Subject(s)
Ataxia Telangiectasia , Hematopoietic Stem Cell Transplantation , Severe Combined Immunodeficiency , Infant, Newborn , Humans , Ataxia Telangiectasia/diagnosis , Ataxia Telangiectasia/genetics , Neonatal Screening , Ataxia Telangiectasia Mutated Proteins , Early Diagnosis , Severe Combined Immunodeficiency/diagnosisABSTRACT
Introduction: Inborn errors of immunity (IEI) are an expanding group of rare diseases whose field has been boosted by next-generation sequencing (NGS), revealing several new entities, accelerating routine diagnoses, expanding the number of atypical presentations and generating uncertainties regarding the pathogenic relevance of several novel variants. Methods: Research laboratories that diagnose and provide support for IEI require accurate, reproducible and sustainable phenotypic, cellular and molecular functional assays to explore the pathogenic consequences of human leukocyte gene variants and contribute to their assessment. We have implemented a set of advanced flow cytometry-based assays to better dissect human B-cell biology in a translational research laboratory. We illustrate the utility of these techniques for the in-depth characterization of a novel (c.1685G>A, p.R562Q) de novo gene variant predicted as probably pathogenic but with no previous insights into the protein and cellular effects, located in the tyrosine kinase domain of the Bruton's tyrosine kinase (BTK) gene, in an apparently healthy 14-year-old male patient referred to our clinic for an incidental finding of low immunoglobulin (Ig) M levels with no history of recurrent infections. Results and discussion: A phenotypic analysis of bone marrow (BM) revealed a slightly high percentage of pre-B-I subset in BM, with no blockage at this stage, as typically observed in classical X-linked agammaglobulinemia (XLA) patients. The phenotypic analysis in peripheral blood also revealed reduced absolute numbers of B cells, all pre-germinal center maturation stages, together with reduced but detectable numbers of different memory and plasma cell isotypes. The R562Q variant allows Btk expression and normal activation of anti-IgM-induced phosphorylation of Y551 but diminished autophosphorylation at Y223 after anti IgM and CXCL12 stimulation. Lastly, we explored the potential impact of the variant protein for downstream Btk signaling in B cells. Within the canonical nuclear factor kappa B (NF-κB) activation pathway, normal IκBα degradation occurs after CD40L stimulation in patient and control cells. In contrast, disturbed IκBα degradation and reduced calcium ion (Ca2+) influx occurs on anti-IgM stimulation in the patient's B cells, suggesting an enzymatic impairment of the mutated tyrosine kinase domain.
Subject(s)
B-Lymphocytes , Protein-Tyrosine Kinases , Male , Humans , Adolescent , Agammaglobulinaemia Tyrosine Kinase/genetics , Protein-Tyrosine Kinases/genetics , NF-KappaB Inhibitor alpha , Flow CytometryABSTRACT
PURPOSE OF REVIEW: This review focuses on the efficacy of internet-based psychological interventions for patients with cardiovascular disease (CVD) and comorbid anxiety and depression. Anxiety and depression comprise barriers for treatment adherence and are associated with poorer patient-reported and clinical outcomes, and greater health care costs. RECENT FINDINGS: Internet-based, therapist-assisted interventions targeting anxiety and depression can be as efficacious as face-to-face therapy and may have some advantages, as patients can do it from their own laptop/smartphone at home at a time of their convenience, which may facilitate a better integration in their lives. To enhance the field of internet-based therapy for patients with CVD, we need to involve patients in the development of interventions, focus on developing standards for adherence and assessment of fidelity, and assess and augment health literacy in patients to safeguard equality in health care.
