Keratinocyte growth factor expression by fibroblasts in pulmonary fibrosis: poor response to interleukin-1beta

Keratinocyte growth factor (KGF) is secreted by fibroblasts and protects from pulmonary fibrosis in animal models. Interleukin (IL)-1beta is the most potent inducer of KGF in fibroblasts, acting through the c-Jun pathway. We evaluated in vitro KGF production by human lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF, n = 10) and from control subjects (n = 7) at baseline and after IL-1beta stimulation. Basal KGF secretion by IPF fibroblasts was similar to controls. In fibroblasts from control subjects, IL-1beta increased c-Jun expression, c-Jun activation, and KGF secretion. SP600125, a specific c-Jun N-terminal kinase (JNK) inhibitor, inhibited the effect of IL-1beta. By contrast, in IPF fibroblasts, IL-1beta did not increase c-Jun expression and c-Jun activation, and weakly increased KGF secretion, whereas SP600125 had no effect. IL-1beta similarly increased JunB expression in fibroblasts from patients with IPF and control subjects. Total JNK content was not different in either unstimulated or IL-1beta-stimulated IPF and control fibroblasts. IL-1beta increased phosphorylated JNK in control and IPF fibroblasts, but this increase was weaker and heterogeneous in IPF. Altogether, our results demonstrate a dysregulation of KGF secretion by IPF fibroblasts. The weak response to IL-1beta is associated with a defect of c-Jun expression and activation and a defect of JNK activation.     

Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia.

PURPOSE: Arsenic trioxide (ATO) is capable of inducing a high hematologic response rate in patients with relapsed acute promyelocytic leukemia (APL). Preclinical observations have indicated that all-trans-retinoic acid (ATRA) may strongly enhance the response to ATO. PATIENTS AND METHODS: Between 1998 and 2001, we conducted a randomized study of ATO alone versus ATO plus ATRA in 20 patients with relapsed APL, all previously treated with ATRA-containing chemotherapy. The primary objective was to demonstrate a significant reduction in the time necessary to obtain a complete remission (CR) in the ATO/ATRA group compared with the ATO group. Secondary objectives were safety and molecular response. RESULTS: The CR rate after one ATO with or without ATRA induction cycle was 80%. Clinical and pharmacokinetic observations indicated that the main mechanism of action of ATO in vivo was the induction of APL cell differentiation. Hematologic and molecular response, time necessary to reach CR, and outcome were comparable in both treatment groups. Of 16 CR patients, three patients who reached a molecular remission after one induction cycle had all received chemotherapy for a treatment-induced hyperleukocytosis. Three additional patients who received further additional ATO with or without ATRA cycles converted later to molecular negativity. CONCLUSION: ATRA did not seem to significantly improve the response to ATO in patients relapsing from APL. Other potential combinations, including ATO plus chemotherapy, have to be tested.     

Estrogen receptor negative and progesterone receptor positive primary breast cancer: Pathological characteristics and clinical outcome

The expression of estrogen (ER) and progesterone (PgR) receptors was analyzed in a retrospective series of 3000 patients who had operable primary breast cancer. Patients were stratified according to ER and PgR status and the study was focused on the two groups (ER–PgR+ and ER–PgR–) of patients whose tumors contained low levels of ER (< 15 fmol/mg protein), regarding potential response to endocrine therapy. The comparison of clinical or histological characteristics between ER–PgR+ and ER–PgR– patients was analyzed as well as the disease-related death and survival. The mean follow-up was 86.3 months. Among the 529 ER–patients, 62 were PgR+ (12%), whereas 467 were PgR– (88%). The ER–PgR+ and ER–PgR– populations represented 2% and 15.6% of the overall population, respectively. In ER– tumors, the PgR status was significantly related to: age, menopausal status, tumor size, SBR grade, and histological type, but not to the type of surgical treatment or to lymph node involvement. ER–PgR+ tumors had smaller size (64% T1 vs 43%) (p=0.004) and were more frequently grade I (28% vs 12%) than ER–PgR– ones (p < 0.001). In addition, the patients with ER–PgR+ tumors were significantly younger (49.4 years vs 58.4 years; p < 0.0001), and were more frequently premenopausal (76% vs 36%; p < 0.001). The disease-free interval and the metastasis-free survival tended to be worse for ER–PgR– than for ER–PgR+ patients, but the difference was not statistically significant at 10 years. However, a small but significant difference in overall survival, in favor of the PgR+ group, was observed between the two groups during the first 5 years (p=0.03).We conclude that in combination with ER, PgR status defines a group of patients with clinical and biological specificity, which could be considered for specific endocrine therapy.     

Dynamics of T cells subsets and lymphoproliferative responses during structured treatment interruption cycles and after definitive interruption of HAART in early chronic HIV type-1-infected patients

Little is known about the consequences of short cycles of structured treatment interruption or definitive interruption of HAART for both T cell subset dynamics and T lymphoproliferative responses (LPR). Immunological follow-up was performed in 45 early chronical HIV-1-infected patients during short STI cycles during the first 12 weeks after the definitive interruption of HAART (DTI) and, thereafter, until VL reached a plateau. During STI cycles, CD8(+), CD8(+), CD28(+), activation markers and naive CD4(+) T cells increased significantly (p < 0.0001), while both naive CD8(+) and memory CD4(+) T cells decreased. During DTI, CD8(+) CD28(+) T cells fell and CD4(+) naive T cells stabilized and the rest of the T cell subsets presented changes similar to those during STI cycles. Despite a transient increase in LPR to recall antigens and HIV proteins during STI cycles, LPR to polyclonal stimuli and pathogens decreased over the study. Differences in T cell subset dynamics and LPR observed throughout the study suggest that multiple exposures to low levels of antigen could improve the immune system, mainly by driving T cell maturation. Conversely, higher and longer viral replication after cessation of HAART overwhelms the immune system. These data may help to guide future immune-based therapies.     

