastatic biliary tract carcinoma. Patients and methods: Twenty-five patients, 10 of them men and 15 womenwith a median age of 58, were entered into the study. The chemotherapyregimen consisted of 5-FU: 1 g/m2/day in continuousintravenous (i.v.) infusion for five consecutive days, and cisplatin: 100mg/m2/day on day 2 in a one-hour infusion with standardhyperhydration. Twenty-two patients had metastatic tumours and three hadlocally advanced disease. Results: Of the 25 patients entered into the study, 24 were evaluable forresponse and 25 for toxicity. Nausea and vomiting was the main toxic sideeffect in 19 patients. Severe, WHO grade 3–4 thrombocytopenia orneutropenia were observed in three and seven patients, respectively. Therewere no toxic deaths. Of 25 patients, six had partial remissions (overallresponse 24%, 95% confidence interval7%–41%). For three patients, tumour reduction permittedlocal radiotherapy and one of these patients with initially advanced diseaseis still alive six years after the beginning of treatment. Conclusions: This study, one of the largest phase II trials performed inthis disease, shows interesting activity of the combination of 5-FU andcisplatin in advanced biliary tract carcinoma.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1573-2568
    Keywords: hilar biliary obstruction ; biliary endoprosthesis ; endoscopy ; endoscopic retrograde cholangiography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Between January 1983 and December 1987, 103 patients who had hilar biliary obstruction (59 men, 44 women, median age 73 years) were referred to our institution. The causes of hilar biliary obstruction were carcinoma of the bile ducts (55), hepatic metastases or hepatocellular carcinoma (30), and carcinoma of the gallbladder (18). When endoscopic retrograde cholangiography was performed, the stricture was classified as type I in 28%, type II in 41%, and type III in 31% of the patients. In 92 patients, we tried to insert endoscopically a 10, 11, or 12 F Amsterdam type prosthesis; it proved possible in 66 (74%), and the prosthesis proved functional without further procedure in 49 cases (53%); no combined percutaneous and endoscopic method was used. At death or discharge, 45 patients (49%) had a successful drainage. Cholangitis was the main procedure-related complication and occurred in 25 patients. The 30-day mortality was 43%. Results varied according to type of stenosis: successful drainage was performed in 15% of the patients with type III stenosis, compared with 86% when the stenosis was of type I. Under a multivariate analysis the independent prognostic factors of 30-day mortality were: (1) development of infectious complications after endoscopic attempt at drainage (P〈0.0001), and (2) absence of successful drainage (P〈0.0001). In conclusion, endoscopic endoprosthesis placement allows a sufficient drainage in 53% of the cases. In type III stenosis, the high rate of 30-day mortality leads us the conclusion that endoscopic drainage must be avoided.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1573-2568
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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