Subject(s)
Cardiovascular Diseases , Cognitive Behavioral Therapy , Humans , Depression/therapy , Cardiovascular Diseases/complications , Cardiovascular Diseases/therapy , Anxiety/therapy , Internet , Treatment OutcomeABSTRACT
PURPOSE: The fibroblast activation protein (FAP) is an emerging target for molecular imaging and therapy in cancer. OncoFAP is a novel small organic ligand for FAP with very high affinity. In this translational study, we establish [68Ga]Ga-OncoFAP-DOTAGA (68Ga-OncoFAP) radiolabeling, benchmark its properties in preclinical imaging, and evaluate its application in clinical PET scanning. METHODS: 68Ga-OncoFAP was synthesized in a cassette-based fully automated labeling module. Lipophilicity, affinity, and serum stability of 68Ga-OncoFAP were assessed by determining logD7.4, IC50 values, and radiochemical purity. 68Ga-OncoFAP tumor uptake and imaging properties were assessed in preclinical dynamic PET/MRI in murine subcutaneous tumor models. Finally, biodistribution and uptake in a variety of tumor types were analyzed in 12 patients based on individual clinical indications that received 163 ± 50 MBq 68Ga-OncoFAP combined with PET/CT and PET/MRI. RESULTS: 68Ga-OncoFAP radiosynthesis was accomplished with high radiochemical yields. Affinity for FAP, lipophilicity, and stability of 68Ga-OncoFAP measured are ideally suited for PET imaging. PET and gamma counting-based biodistribution demonstrated beneficial tracer kinetics and high uptake in murine FAP-expressing tumor models with high tumor-to-blood ratios of 8.6 ± 5.1 at 1 h and 38.1 ± 33.1 at 3 h p.i. Clinical 68Ga-OncoFAP-PET/CT and PET/MRI demonstrated favorable biodistribution and kinetics with high and reliable uptake in primary cancers (SUVmax 12.3 ± 2.3), lymph nodes (SUVmax 9.7 ± 8.3), and distant metastases (SUVmax up to 20.0). CONCLUSION: Favorable radiochemical properties, rapid clearance from organs and soft tissues, and intense tumor uptake validate 68Ga-OncoFAP as a powerful alternative to currently available FAP tracers.
Subject(s)
Gallium Radioisotopes , Neoplasms , Animals , Fibroblasts/metabolism , Humans , Ligands , Mice , Neoplasms/metabolism , Positron Emission Tomography Computed Tomography/methods , Radiopharmaceuticals , Tissue DistributionABSTRACT
Bloom Syndrome (BS) is a genetic DNA repair disorder, caused by mutations in the BLM gene. The clinical phenotype includes growth retardation, immunodeficiency and a strong predisposition to different types of malignancies. Treatment of malignancies in BS patients with radiotherapy or chemotherapy is believed to be associated with increased toxicity, but clinical and laboratory data are lacking. We collected clinical data of two Dutch BS patients with solid tumors. Both were treated with radiotherapy before the diagnosis BS was made and tolerated this treatment well. In addition, we collected fibroblasts from BS patients to perform in vitro clonogenic survival assays to determine radiosensitivity. BS fibroblasts showed less radiosensitivity than the severely radiosensitive Artemis fibroblasts. Moreover, studies of double strand break kinetics by counting 53BP1 foci after irradiation showed similar patterns compared to healthy controls. In combination, the clinical cases and laboratory experiments are valuable information in the discussion whether radiotherapy is absolutely contraindicated in BS, which is the Case in other DNA repair syndromes like Ataxia Telangiectasia and Artemis.
Subject(s)
Bloom Syndrome/complications , Carcinoma/radiotherapy , Radiotherapy/adverse effects , Adult , Bloom Syndrome/genetics , Carcinoma/complications , Cells, Cultured , DNA Breaks, Double-Stranded , DNA Repair , Female , Fibroblasts/radiation effects , Humans , Male , Middle Aged , Radiation Tolerance , RecQ Helicases/geneticsABSTRACT
BACKGROUND: Anterior shoulder dislocations (ASDs) are frequent painful injuries commonly treated in the emergency department. The last decade new potentially less traumatic and painful reduction techniques for ASDs have been introduced. Recent literature comparing best reduction techniques, medication use, and approaches is limited. To better guide future research including the use of these newer techniques, information about the current use of different reduction techniques and medication is needed. METHODS: Our primary aim was to survey the techniques used by emergency practitioners to reduce ASDs. Our secondary objective was to gather data on medication usage during reduction. To these ends, we surveyed members of the Netherlands Society of Emergency Physicians. RESULTS: Forty-four percent of respondents reported using a traction-based technique (Hippocrates or Stimson). Biomechanical techniques were used by 40% of respondents. Twelve percent reported using the Kocher leverage-based technique. Five percent of the techniques used could not be classified. A wide variety of procedural sedation and pain management interventions were reported, with an opioid and propofol being used most commonly. Approximately 9% of the reductions were attempted without any medications. CONCLUSIONS: To our knowledge, this is the first study of its kind on ASD management by emergency practitioners. Our results indicate that Dutch emergency practitioners employ all three classes of reduction techniques: traction-countertraction most commonly, closely followed by biomechanical techniques. Medication use during repositioning varied widely. Per our survey, emergency practitioners are desirous of an evidence-based guideline for ASD management.
