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1.
Int J Radiat Oncol Biol Phys ; 107(2): 279-287, 2020 06 01.
Article in English | MEDLINE | ID: mdl-32142869

ABSTRACT

PURPOSE: Our purpose was to evaluate neurocognitive function (NCF) and clinical outcomes after early hippocampal avoidance (HA) prophylactic cranial irradiation (PCI) in limited disease (LD) small cell lung cancer (SCLC). METHODS AND MATERIALS: In a phase 2 trial, patients with LD SCLC received HA-PCI concomitant with the second cycle of chemotherapy and thoracic radiation therapy. All patients underwent objective NCF testing at baseline, 6 weeks, and 6 and 12 months after HA-PCI. NCF tests included Hopkins Verbal Learning Test Revised, Controlled Oral Word Association, and Trail Making Tests A and B. The primary endpoint was NCF decline at 6 months after HA-PCI. We assumed ≤30% of patients with no NCF decline to be unpromising. Secondary endpoints included brain metastases-free survival (BMFS), overall survival (OS), and safety of the concomitant treatment. RESULTS: Among the 44 patients enrolled in the trial, 38 had evaluable NCF assessment at 6 months after HA-PCI. The proportion of evaluable patients showing no NCF decline at 6 and 12 months was 34.2% (90% confidence interval [CI], 21.6-48.8) and 48.5% (95% CI, 30.8-66.5), respectively. Median follow-up was 13.2 months (95% CI, 12.6-14.1). At 12 months, BMFS was 84.2% and OS was 87.7% (95% CI, 73.0-94.7). Four patients died of SCLC, 1 of respiratory failure, 1 of hemorrhage, and 1 for unknown reason. The most frequently reported grade ≥3 acute adverse events were anemia (21.4%), febrile neutropenia (19.1%), and fatigue (14.3%). CONCLUSIONS: The proportion of patients showing no NCF decline 6 and 12 months after early HA-PCI does not appear to be better than, but rather similar to, that observed in patients receiving sequential PCI without HA. Early HA-PCI in LD SCLC is feasible, with observation of promising BMFS and OS in this selected population.


Subject(s)
Cranial Irradiation , Hippocampus/radiation effects , Lung Neoplasms/physiopathology , Lung Neoplasms/radiotherapy , Organs at Risk/radiation effects , Small Cell Lung Carcinoma/physiopathology , Small Cell Lung Carcinoma/radiotherapy , Adult , Aged , Cranial Irradiation/adverse effects , Female , Humans , Lung Neoplasms/psychology , Male , Mental Status and Dementia Tests , Middle Aged , Quality of Life , Small Cell Lung Carcinoma/psychology , Stress, Psychological/complications , Time Factors
2.
Haematologica ; 104(4): 710-716, 2019 04.
Article in English | MEDLINE | ID: mdl-30409796

ABSTRACT

The ß-3 sympathomimetic agonist BRL37344 restored nestin-positive cells within the stem cell niche, and thereby normalized blood counts and improved myelofibrosis in a mouse model of JAK2-V617F-positive myeloproliferative neoplasms. We therefore tested the effectiveness of mirabegron, a ß-3 sympathomimetic agonist, in a phase II trial including 39 JAK2-V617F-positive patients with myeloproliferative neoplasms and a mutant allele burden more than 20%. Treatment consisted of mirabegron 50 mg daily for 24 weeks. The primary end point was reduction of JAK2-V617F allele burden of 50% or over, but this was not reached in any of the patients. One patient achieved a 25% reduction in JAK2-V617F allele burden by 24 weeks. A small subgroup of patients showed hematologic improvement. As a side study, bone marrow biopsies were evaluated in 20 patients. We found an increase in the nestin+ cells from a median of 1.09 (interquartile range 0.38-3.27)/mm2 to 3.95 (interquartile range 1.98-8.79)/mm2 (P<0.0001) and a slight decrease of reticulin fibrosis from a median grade of 1.0 (interquartile range 0-3) to 0.5 (interquartile range 0-2) (P=0.01) between start and end of mirabegron treatment. Despite the fact that the primary end point of reducing JAK2-V617F allele burden was not reached, the observed effects on nestin+ mesenchymal stem cells and reticulin fibrosis is encouraging, and shows that mirabegron can modify the microenvironment where the JAK2-mutant stem cells are maintained. (Registered at clinicaltrials.gov identifier: 02311569).


