Role of bone marrow-derived cells in experimental chronic pancreatitis.

BACKGROUND: Chronic pancreatitis is a known risk factor for pancreatic adenocarcinoma. Recent work has pointed to a role for bone marrow-derived progenitor cells (BMDCs) in chronic inflammation-based carcinogenesis. Consequently, the role of BMDCs in chronic pancreatitis was investigated. METHODS: The fate of BMDCs was followed using green fluorescent protein and the Y chromosome as bone marrow markers in gender-mismatched transplanted mice treated with repeated injections of cerulein for up to 45 weeks. The phenotype of engrafted BMDCs was assessed based on the co-expression of bone marrow and pancreatic markers. RESULTS: After 45 weeks of cerulein treatment, mice developed severe chronic pancreatitis but no preneoplastic lesions. BMDCs did engraft in the pancreas. Most of the BMDCs were desmin positive and contributed to 5.12% (1.12%) (mean (SEM)) of the pancreatic stellate cell population. Pancreatic stellate cells derived from the bone marrow could be activated, as demonstrated by alpha-smooth muscle actin expression, suggesting a role in tissue repair. BMDCs could also be found in pancreatic ducts, based on dolichos biflorus agglutinin and cytokeratin 19 stainings, but at a much lower frequency (0.62% (0.11%)). CONCLUSION: BMDCs contribute to the pancreatic stellate cell population, suggesting a role in pancreatic tissue repair. In the absence of preneoplastic lesions, BMDCs contribute at a very low level to the ductal epithelium of the chronically inflamed pancreas. The role of BMDCs in pancreatic carcinogenesis remains to be defined.

Replication-deficient rSV40 mediate pancreatic gene transfer and long-term inhibition of tumor growth.

Pancreatic cancer is one of the most aggressive and devastating human malignancies. There is an urgent need for more effective therapy for patients with advanced disease. In this context, genetic therapy potentially represents a rational new approach to treating pancreatic cancer, which could provide an adjunct to conventional options. Because of the promise of recombinant SV40 vectors, we tested their ability to deliver a transgene, and to target a transcript, so as to inhibit pancreatic tumors growth in vivo. BxPC3 and Capan-1 cells were efficiently transduced using SV40 vectors without selection, as compared to synthetic vectors PEI. SV40 vectors were as efficient as adenoviral vectors, and provided long-term transgene expression. Next, we devised a SV40-derived, targeted gene therapy approach of pancreatic cancer, by combining hTR tumor-specific promoter with sst2 somatostatin receptor tumor-suppressor gene. In vitro cell proliferation was strongly impaired following administration of SV(hTR-sst2). SV40-derived sst2-mediated antiproliferative effect was dependent on the local production of somatostatin. In vivo, intratumoral gene transfer of sst2 using rSV40 vectors resulted in a marked inhibition of Capan-1 tumor progression, and proliferation. These results represent the initial steps toward a novel approach to the gene therapy of pancreatic cancer using SV40 as a vector.

Arterial phase enhancement and body mass index are predictors of response to chemoembolisation for liver metastases of endocrine tumours.

Transcatheter arterial chemoembolisation (TACE) has been reported to be an efficient treatment of liver metastases of endocrine tumours in short series of patients. However, several factors seem to affect its results. The aim of this work is to identify predictors of response to TACE for liver metastases of endocrine tumours. A total of 163 TACE procedures were performed in 67 patients between 1994 and 2004. Forty-four patients were treated with streptozotocin and 23 with doxorubicin. Primary tumour was located in the pancreas for 19 patients, and had been removed in 43. Thirty-eight tumours were functioning. Response rate was 37% (confidence interval [CI] 95%: 28-49%). Median time to progression (TTP) was 14.5 months (CI 95%: 9-41). In multivariate analysis (n=43), predictors of tumour response were body mass index (BMI) (odds ratio [OR]: 1.3; CI 95%: 1.04-1.63; P=0.022), functioning type of tumour (OR: 7.31; CI 95%: 1.26-42.5; P=0.027), arterial phase enhancement on abdominal computed tomography (CT) (OR: 8.11; CI 95%:1.06-62; P=0.044) and use of streptozotocin for cytotoxic agent (OR: 21.3; CI 95%: 1.48-306; P=0.025). Analysis of TTP predictors showed that BMI (hazard ratio [HR]: 0.85; CI 95%: 0.76-0.86; P=0.01) and arterial phase enhancement (HR: 0.3; CI 95%: 0.12-0.73; P=0.008) were associated with delayed progression. This large study confirms the previously reported results of TACE regarding its efficacy for the treatment of liver metastases of endocrine tumours. Arterial phase enhancement on abdominal CT and BMI are predictors of treatment's efficacy. Streptozotocin should be the preferred cytotoxic agent in order to save anthracycline for systemic chemotherapy.