ABSTRACT
Ataxia telangiectasia (A-T) is a severe neurodegenerative disorder with variable immunodeficiency. Together with the Dutch A-T community, we investigated the opinion of A-T parents on an early A-T diagnosis in the asymptomatic phase of the disease. During an annual national meeting for A-T patients and families, the topic of an early A-T diagnosis was discussed in relation to the recent introduction of neonatal screening for severe combined immunodeficiency (SCID) in the Netherlands. Based on the discussion, individual arguments were identified and processed into a questionnaire, which was sent out to 64 A-T parents (32 families). Arguments included were insecurity to diagnosis, possible medical advantages, appropriate genetic counseling and family planning, loss of "golden" year(s), and early cancer screening for parents. The response rate was 55% (n = 35 parents). Twenty-six (74%) parents felt that the advantages of an early diagnosis outweighed the disadvantages, five parents thought that the disadvantages would outweigh the advantages (14%), and four parents did not indicate a preference.Conclusion: The majority of parents of a child with A-T would have preferred an early diagnosis during the asymptomatic phase of the disease, because the uncertainty during the diagnostic process had had a major impact on their lives. In addition, the knowledge of being carriers of an ATM gene mutation influenced decisions about family planning. Parents who opposed against an early diagnosis emphasized the joy of having a seemingly healthy child until diagnosis.What is Known:⢠Ataxia telangiectasia (A-T) is a devastating DNA repair disorder with a huge impact on quality of life of patients and their parents.⢠Patients with A-T may incidentally be identified at birth as the consequence of neonatal screening for severe combined immunodeficiency (SCID).What is New:⢠The majority of Dutch parents of A-T patients (74%) would have preferred an early diagnosis of their child in the asymptomatic phase of the disease.⢠Major arguments for an early A-T diagnosis were (1) the experienced insecurity in diagnostic trajectories and its impact on families and (2) the knowledge of being ATM mutation carriers when deciding about family planning. An argument against an early diagnosis is losing the joy of having a seemingly healthy child until diagnosis.
Subject(s)
Ataxia Telangiectasia/diagnosis , Ataxia Telangiectasia/genetics , Early Diagnosis , Genetic Counseling , Neonatal Screening/methods , Surveys and Questionnaires , Adult , Ataxia Telangiectasia/epidemiology , Child, Preschool , Female , Genetic Predisposition to Disease , Humans , Incidence , Infant, Newborn , Male , Middle Aged , Netherlands/epidemiology , Parent-Child Relations , Parents/psychology , Risk AssessmentABSTRACT
Mutations affecting recombination activation genes RAG1 and RAG2 are associated with variable phenotypes, depending on the residual recombinase activity. The aim of this study is to describe a variety of clinical phenotypes in RAG-deficient patients from the highly consanguineous Egyptian population. Thirty-one patients with RAG mutations (from 28 families) were included from 2013 to 2017. On the basis of clinical, immunological and genetic data, patients were subdivided into three groups; classical T- B- severe combined immunodeficiency (SCID), Omenn syndrome (OS) and atypical SCID. Nineteen patients presented with typical T- B- SCID; among these, five patients carried a homozygous RAG2 mutation G35V and five others carried two homozygous RAG2 mutations (T215I and R229Q) that were detected together. Four novel mutations were reported in the T- B- SCID group; three in RAG1 (A565P, N591Pfs*14 and K621E) and one in RAG2 (F29S). Seven patients presented with OS and a novel RAG2 mutation (C419W) was documented in one patient. The atypical SCID group comprised five patients. Two had normal B cell counts; one had a previously undescribed RAG2 mutation (V327D). The other three patients presented with autoimmune cytopaenias and features of combined immunodeficiency and were diagnosed at a relatively late age and with a substantial diagnostic delay; one patient had a novel RAG1 mutation (C335R). PID disorders are frequent among Egyptian children because of the high consanguinity. RAG mutations stand behind several variable phenotypes, including classical SCID, OS, atypical SCID with autoimmunity and T- B+ CID.
