In vivo growth-inhibition of S 180 tumor by mixture of 5-Fu and low molecular lambda-carrageenan from Chondrus ocellatus

POLYSACCHARIDES; ANTICOAGULANT; SURVIVAL

An EORTC phase I study of epirubicin in combination with fixed doses of cyclophosphamide and infusional 5-fu (CEF-infu) as primary treatment of large operable or locally advanced/inflammatory breast cancer.

PURPOSE: The association of continuous infusion 5-fluorouracil, epirubicin (50 mg/m2 q 3 weeks) and a platinum compound (cisplatin or carboplatin) was found to be very active in patients with either locally advanced/inflammatory (LA/I) [1, 2] or large operable (LO) breast cancer (BC) [3]. The same rate of activity in terms of response rate (RR) and response duration was observed in LA/I BC patients when cisplatin was replaced by cyclophosphamide [4]. The dose of epirubicin was either 50 mg/m2 [ 1, 2, 3] or 60 mg/m2/cycle [4]. The main objective of this study was to determine the maximum tolerated dose (MTD) of epirubicin when given in combination with fixed doses of cyclophosphamide and infusional 5-fluorouracil (CEF-infu) as neoadjuvant therapy in patients with LO or LA/I BC for a maximum of 6 cycles. PATIENTS AND METHODS: Eligible patients had LO or LA/I BC, a performance status 0-1, adequate organ function and were <65 years old. Cyclophosphamide was administered at the dose of 400 mg/m2 day 1 and 8, q 4 weeks and infusional 5-fluorouracil 200 mg/m2/day was given day 1-28, q 4 weeks. Epirubicin was escalated from 30 to 45 and to 60 mg/m2 day 1 and 8; dose escalation was permitted if 0/3 or 1/6 patients experienced dose limiting toxicity (DLT) during the first 2 cycles of therapy. DLT for epirubicin was defined as febrile neutropenia, grade 4 neutropenia lasting for >7 days, grade 4 thrombocytopenia, or any non-haematological toxicity of CTC grade > or =3, excluding alopecia and plantar-palmar erythrodysesthesia (this toxicity was attributable to infusional 5-fluorouracil and was not considered a DLT of epirubicin). RESULTS: A total of 21 patients, median age 44 years (range 29-63) have been treated. 107 courses have been delivered, with a median number of 5 cycles per patient (range 4-6). DLTs on cycles I and 2 on level 1, 2, 3: grade 3 (G3) mucositis occurred in 1/10 patients treated at the third dose level. An interim analysis showed that G3 PPE occurred in 5/16 pts treated with the 28-day infusional 5-FU schedule at the 3 dose levels. The protocol was subsequently amended to limit the duration of infusional 5-fluorouracil infusion from 4 to 3 weeks. No G3 PPE was detected in 5 patients treated with this new schedule. CONCLUSIONS: This study establishes that epirubicin 60mg/m2 day 1 and 8, cyclophosphamide 400mg/m2 day 1 and 8 and infusional 5-fluorouracil 200 mg/m2/day day 1-21. q 4 weeks is the recommended dose level. Given the encouraging activity of this regimen (15/21 clinical responses) we have replaced infusional 5-fluorouracil by oral capecitabine in a recently activated study.

Oxaliplatin/capecitabine versus oxaliplatin/infusional 5-FU in advanced colorectal cancer: The MRC COIN Trial.

Background:

COIN compared first-line continuous chemotherapy with the same chemotherapy given intermittently or with cetuximab in advanced colorectal cancer (aCRC).


Methods:

Choice between oxaliplatin/capecitabine (OxCap) and oxaliplatin/leucovorin (LV)/infusional 5-FU (OxFU) was by physician and patient choice and switching regimen was allowed. We compared OxCap with OxFU and OxCap+cetuximab with OxFU+cetuximab retrospectively in patients and examined efficacy, toxicity profiles and the effect of mild renal impairment.


Results:

In total, 64% of 2397 patients received OxCap(±cetuximab). Overall survival, progression free survival and overall response rate were similar between OxCap and OxFU but rate of radical surgeries was higher for OxFU. Progression free survival was longer for OxFU+cetuximab compared with OxCap+cetuximab but other efficacy measures were similar. Oxaliplatin/LV/infusional 5-FU (±cetuximab) was associated with more mucositis and infection whereas OxCap(±cetuximab) caused more gastrointestinal toxicities and palmar-plantar erythema. In total, 118 patients switched regimen, mainly due to toxicity; only 16% came off their second regimen due to intolerance. Patients with creatinine clearance (CrCl) 50–80?ml?min-1 on OxCap(±cetuximab) or OxFU+cetuximab had more dose modifications than those with better renal function.


Conclusions:

Overall, OxFU and OxCap are equally effective in treating aCRC. However, the toxicity profiles differ and switching from one regimen to the other for poor tolerance is a reasonable option. Patients with CrCl 50–80?ml?min-1 on both regimens require close toxicity monitoring.

Slug-dependent upregulation of L1CAM is responsible for the increased invasion potential of pancreatic cancer cells following long-term 5-FU treatment

BACKGROUND: Pancreatic adenocarcinoma is a lethal disease with 5-year survival of less than 5%. 5-fluorouracil (5-FU) is a principal first-line therapy, but treatment only extends survival modestly and is seldom curative. Drug resistance and disease recurrence is typical and there is a pressing need to overcome this. To investigate acquired 5-FU resistance in pancreatic adenocarcinoma, we established chemoresistant monoclonal cell lines from the Panc 03.27 cell line by long-term exposure to increasing doses of 5-FU.