Survival advantage from imatinib compared with the combination interferon-alpha plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials

In the multinational IRIS study comparing imatinib with interferon plus cytarabine (IFN/Ara-C) in patients with newly diagnosed chronic-phase chronic myelogenous leukemia (CP CML), imatinib demonstrated significantly higher rates of complete cytogenetic responses (CCyRs) and improved progression-free survival (PFS). However, because of a high early crossover rate to imatinib, survival benefit was not assessable. Here, we report the result of a study comparing long-term outcome of patients included in 2 prospective randomized trials: 551 patients assigned to imatinib in the IRIS trial from 2000 to 2001 and 325 patients who received the combination IFN/Ara-C in the CML91 trial between 1991 and 1996 before imatinib was available. With a follow-up of 42 months for both groups of patients, estimated CCyR, survival free of transformation, and overall survival were significantly higher with imatinib compared with IFN/Ara-C (P < .001, P = .004, and P < .001, respectively). Improved overall survival was also confirmed within different Sokal prognostic risk groups. Of interest, among all patients who achieved major cytogenetic response or CCyR at 12 months, the survival rate was similar irrespective of their treatment. In conclusion, within the limitation of this historical comparison, there is a survival advantage from first-line therapy with imatinib over IFN/Ara-C.     

Evaluation of the association of nine Helicobacter pylori virulence factors with strains involved in low-grade gastric mucosa-associated lymphoid tissue lymphoma

Helicobacter pylori has been associated with the development of two malignant diseases: gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Although the cag pathogenicity island, especially the cagA gene, has been linked with adenocarcinoma, few data concerning H. pylori pathogenic factors involved in low-grade gastric MALT lymphoma are available. The goal of this study was to analyze the prevalence of and correlation between genes coding for seven H. pylori virulence factors (cagA, cagE, vacA, iceA, babA, hopQ, and oipA) and two novel adhesins (sabA and hopZ) by comparing a collection of 43 H. pylori strains isolated from patients with low-grade gastric MALT lymphoma to 39 strains isolated from age-matched patients with gastritis only. Our results show that taken individually, none of the nine genes tested can be considered associated with MALT strains and allow us to conclude that MALT pathogenesis is not linked with more proinflammatory H. pylori strains. We demonstrated that in patients infected with strains harboring the iceA1 allele, sabA functional status, and hopZ "off" status, the odds of developing a MALT lymphoma were 10 times higher. However, the low prevalence of such strains (10 of 43 MALT strains) renders this triple association a low-sensitivity marker for MALT strains. Our data confirmed that H. pylori virulence factors are correlated with one another. If the involvement of H. pylori in MALT lymphoma is well established, the pathomechanism by which gastric lymphoma occurs remains to be identified.     

Mediastinal tuberculosis in an adult patient with cystic fibrosis

Tuberculosis (TB) is rarely observed in cystic fibrosis (CF) patients. We report the first case of mediastinal TB, associated with leg pain and skin rash, in an adult patient with CF, and discuss factors suggestive of TB in the course of CF.     

Inflammatory malignant fibrous histiocytomas and dedifferentiated liposarcomas: histological review, genomic profile, and MDM2 and CDK4 status favour a single entity

Inflammatory malignant fibrous histiocytoma (inflammatory MFH) is a very rare tumour that occurs most often in the retroperitoneum. So far, it has been considered to be a special subtype of MFH. As it is now widely accepted that most retroperitoneal pleomorphic MFHs are dedifferentiated liposarcomas, the present study compared histological features, genomic profile (CGH analysis), and MDM2 and CDK4 status (immunohistochemistry, FISH, and quantitative PCR) in inflammatory MFHs from 12 patients and dedifferentiated liposarcomas that had an inflammatory MFH component from eight patients. Metaphase cytogenetic and FISH analyses were also performed on one inflammatory MFH. Histological review showed areas of well-differentiated liposarcoma in nine inflammatory MFHs. CGH analysis showed 12q13-15 amplification or gain in six of seven inflammatory MFHs and in seven of seven dedifferentiated liposarcomas. Immunohistochemistry showed positivity of tumour cells for MDM2 in every tumour in both groups and for CDK4 in ten and seven inflammatory MFHs and dedifferentiated liposarcomas, respectively. Metaphase cytogenetic and FISH analysis performed on one inflammatory MFH showed the presence of a supernumerary large marker chromosome and ring chromosome with high-level amplification of both MDM2 and CDK4 genes. FISH analysis on paraffin wax-embedded sections showed amplifications of MDM2 and CDK4 in seven of seven inflammatory MFHs and in seven of seven dedifferentiated liposarcomas. Quantitative PCR showed amplification of MDM2 in six and of CDK4 in seven of nine inflammatory MFHs. In conclusion, this study strongly suggests that most so-called inflammatory MFHs are dedifferentiated liposarcomas.