Subject(s)
DNA-Binding Proteins/genetics , Homeodomain Proteins/genetics , Nuclear Proteins/genetics , Severe Combined Immunodeficiency/genetics , Severe Combined Immunodeficiency/pathology , Adolescent , Adult , B-Lymphocytes/immunology , Child , Consanguinity , Egypt , Female , Humans , Male , Molecular Diagnostic Techniques , T-Lymphocytes/immunology , Exome Sequencing , Young AdultSubject(s)
Encephalocele/complications , Meningocele/diagnostic imaging , Petrous Bone/diagnostic imaging , Subarachnoid Space/diagnostic imaging , Trigeminal Neuralgia/etiology , Aged , Diagnosis, Differential , Encephalocele/diagnostic imaging , Female , Humans , Image Interpretation, Computer-Assisted , Magnetic Resonance Imaging , Tomography, Spiral Computed , Tomography, X-Ray Computed , Trigeminal Neuralgia/diagnostic imagingABSTRACT
INTRODUCTION: Little is known about health activation and self-management behavior in preventing pressure ulcers (PU) in paraplegic patients. Therefore this study aimed to describe the extent of health activation and self-management behavior in paraplegics to prevent PU's and associations between this behavior and patient characteristics. Furthermore, we aimed to find differences in health activation in paraplegics who never had a PU compared to paraplegics with a previous history of PU's or a new-onset PU's. METHODS: A cross-sectional survey on health activation and self-management behavior was conducted among adult paraplegics recruited from two rehabilitation centers in the Netherlands. The Patient Activation Measure (PAM-score) was used to measure the extent of health activation. Patient statements on their level of self management behavior to prevent PU were evaluated. RESULTS: The mean PAM-score (0-100) was 54 (±8.1; n = 162) indicating a low level of health activation. Two indicators turned out to be statistically significant associated with health activation: level of education (OR = 2.2, p = 0.017) and degree of paraplegia (OR = 2.8, p = 0.036). Evaluation of health activation levels amongst paraplegics with or without a PU- history showed no significant difference. Analysis of patients statements demonstrated a large discrepancy between intended and actual behavior to prevent pressure ulcers. CONCLUSION: Level of education and level of paraplegia are significantly associated with health activation. A positive PU-history is not associated with future responsible behavior nor for compliant behavior in terms of health management.
Subject(s)
Paraplegia/psychology , Patient Participation/psychology , Pressure Ulcer/prevention & control , Self-Management/psychology , Adult , Aged , Cross-Sectional Studies , Female , Health Knowledge, Attitudes, Practice , Humans , Male , Middle Aged , Paraplegia/complications , Patient Participation/statistics & numerical data , Pressure Ulcer/etiology , Pressure Ulcer/psychology , Self Report , Skin CareABSTRACT
INTRODUCTION: The diffuse epidermal exfoliation seen in Steven Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) is similar to skin loss in second degree burns, and many of these patients are referred for treatment at burn centers. Treatment can differ markedly from center to center, and mortality can range from 25% to 70%, including a considerable morbidity. However, our experience over a 15-year period from 2000 to 2015 with 40 patients found a mortality rate of only 10% (4/40). The purpose of this paper is to discuss our treatment algorithm as a model for other centers treating SJS/TENs patients. METHODS: Records were reviewed for all patients admitted to the LAC+USC burn unit between 2000 and 2015 and 40 patients were identified with biopsy-proven SJS or TENS. These cases were reviewed for age, gender, initial and greatest TBSA, causative drug, pre-existing medical conditions, and morbidity and mortality. All data were entered into the SPSS statistical software package and all statistical analyses were performed using this program. RESULTS: Our treatment algorithm focused on early referral to a specialty burn unit, immediate discontinuation of the offending drug, fluid resuscitation, nutritional supplementation, and meticulous wound care. Average time to transfer to a burn unit was 3.36 days. Silver-releasing antimicrobial dressings were applied to the affected skin surface and changed every 3 days. Mupirocin coated petroleum gauze was used for facial involvement. Steroids were tapered and discontinued if initiated at an outside facility (58% of patients), and starting after 2001, all patients received a course of IVIG. All patients received fluid resuscitation and the majority received supplemental tube feedings (69%). Average length of total stay was 17.1 days and length of ICU stay 15.9 days. While 44% were transferred to another facility for further rehabilitative care, 37% of patients discharge to home. In patients discharged home with complete resolution of skin lesions, time to healing was an average of 14 days. DISCUSSION: With our 10% mortality rate in 40 patients, our study represents a relatively large study population while maintaining a relatively low mortality rate. The demographic data from our study largely aligns with the existing literature, and we therefore feel that our low mortality rate is due to our treatment algorithm, rather than to a less severe pathology in our patient population. This claim is supported by a standard mortality ratio of 1.68. This ratio proves a significantly improved mortality than would be expected based on disease severity on admission.
