Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: a phase II study

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Pathophysiology of acute experimental pancreatitis: Lessons from genetically engineered animal models and new molecular approaches

The incidence of acute pancreatitis is growing and worldwide population-based studies report a doubling or tripling since the 1970s. 25% of acute pancreatitis are severe and associated with histological changes of necrotizing pancreatitis. There is still no specific medical treatment for acute pancreatitis. The average mortality resides around 10%. In order to develop new specific medical treatment strategies for acute pancreatitis, a better understanding of the pathophysiology during the onset of acute pancreatitis is necessary. Since it is difficult to study the early acinar events in human pancreatitis, several animal models of acute pancreatitis have been developed. By this, it is hoped that clues into human pathophysiology become possible. In the last decade, while employing molecular biology techniques, a major progress has been made. The genome of the mouse was recently sequenced. Various strategies are possible to prove a causal effect of a single gene or protein, using either gain-of-function (i.e., overexpression of the protein of interest) or loss-of-function studies (i.e., genetic deletion of the gene of interest). The availability of transgenic mouse models and gene deletion studies has clearly increased our knowledge about the pathophysiology of acute pancreatitis and enables us to study and confirm in vitro findings in animal models. In addition, transgenic models with specific genetic deletion or overexpression of genes help in understanding the role of one specific protein in a cascade of inflammatory processes such as pancreatitis where different proteins interact and co-react. This review summarizes the recent progress in this field. Copyright (c) 2005 S. Karger AG, Basel

Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: a phase II study of the Belgian Group of Digestive Oncology

Background: Cholangiocarcinomas are uncommon tumours with a poor prognosis, that frequently present epidermal growth factor receptor overexpression. Methods: In a multi-centre phase II trial, patients with unresectable cholangiocarcinoma, naïve to chemotherapy, received Cetuximab (400 mg/m2 at week 1, then 250 mg/m2/week) and Gemcitabine (1 g/m2 on day 1, 8 and 15 every 4 weeks). Primary end point was progression-free survival (PFS) rate at 6 months, using a Simon 2-stage design. Moreover, we assessed the impact of KRAS status and skin toxic effect on efficacy. Results: Forty-four patients (41% locally advanced/59% metastatic) were enrolled. Median age was 61.5 years; ECOG PS was 0 (68%) or 1. Six months PFS reached 47%. Median OS was 13.5 months [95% confidence interval (CI) 9.8-31.8 months]. Nine patients (20.4%) had PR and disease-control rate was 79.5%. Grade 3/4-related toxic effects were haematological (52.2%), skin rash (13.6%) and fatigue (11.4%). KRAS mutations were found in 7 of 27 patients and had no influence on PFS. Skin toxic effect =grade 2 was associated with increased PFS (P = 0.05).Conclusion(s): Our study met its primary end point, suggesting that Gemcitabine-Cetuximab has activity in cholangiocarcinoma. KRAS status was not associated with PFS, unlike skin toxic effect, which could be used as a surrogate marker for efficacy

Immunomodulation de la pancreatite experimentale

Doctorat en sciences médicalesinfo:eu-repo/semantics/nonPublishe

New frontiers in the pharmacological prevention of post-ERCP pancreatitis: the cytokines.

Acute pancreatitis is a major complication of endoscopic retrograde cholangiopancreatography (ERCP), its incidence varying with the indications for the procedure (<5% for the management of common bile duct stones and up to 20% in the case of sphincter of Oddi dysfunction) and also with events occurring during the ERCP such as acinarization and pancreatic sphincterotomy. If the triggering event of premature intra-acinar activation of trypsinogen is unknown, the acinar cell injury leads to oxidative stress, nuclear translocation of nuclear factor kappa B and subsequent transcription of chemo- and pro-inflammatory cytokines. These events are followed by chemoattraction and activation of monomacrophages, T lymphocytes and neutrophils which are responsible for acinar necrosis and amplification of the pro-inflammatory cascade. Finally, after amplification by Kupffer cells, systemic inflammatory response syndrome and multiple organ failure occur. All these events take place within a very short period of time, thus offering a very short therapeutic window during which it is theoretically possible to modulate the severity of human pancreatitis. Prophylactic immunomodulation of this pro-inflammatory cascade is attractive, using anti-inflammatory cytokines, specific inhibitors of pro-inflammatory cytokines or inhibitors of the nuclear translocation of the nuclear factor kappa B. Good results have been obtained in experimental models, reducing the acute pancreatitis severity and its systemic complications. The use of immunomodulators in the prevention of human post-ERCP pancreatitis is actually restricted to recombinant interleukin-10. Three of four randomized clinical trials, confirmed by a meta-analysis, have shown that prophylactic injection of recombinant interleukin-10 can significantly reduce the incidence of acute pancreatitis and may decrease the length of the hospital stay. The use of recombinant interleukin-10 in this indication has to be established in a multicenter prospective trial and we need to investigate the safety and efficacy of other immunomodulatory drugs and develop new specific targets.Journal ArticleReviewinfo:eu-repo/semantics/publishe