RESULTS: 5-FU-resistant cell lines exhibited increased expression of markers associated with multidrug resistance explaining their reduced sensitivity to 5-FU. In addition, 5-FU-resistant cell lines showed alterations typical for an epithelial-to-mesenchymal transition (EMT), including upregulation of mesenchymal markers and increased invasiveness. Microarray analysis revealed the L1CAM pathway as one of the most upregulated pathways in the chemoresistant clones, and a significant upregulation of L1CAM was seen on the RNA and protein level. In pancreatic cancer, expression of L1CAM is associated with a chemoresistant and migratory phenotype. Using esiRNA targeting L1CAM, or by blocking the extracellular part of L1CAM with antibodies, we show that the increased invasiveness observed in the chemoresistant cells functionally depends on L1CAM. Using esiRNA targeting β-catenin and/or Slug, we demonstrate that in the chemoresistant cell lines, L1CAM expression depends on Slug rather than β-catenin.

CONCLUSION: Our findings establish Slug-induced L1CAM expression as a mediator of a chemoresistant and migratory phenotype in pancreatic adenocarcinoma cells.

A phase I/II trial of vorinostat in combination with 5-fluorouracil in patients with metastatic colorectal cancer who previously failed 5-FU-based chemotherapy

PURPOSE: We conducted a phase I/II clinical trial to determine the safety and feasibility of combining vorinostat with 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer (mCRC) and elevated intratumoral thymidylate synthase (TS).

METHODS: Patients with mCRC who had failed all standard therapeutic options were eligible. Intratumoral TS mRNA expression and peripheral blood mononuclear cell (PBMC) histone acetylation were measured before and after 6 consecutive days of vorinostat treatment at 400 mg PO daily. 5-FU/LV were given on days 6 and 7 and repeated every 2 weeks, along with continuous daily vorinostat. Dose escalation occurred in cohorts of three to six patients.

RESULTS: Ten patients were enrolled. Three dose levels were explored in the phase I portion of the study. Two dose-limiting toxicities (DLTs) were observed at the starting dose level, which resulted in dose de-escalation to levels -1 and -2. Given the occurrence of two DLTs at each of the dose levels, we were unable to establish a maximum tolerated dose (MTD). Two patients achieved significant disease stabilization for 4 and 6 months. Grade 3 and 4 toxicities included fatigue, thrombocytopenia and mucositis. Intratumoral TS downregulation > or = 50% was observed in one patient only. Acetylation of histone 3 was observed in PBMCs following vorinostat treatment.

CONCLUSIONS: The study failed to establish a MTD and was terminated. The presence of PBMC histone acetylation indicates biological activity of vorinostat, however, consistent reductions in intratumoral TS mRNA were not observed. Alternate vorinostat dose-scheduling may alleviate the toxicity and achieve optimal TS downregulation.

The cyclin D1 (CCND1) rs9344 G>A polymorphism predicts clinical outcome in colon cancer patients treated with adjuvant 5-FU-based chemotherapy

Recent evidence indicates a potential prognostic and predictive value for germline polymorphisms in genes involved in cell cycle control. We investigated the effect of cyclin D1 (CCND1) rs9344 G>A in stage II/III colon cancer patients and validated the findings in an independent study cohort. For evaluation and validation set, a total of 264 and 234 patients were included. Patients treated with 5-fluorouracil-based chemotherapy, carrying the CCND1 rs9344 A/A genotype had significantly decreased time-to-tumor recurrence (TTR) in univariate analysis and multivariate analysis (hazard ratio (HR) 2.47; 95% confidence interval (CI) 1.16-5.29; P=0.019). There was no significant association between CCND1 rs9344 G>A and TTR in patients with curative surgery alone. In the validation set, the A allele of CCND1 rs9344 G>A remained significantly associated with decreased TTR in univariate and multivariate analyses (HR 1.94; 95% CI 1.05-3.58; P=0.035). CCND1 rs9344 G>A may be a predictive and/or prognostic biomarker in stage II/III colon cancer patients, however, prospective trials are warranted to confirm our findings.

« Li rommans de Godefroy de Buillon et de Salehadin et de tous lez autres roys qui ont esté outre mer jusques a saint Loys qui darrenierement y fu ».

Début : « Si povés vous savoir les sains leus de la terre... — Fin : «... Adonc estoient l'an de l'incarnation Nostre Seigneur mil CCLXI. Explicit les Feiz d'Outremer. Ce livre ci fu complet d'escripture l'an de l'incarnation Nostre Seigneur mil trois cens et trante et VII, le jeudi devant la feste mon seigneur saint Thomas l'apostre devant Noël. » — Nombreuses miniatures. — Au fol. 1, on lit : « Au duc d'Arschot en 1584 ».

1.° Onuphrii Panvini, Veronensis, Fratris Eremitae Augustiniani, librorum decem de Pontifici Romanis varia creatione epitome : praemittuntur 1.° Roberti Bellarmini epistola ad Clementem VIII. de officio primario summi Pontificis : 2.° ejusdem Bellarmini instructio ad Episcopum Bambergensem, Matthiae I. Caesaris Legatum ad Paulum V. 3.° Benamini Antonii Lanerii, theologiae Doctoris, Angli, ad Robertum Bellarminum epistola, cum Bellarmini responso. — 2.° Indice de' libri di Honofrio Panvinio, copiato da una scrittura di mano propria di esso Panvinio. — 3.° Conclave di Paolo V. nel quale fu creato Gregorio XV. alli 9. di Febbraro 1621. — 4.° Conclave di Gregorio XV. nel quale fu creato Urbano VIII. alli 6. Agosto 1623. — 5.° Conclave nel quale fu creato Clemente V. che fu l'anno 1305

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