Subject(s)
Algorithms , Anti-Bacterial Agents/therapeutic use , Anti-Infective Agents, Local/therapeutic use , Enteral Nutrition , Fluid Therapy , Immunoglobulins, Intravenous/therapeutic use , Immunologic Factors/therapeutic use , Stevens-Johnson Syndrome/therapy , Administration, Cutaneous , Allopurinol/adverse effects , Anti-Bacterial Agents/adverse effects , Anticonvulsants/adverse effects , Bandages , Body Surface Area , Burn Units , Clinical Protocols , Female , Gout Suppressants/adverse effects , Hospitalization , Humans , Intensive Care Units , Length of Stay , Male , Middle Aged , Mupirocin/therapeutic use , Patient Transfer , Polyesters/therapeutic use , Polyethylenes/therapeutic use , Rehabilitation Centers , Retrospective Studies , Severity of Illness Index , Stevens-Johnson Syndrome/etiology , Stevens-Johnson Syndrome/mortalityABSTRACT
Purpose: There are ongoing arguments as to how cardiomyocytes are aggregated together within the ventricular walls. We used pneumatic distension through the coronary arteries to exaggerate the gaps between the aggregated cardiomyocytes, analyzing the pattern revealed using computed tomography, and validating our findings by histology. Methods: We distended 10 porcine hearts, arresting 4 in diastole by infusion of cardioplegic solutions, and 4 in systole by injection of barium chloride. Mural architecture was revealed by computed tomography, measuring also the angulations of the long chains of cardiomyocytes. We prepared the remaining 2 hearts for histology by perfusion with formaldehyde. Results: Increasing pressures of pneumatic distension elongated the ventricular walls, but produced insignificant changes in mural thickness. The distension exaggerated the spaces between the aggregated cardiomyocytes, compartmenting the walls into epicardial, central, and endocardial regions, with a feathered arrangement of transitions between them. Marked variation was noted in the thicknesses of the parts in the different ventricular segments, with no visible anatomical boundaries between them. Measurements of angulations revealed intruding and extruding populations of cardiomyocytes that deviated from a surface-parallel alignment. Scrolling through the stacks of tomographic images revealed marked spiraling of the aggregated cardiomyocytes when traced from base to apex. Conclusion: Our findings call into question the current assumption that cardiomyocytes are uniformly aggregated together in a tangential fashion. There is marked heterogeneity in the architecture of the different ventricular segments, with the aggregated units never extending in a fully transmural fashion. Key Points: â¢âPneumographic computed tomography reveals an organized structure of the ventricular walls.â¢âAggregated cardiomyocytes form a structured continuum, with marked regional heterogeneity.â¢âGlobal ventricular function results from antagonistic forces generated by aggregated cardiomyocytes. Citation Format: â¢âBurg MC, Lunkenheimer P, Niederer P etâal. Pneumatic Distension of Ventricular Mural Architecture Validated Histologically. Fortschr Röntgenstr 2016; 188: 1045â-â1053.
