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1.
Z Gastroenterol ; 60(10): 1510-1516, 2022 Oct.
Article in German | MEDLINE | ID: mdl-34905798

ABSTRACT

BACKGROUND: Pancreatic cancer is still considered one of the most aggressive types of cancer and is associated with a very poor prognosis although there have been improvements in diagnostics and chemotherapy regimes in recent years. A cure can only be achieved through complete resection which is only possible when diagnosed at a very early stage, though this is rarely the case. We report on a patient with stage IV adenocarcinoma of the pancreas in which several therapeutically actionable mutations could be detected and discuss new options of targeted therapies. CASE REPORT: A patient in his 50s was diagnosed with metastatic adenocarcinoma of the pancreas. The patient showed an excellent response to platinum-based chemotherapy with FOLFIRINOX. When a germline mutation in the BRCA-2 gene could be identified, he took part in the POLO-study receiving a maintenance therapy with the PARP-Inhibitor Olaparib. Due to a relapse, 2nd and 3rd line chemotherapy regimens were applied with Gemcitabine combined with Nab-Paclitaxel and later with Erlotinib. Although an activating mutation in the KRAS-gene could be detected as well, the patient rejected further experimental treatment. CONCLUSION: Identifying predictive factors and specific targetable mutations in patients with advanced pancreatic cancer is needed to be able to apply more individual and specific therapies in order to improve outcomes.


Subject(s)
Adenocarcinoma , Pancreatic Neoplasms , Adenocarcinoma/diagnosis , Adenocarcinoma/drug therapy , Adenocarcinoma/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Erlotinib Hydrochloride/therapeutic use , Humans , Male , Neoplasm Recurrence, Local/drug therapy , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Proto-Oncogene Proteins p21(ras) , Pancreatic Neoplasms
2.
Immunol Cell Biol ; 96(10): 1060-1071, 2018 11.
Article in English | MEDLINE | ID: mdl-29790605

ABSTRACT

Premature T-cell immunosenescence with CD57+ CD8+ T-cell accumulation has been linked to immunodeficiency and autoimmunity in primary immunodeficiencies including activated PI3 kinase delta syndrome (APDS). To address whether CD57 marks the typical senescent T-cell population seen in adult individuals or identifies a distinct population in APDS, we compared CD57+ CD8+ T cells from mostly pediatric APDS patients to those of healthy adults with similarly prominent senescent T cells. CD57+ CD8+ T cells from APDS patients were less differentiated with more CD27+ CD28+ effector memory T cells showing increased PD1 and Eomesodermin expression. In addition, transition of naïve to CD57+ CD8+ T cells was not associated with the characteristic telomere shortening. Nevertheless, they showed the increased interferon-gamma secretion, enhanced degranulation and reduced in vitro proliferation typical of senescent CD57+ CD8+ T cells. Thus, hyperactive PI3 kinase signaling favors premature accumulation of a CD57+ CD8+ T-cell population, which shows most functional features of typical senescent T cells, but is different in terms of differentiation and relative telomere shortening. Initial observations indicate that this specific differentiation state may offer the opportunity to revert premature T-cell immunosenescence and its potential contribution to inflammation and immunodeficiency in APDS.


Subject(s)
CD57 Antigens/metabolism , Cell Differentiation , Immunologic Deficiency Syndromes/etiology , Immunologic Deficiency Syndromes/metabolism , Phosphatidylinositol 3-Kinases/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Telomere Shortening , Cell Differentiation/genetics , Cell Differentiation/immunology , Cellular Senescence/genetics , Cellular Senescence/immunology , Class I Phosphatidylinositol 3-Kinases/metabolism , Cytokines/metabolism , Humans , Immunophenotyping , Lymphocyte Count , Primary Immunodeficiency Diseases , Sirolimus/pharmacology , T-Lymphocyte Subsets/drug effects
3.
Pediatr Allergy Immunol ; 27(6): 640-4, 2016 09.
Article in English | MEDLINE | ID: mdl-27116393

ABSTRACT

BACKGROUND: Autosomal dominant gain-of-function mutations in PIK3R1 encoding for the regulatory subunit (p85α, p55α, and p50α) of Class IA phosphoinositide 3-kinase (PI3K) result in the activated PI3Kδ syndrome (APDS) type 2 characterized by childhood-onset combined immunodeficiency, lymphoproliferation, and immune dysregulation. To improve clinical awareness and understanding of these rare diseases, we reviewed all hitherto published cases with APDS type 1 and type 2 for their clinical and immunologic symptoms and added novel clinical, immunologic, and genetic findings of two patients with APDS type 2. METHODS: Clinical, immunologic, and genetic evaluation of two new patients with APDS2 was performed followed by the systematic collection of all available previously published data of patients with APDS1 and APDS2. RESULTS: Patients with APDS type 1 (n = 49) and type 2 (n = 15) showed an indistinguishable immunologic phenotype. Overlapping clinical features shared by APDS type 1 and type 2 were observed, but our review also revealed previously unnoticed clinical differences such as remarkably high incidence of microcephaly, poor growth/short stature in patients with APDS2. Clinical management and outcome were variable and included prophylactic antibiotics, immunosuppression, immunoglobulin substitution, and hematopoietic stem cell transplantation. CONCLUSIONS: A disease-specific registry collecting prospective and long-term follow-up data of patients with APDS, as currently set up by the European Society for Immunodeficiencies, are needed to better understand the natural history and to optimize treatment concepts and thereby improving the outcome of this heterogenous patient group.


Subject(s)
Class I Phosphatidylinositol 3-Kinases/genetics , Hematopoietic Stem Cell Transplantation , Immunologic Deficiency Syndromes/genetics , Microcephaly , Mutation/genetics , Antibiotic Prophylaxis , Child, Preschool , Female , Genotype , Growth and Development , Humans , Immunoglobulins, Intravenous/therapeutic use , Immunosuppression Therapy , Male , Pedigree , Phenotype , Primary Immunodeficiency Diseases , Sequence Analysis, DNA
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