Subject(s)
Acetanilides/administration & dosage , Hematologic Neoplasms , Janus Kinase 2 , Mutation, Missense , Myeloproliferative Disorders , Nestin , Reticulin , Sympathomimetics/administration & dosage , Thiazoles/administration & dosage , Acetanilides/adverse effects , Adult , Amino Acid Substitution , Animals , Female , Fibrosis , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/genetics , Hematologic Neoplasms/metabolism , Hematologic Neoplasms/pathology , Humans , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Male , Mice , Middle Aged , Myeloproliferative Disorders/drug therapy , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/metabolism , Myeloproliferative Disorders/pathology , Nestin/genetics , Nestin/metabolism , Reticulin/genetics , Reticulin/metabolism , Sympathomimetics/adverse effects , Thiazoles/adverse effects
3.
J Exp Med ; 207(13): 2843-54, 2010 Dec 20.
Article in English | MEDLINE | ID: mdl-21098096

ABSTRACT

Milk oligosaccharides contribute to the development of the intestinal environment by acting as decoy receptors for pathogens and as prebiotics, which promote the colonization of commensal bacteria. Here, using α2,3- and α2,6-sialyltransferase-deficient mice, we investigated the role of the sialylated milk oligosaccharides sialyl(α2,3)lactose and sialyl(α2,6)lactose on mucosal immunity. The exposure of newborn mice to milk containing or deficient in sialyllactose had no impact on the development of mucosal leukocyte populations. However, when challenged by dextran sulfate sodium (DSS) in drinking water, adult mice that had been fostered on sialyl(α2,3)lactose-deficient milk were more resistant to colitis compared with mice fostered on normal milk or sialyl(α2,6)lactose-deficient milk. Analysis of intestinal microbiota showed different colonization patterns depending on the presence or absence of sialyl(α2,3)lactose in the milk. Germ-free mice reconstituted with intestinal microbiota isolated from mice fed on sialyl(α2,3)lactose-deficient milk were more resistant to DSS-induced colitis than germ-free mice reconstituted with standard intestinal microbiota. Thus, exposure to sialyllactose during infancy affects bacterial colonization of the intestine, which influences the susceptibility to DSS-induced colitis in adult mice.


Subject(s)
Bacteria/growth & development , Colitis/metabolism , Intestines/microbiology , Oligosaccharides/metabolism , Animals , Animals, Newborn , Bacteria/classification , Bacteria/genetics , Base Sequence , Chemokines/genetics , Colitis/chemically induced , Colitis/genetics , Cytokines/genetics , Dextran Sulfate , Drug Resistance , Female , Gene Expression , Intestinal Mucosa/metabolism , Intestines/drug effects , Male , Metagenome , Mice , Mice, Inbred C57BL , Mice, Knockout , Milk/chemistry , Molecular Sequence Data , Oligosaccharides/pharmacology , Reverse Transcriptase Polymerase Chain Reaction , Sequence Homology, Nucleic Acid , Sialyltransferases/deficiency , Sialyltransferases/genetics , Sialyltransferases/metabolism , Time Factors
4.
J Exp Med ; 203(9): 2057-62, 2006 Sep 04.
Article in English | MEDLINE | ID: mdl-16923850

ABSTRACT

The nuclear receptor liver receptor homologue-1 (LRH-1, NR5A2) is a crucial transcriptional regulator of many metabolic pathways. In addition, LRH-1 is expressed in intestinal crypt cells where it regulates the epithelial cell renewal and contributes to tumorigenesis through the induction of cell cycle proteins. We have recently identified the intestinal epithelium as an important extra-adrenal source of immunoregulatory glucocorticoids. We show here that LRH-1 promotes the expression of the steroidogenic enzymes and the synthesis of corticosterone in murine intestinal epithelial cells in vitro. Interestingly, LRH-1 is also essential for intestinal glucocorticoid synthesis in vivo, as LRH-1 haplo-insufficiency strongly reduces the intestinal expression of steroidogenic enzymes and glucocorticoid synthesis upon immunological stress. These results demonstrate for the first time a novel role for LRH-1 in the regulation of intestinal glucocorticoid synthesis and propose LRH-1 as an important regulator of intestinal tissue integrity and immune homeostasis.