Adjuvant therapy in gastric and cardia cancer: should we irradiate?

The purpose of this review is to comment on the current status and the place of the (neo)adjuvant therapy of gastric cancer, and on the standardization of care in this setting.Journal ArticleReviewinfo:eu-repo/semantics/publishe

Adjuvant chemotherapy for colorectal cancer.

Colorectal cancer is the second leading cause of cancer death in Western countries. If surgery remains the only cure, recurrence rates for colon cancer range from 30% to 60% for stage III tumors. Adjuvant chemotherapy is the standard treatment for stage III colon tumors and consists of monthly administration of bolus 5-fluorouracil and leucovorin for 5 consecutive days a month over a 6-month period (Mayo regimen). Adjuvant chemotherapy for stage II colon cancer remains controversial, and its administration is not routinely recommended except in certain high-risk and selected patients. Immunotherapy, new drug-based therapies or combinations, and cyclooxygenase-2 inhibitors are being tested in the adjuvant setting. Total mesorectum excision is now the gold standard surgical technique for rectal cancer resection, and this procedure has dramatically decreased local recurrence. Nevertheless, adjuvant chemoradiotherapy is commonly indicated in the United States. In Europe, neoadjuvant radiotherapy is recommended for stage II and III resectable rectal cancers; the role of chemotherapy remains mostly investigational.Journal ArticleReviewinfo:eu-repo/semantics/publishe

The path to personalized treatment in advanced and metastatic biliary tract cancers: A review of new targeted therapies and immunotherapy

Purpose of reviewTo summarize targeted therapies and immunotherapy as treatment for advanced/metastatic biliary tract cancers and discuss ongoing clinical trials.Recent findingsFor the first time since gemcitabine-cisplatin was set as the standard of care in first-line advanced/metastatic biliary tract cancers in the ABC-02 trial, the combination of durvalumab and gemcitabine-cisplatin has demonstrated a statistically significant improvement of median overall survival in the TOPAZ-1 phase 3 trial. The ABC-06 trial showed a significant increase of median overall survival for FOLFOX and active symptom control compared with active symptom control alone in second-line regardless of molecular and genetic alterations. However, faced with a heterogeneous cancer, patient prognosis remains poor, leaving room for new, personalized, treatment options such as targeted therapies. Efficacy of fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors has been demonstrated in different phase 2 trials for previously treated intrahepatic cholangiocarcinomas harboring FGFR2 fusions. Ivosidenib increases significantly median progression-free survival in previously treated cholangiocarcinomas with isocitrate dehydrogenase-1 (IDH-1) mutation. Other targeted therapies are tested for tumors with HER2 amplifications/mutations, BRAFV600Emutations or KRASG12Cmutations.SummaryIn this review, we aim to follow the changes in the treatment of these tumors, moving from very few chemotherapy options to immunotherapy and targeted therapies in the context of molecular selection of biliary tract cancers subtypes.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Vitrectomie dans l'oedème maculaire diabétique associé à une hyaloïde postérieure tractionnelle.

The vitreomacular relationship has been demonstrated to play a role in the physiopathology of the diabetic macular edema. We review the functional and anatomic results of vitrectomy performed on four eyes of three patients with diabetic cystoid macular edema unresolved by photocoagulation. The preoperative visual acuity was "finger counting" at one meter to 1/20. After surgery, for three eyes, the visual acuity raised between 2/10 and 4/10. There was no change for one eye, which presented a subretinal fibrosis. The macular edema resolved in three eyes and improved in one eye. The mean postoperative follow-up is 13 months. The vitrectomy may be effective in cases of diabetic macular traction and edema without posterior vitreous detachment.SCOPUS: ar.jinfo:eu-repo/semantics/publishe