Safety and efficacy of peginterferon plus ribavirin in patients with chronic hepatitis C and bridging fibrosis or cirrhosis.

The combination of pegylated interferon and ribavirin is the most effective therapy in patients with chronic hepatitis C. We evaluated this combination in unselected patients with bridging fibrosis or cirrhosis. Eighty patients were treated with peginterferon alpha-2b plus ribavirin. Hepatitis C virus serum RNA was monitored. Tolerance and safety were evaluated by the rate of treatment's discontinuation for any reason, and occurrence of serious clinical adverse events, respectively. Sustained virologic response (SVR) rate was 36.3% overall, and was observed in every group of patients except those who had previously failed to respond to the combination of interferon and ribavirin. No serious clinical adverse event occurred. Treatment was withdrawn in 18.7% of patients. Variables associated with discontinuation of treatment were low prothrombin index [OR: 1.16 (1.05;1.27)] and low body mass index [OR: 1.47 (1.12;1.92)]. Initial blood count abnormalities were not associated with cessation of treatment. Furthermore, early virologic response at week 8 and week 12 of treatment had similar predictive value for SVR. Combination therapy with peginterferon plus ribavirin seems effective in this group of patients, except in those who had previously failed to respond to the combination of interferon and ribavirin. This therapy is safe with appropriate monitoring, but tolerance seems worse in patients with the most advanced liver disease.

[Treatment of systemic mastocytosis]. / Traitement des mastocytoses systémiques.

BACKGROUND: Systemic mastocytosis is a rare disease, characterized by mast cells proliferation in various organs. Two types of clinical manifestations can be distinguished: those related to mast cells mediators release and those related to tumoral proliferation involving different organs, these later defining aggressive systemic mastocytosis. Until recently, treatment was mainly symptomatic, without anti tumoral effect. RECENT FACTS: These last years, advances have been made in the understanding of the disease with the discovery of the c-kit oncogene mutation and the approach of the disease as a myeloproliferative disorder. PERSPECTIVES: Based on experiences acquired in the treatment of this kind of disorders, evaluation of new therapeutics, such as cladribine or combination of interferon-alpha and cytarabine is in progress. At least, tyrosine kinase inhibitors, a new family of molecules, are able of inhibiting some types of the mutated c-kit protein and one of them, imatinib mesylate, has shown a great efficacy in the treatment of gastro intestinal stromal tumors (GIST) which also involves the c-kit mutation. By analogy, treatment of patients with c-kit susceptible mutation might be treated with this molecule.

[Test of human basophil degranulation. The interpretation and analysis of variability factors in the absence of antigen]. / Test de dégranulation des basophiles humains. Interprétation et analyse des facteurs de variabilité en l'absence d'antigène.

The human basophil degranulation test (TDBH) is performed using a concentrated cell suspension enriched for polymorphonuclear basophils. This preparation is placed in wells on a glass slide with an allergen solution of decreasing concentration. After incubation the cells are fixed in the wells and stained with toluidine blue. Preparations containing fewer metachromatic basophils than in control preparation of the same cell suspension without antigen contain degranulated basophils and in this way a degranulation index can be calculated. By considering the variability in the number of basophils between duplicate control wells from the same cell suspension, it can be shown that the test can be considered to be positive only if the number of degranulated basophils equals or exceeds 50% of the total number of basophils. This variance can be attributed to the subjectivity of the reader, and to differences in the differential cell counts from well to well. On the other hand, the presence of atopic allergy had no effect on the basophil counts.