Subject(s)
Gene Expression Regulation , Glucocorticoids/biosynthesis , Intestinal Mucosa/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Adrenal Glands/metabolism , Animals , Cell Line , Cholesterol Side-Chain Cleavage Enzyme/genetics , Cholesterol Side-Chain Cleavage Enzyme/metabolism , Epithelial Cells/cytology , Epithelial Cells/immunology , Epithelial Cells/metabolism , Intestinal Mucosa/cytology , Intestinal Mucosa/immunology , Lymphocyte Activation , Mice , Promoter Regions, Genetic , Receptors, Cytoplasmic and Nuclear/genetics , Steroid 11-beta-Hydroxylase/genetics , Steroid 11-beta-Hydroxylase/metabolism , T-Lymphocytes/metabolism
5.
Immunol Lett ; 106(1): 99-102, 2006 Jul 15.
Article in English | MEDLINE | ID: mdl-16723155

ABSTRACT

Glucocorticoids (GCs) are steroidal compounds widely used to treat chronic and acute inflammatory diseases. In particular, GCs at pharmacological doses induce apoptosis of activated and naïve T cells, inhibit their proliferation and block pro-inflammatory cytokine secretion. At physiological concentrations, the effect of these steroids on T cell immunity are not yet fully understood, and various studies reported paradoxical roles exerted by GCs on T cell immunity. Here, we show that GCs surprisingly induce proliferation of activated CD4(+) T cells in the presence of IL-7, a cytokine secreted in the thymus and at mucosal sites. Increased proliferation is dependent on a GC-mediated survival of mitotic cells. Moreover, we observe a downmodulation of Th1 cytokine secretion in cells treated with GCs, an outcome which is not affected by the presence of IL-7. GCs exert thus a positive role in the presence of IL-7 by enhancing proliferation of CD4(+) T cells and simultaneously a negative role by suppressing pro-inflammatory cytokine production.


Subject(s)
CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , Glucocorticoids/pharmacology , Interleukin-7/pharmacology , Lymphocyte Activation/drug effects , Animals , CD4-Positive T-Lymphocytes/cytology , Cell Proliferation , Cells, Cultured , Drug Antagonism , Drug Synergism , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL
6.
J Exp Med ; 200(12): 1635-46, 2004 Dec 20.
Article in English | MEDLINE | ID: mdl-15596520

ABSTRACT

Glucocorticoids (GCs) are important steroid hormones with widespread activities in metabolism, development, and immune regulation. The adrenal glands are the major source of GCs and release these hormones in response to psychological and immunological stress. However, there is increasing evidence that GCs may also be synthesized by nonadrenal tissues. Here, we report that the intestinal mucosa expresses steroidogenic enzymes and releases the GC corticosterone in response to T cell activation. T cell activation causes an increase in the intestinal expression of the steroidogenic enzymes required for GC synthesis. In situ hybridization analysis revealed that these enzymes are confined to the crypt region of the intestinal epithelial layer. Surprisingly, in situ-produced GCs exhibit both an inhibitory and a costimulatory role on intestinal T cell activation. In the absence of intestinal GCs in vivo, activation by anti-CD3 injection resulted in reduced CD69 expression and interferon-gamma production by intestinal T cells, whereas activation by viral infection led to increased T cell activation. We conclude that the intestinal mucosa is a potent source of immunoregulatory GCs.


Subject(s)
Gene Expression Regulation/immunology , Glucocorticoids/metabolism , Intestinal Mucosa/metabolism , Lymphocyte Activation/immunology , T-Lymphocytes/immunology , Adrenal Glands/metabolism , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/immunology , Antigens, CD/biosynthesis , Antigens, Differentiation, T-Lymphocyte/biosynthesis , Arenaviridae Infections/immunology , Arenaviridae Infections/pathology , CD3 Complex/immunology , Glucocorticoids/immunology , Interferon-gamma/biosynthesis , Lectins, C-Type , Lymphocytic choriomeningitis virus/immunology , Mice , Mice, Transgenic
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