Subject(s)
Heart Ventricles/cytology , Heart Ventricles/diagnostic imaging , Myocytes, Cardiac/cytology , Myocytes, Cardiac/physiology , Tomography, X-Ray Computed/methods , Ventricular Function, Left/physiology , Animals , Cardioplegic Solutions/administration & dosage , Heart Ventricles/drug effects , In Vitro Techniques , Myocardial Contraction/drug effects , Myocardial Contraction/physiology , Myocytes, Cardiac/drug effects , Pressure , Swine , Ventricular Function, Left/drug effectsSubject(s)
Diffusion Magnetic Resonance Imaging , Encephalocele/complications , Encephalocele/diagnosis , Magnetic Resonance Imaging , Petrous Bone/pathology , Trigeminal Neuralgia/diagnosis , Trigeminal Neuralgia/etiology , Contrast Media , Decompression, Surgical , Encephalocele/surgery , Gadolinium , Humans , Image Enhancement , Microsurgery , Trigeminal Nerve/pathology , Trigeminal Nerve/surgery , Trigeminal Neuralgia/surgeryABSTRACT
Rapadilino syndrome is a genetic disease characterized by a characteristic clinical tableau. It is caused by mutations in RECQL4 gene. Immunodeficiency is not described as a classical feature of the disease. We present a 2-year-old girl with Rapadilino syndrome with important lymphadenopathies and pneumonia due to disseminated Mycobacterium lentiflavum infection. An immunological work-up showed several unexpected abnormalities. Repeated blood samples showed severe lymphopenia. Immunophenotyping showed low T, B, and NK cells. No Treg cells were seen. T cell responses to stimulations were insufficient. The IL12/IL23 interferon gamma pathway was normal. Gamma globulin levels and vaccination responses were low. With this report, we aim to stress the importance of screening immunodeficiency in patients with RECQL4 mutations for immunodeficiency and the need to further research into its physiopathology.
ABSTRACT
BACKGROUND: Mammographic screening may reduce breast cancer mortality by about 20%, provided participation is high and women screen regularly. We quantified independent risk factors for failing to rescreen and built a model to predict how rescreening rates change if these risk factors would be modified. METHODS: Multivariate analysis was used to analyze data from a prospective study which included a self-administered questionnaire and rescreening status 30months after a t0 mammogram, using a random sample of women 50-67years (Belgium 2010-2013). RESULTS: A false positive result at the most recent past mammogram (Odds Ratio=5.0, 95% Confidence Interval 3.6-6.8), an interval until new invitation greater than 25months (Odds Ratio=4.8 for >29months, 95% Confidence Interval 2.9-8.1), waiting times in the mammography unit >1h (Odds Ratio=2.1, 95% Confidence Interval 1.2-3.7) and difficulties in reaching the unit (Odds Ratio=2.5, 95% Confidence Interval 1.4-4.4) were the strongest independent predictors for failing to rescreen. The area under the curve of the receiver operating characteristic analysis was 0.705 for the model development stage and 0.717 for the validation stage and goodness-of-fit was good. CONCLUSIONS: Maintaining an invitation cycle of maximum 25months, limiting waiting time in the mammography unit and lowering the number of false positives could increase breast cancer screening compliance.
Subject(s)
Mammography/psychology , Mammography/statistics & numerical data , Patient Compliance/psychology , Patient Compliance/statistics & numerical data , Aged , Belgium , Breast Neoplasms/diagnosis , False Positive Reactions , Female , Health Services Accessibility , Humans , Middle Aged , Prospective Studies , ROC Curve , Risk Factors , Surveys and QuestionnairesABSTRACT
BACKGROUND: Weekly paclitaxel/carboplatin might improve survival in platinum-resistant epithelial ovarian cancer (EOC). We compared efficacy of first-line weekly to three-weekly paclitaxel/cis- or carboplatin (PCw and PC3w) induction therapy, followed by either three or six PC3w cycles. PATIENTS AND METHODS: In this multicentre, randomised phase III trial with 2×2 design, patients with FIGO stage IIb-IV EOC were randomised to six cycles PCw (paclitaxel 90mg/m(2), cisplatin 70mg/m(2) or carboplatin AUC 4) or three cycles PC3w (paclitaxel 175mg/m(2), cisplatin 75mg/m(2) or carboplatin AUC 6), followed by either three or six cycles PC3w. Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints were response rate (RR) and toxicity. RESULTS: Of 267 eligible patients, 133 received PCw and 134 PC3w. The first 105 patients received cisplatin, after protocol amendment the subsequent 162 patients received carboplatin. Weekly cisplatin was less well tolerated than weekly carboplatin. All PC3w cycles were well tolerated. At the end of all treatments, RR was 90.8% with no differences between the treatment arms. After a follow-up of median 10.3years (range 7.1-14.8), median PFS was 18.5 (95% confidence interval (CI) 15.9-21.0) months for PCw and 16.4 (95% CI 13.5-19.2) months for PC3w (p=0.78). Median OS was 44.8 (95% CI 33.1-56.5) months for PCw and 41.1 (95% CI 34.4-47.7) months for PC3w (p=0.98). CONCLUSIONS: There was no benefit in terms of OS, PFS or RR for a weekly regimen nor for extended chemotherapy as first-line treatment for EOC in European patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms, Glandular and Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Carboplatin/adverse effects , Cisplatin/administration & dosage , Cisplatin/adverse effects , Disease-Free Survival , Drug Administration Schedule , Europe , Fatigue/chemically induced , Female , Follow-Up Studies , Humans , Induction Chemotherapy , Middle Aged , Nausea/chemically induced , Neoplasms, Glandular and Epithelial/pathology , Neutropenia/chemically induced , Ovarian Neoplasms/pathology , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Time Factors , Treatment Outcome , Vomiting/chemically induced , Young AdultABSTRACT
Somatic hypermutation (SHM) is an important step in antigen-driven B cell development creating B lymphocytes expressing high-affinity antibody receptors. It is known that the peripheral B lymphocyte compartments of healthy children and adults differ considerably. However, the development of SHM with age has not been studied in detail previously. Therefore, we used the immunoglobulin (Ig)κ-restriction enzyme hot-spot mutation assay (Igκ-REHMA) to gain an estimation of SHM levels in different age groups in order to relate this to the size of the memory B lymphocyte subpopulations. We show that the level of SHM increases rapidly during the first 2 years of life. This reflects the changes of the memory B cell subpopulations, but also changes in the SHM within memory B cell subsets, probably reflecting an increase of secondary memory B cell responses.
Subject(s)
B-Lymphocyte Subsets/metabolism , Gene Rearrangement, B-Lymphocyte , Receptors, Antigen, B-Cell/genetics , Somatic Hypermutation, Immunoglobulin , Adolescent , Child , Child, Preschool , Common Variable Immunodeficiency/genetics , Humans , Infant , Infant, NewbornABSTRACT
The patients with CD3γ deficiency can present with different clinical findings despite having the same homozygous mutation. We report three new CD3gamma-deficient siblings from a consanguineous family with a combined T-B+NK+ immunodeficiency and their variable clinical and cellular phenotypes despite the same homozygous mutation of the CD3G gene (c.80-1G>C). We also re-evaluate a previously reported non-consanguineous family with two CD3gamma-deficient siblings with the same mutation. The median age at diagnosis was 11 years (14 months-20 years). We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as well as high IgE (n = 2) and atopic eczema (n = 2). While CD3(+) TCRαß+T cell percentages were low in all patients, only one had lymphopenia and 3 had CD3(+) T cell lymphopenia. Strikingly, we report frequent and multiple autoimmunity in tested heterozygous carriers in both families (n = 6; in 67%), and frequent autoimmunity in family members not available for testing (n = 5, in 80%). The results suggest that CD3G should be studied as a candidate gene for autoimmunity and that CD3gamma deficiency should be considered among other primary immunodeficiencies with predominantly autoimmune manifestations.
Subject(s)
Autoimmunity/genetics , CD3 Complex/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Thyroiditis, Autoimmune/genetics , Adult , Anemia, Hemolytic, Autoimmune/genetics , Antibodies, Antinuclear/genetics , B-Lymphocytes/immunology , Child , Dermatitis, Atopic/genetics , Female , Hepatitis, Autoimmune/genetics , Humans , Immunoglobulin E/biosynthesis , Immunoglobulin E/genetics , Immunoglobulin E/immunology , Infant , Killer Cells, Natural/immunology , Lymphopenia/genetics , Lymphopenia/immunology , Male , Nephrosis, Lipoid/genetics , Pedigree , Purpura, Thrombocytopenic, Idiopathic/genetics , T-Lymphocytes/immunology , Vitiligo/genetics , Young AdultABSTRACT
UNLABELLED: We present a case of a fatal Epstein-Barr infection in a 17-year-old male patient suspected to be caused by X-linked lymphoproliferative disease. At the time of hospitalization, DNA diagnostics was not available. The suspected diagnosis was confirmed several years later when a SH2D1A missense mutation was identified in stored patient DNA. Extended pedigree analysis showed that this mutation occurred de novo in his mother. In addition, we provide a summary of the currently listed SH2D1A mutations. CONCLUSION: This case report underlines the importance of DNA storage, pedigree analysis, and multidisciplinary care in patients with rare diseases and their families.