Four patients from two unrelated families with increased susceptibility to infection, hypogammaglobulinemia, and normal numbers of B cells in the blood were found to have mutations in the
CD19
gene. ...CD19, a protein on the B-cell surface, forms a complex with other proteins that participates in the activation of B cells by antigens.
Four patients from two unrelated families with increased susceptibility to infection, hypogammaglobulinemia, and normal numbers of B cells in the blood were found to have mutations in the
CD19
gene.
Primary antibody deficiencies, which are associated mainly with susceptibility to bacterial infections, can be caused by mutations in genes involved in B-cell differentiation.
1
Such genetic defects block the differentiation of immature B cells in bone marrow, thereby causing both a deficiency of mature B cells in the peripheral circulation and agammaglobulinemia.
2
–
8
In disorders involving defects in the maturation process of antigen-responsive B cells, by contrast, there are mature B cells in blood and a deficiency of some, but not all, immunoglobulin classes (dysgammaglobulinemia) or hypogammaglobulinemia. These disorders fall into two categories. The hyper-IgM syndromes are those in which a . . .
Colon cancer is a clinically diverse disease. This heterogeneity makes it difficult to determine which patients will benefit most from adjuvant therapy and impedes the development of new targeted ...agents. More insight into the biological diversity of colon cancers, especially in relation to clinical features, is therefore needed. We demonstrate, using an unsupervised classification strategy involving over 1,100 individuals with colon cancer, that three main molecularly distinct subtypes can be recognized. Two subtypes have been previously identified and are well characterized (chromosomal-instable and microsatellite-instable cancers). The third subtype is largely microsatellite stable and contains relatively more CpG island methylator phenotype-positive carcinomas but cannot be identified on the basis of characteristic mutations. We provide evidence that this subtype relates to sessile-serrated adenomas, which show highly similar gene expression profiles, including upregulation of genes involved in matrix remodeling and epithelial-mesenchymal transition. The identification of this subtype is crucial, as it has a very unfavorable prognosis and, moreover, is refractory to epidermal growth factor receptor-targeted therapy.
Summary Background Anal cancer is an increasing issue in HIV-positive men who have sex with men (MSM). Screening for its precursor, anal intraepithelial neoplasia (AIN), is subject of discussion. ...Current treatment options are suboptimum and have not been compared in a prospective trial. We compared efficacy and side-effects of imiquimod, topical fluorouracil, and electrocautery for the treatment of AIN. Methods In this open-label randomised trial, we included HIV-positive MSM older than 18 years visiting the HIV outpatient clinic of the Academic Medical Center, Amsterdam, Netherlands. Patients with histologically confirmed AIN were randomly assigned to receive either 16 weeks of imiquimod (three times a week), 16 weeks of topical fluorouracil (twice a week), or monthly electrocautery for 4 months. Randomisation was done with random block sizes of three and six, stratified for AIN grade (AIN grades 1, 2, or 3) and AIN location (peri-anal or intra-anal). Participants were assessed by high-resolution anoscopy 4 weeks after treatment. Responding patients returned for follow-up 24 weeks, 48 weeks, and 72 weeks after treatment. The primary endpoint was histological resolution of AIN measured 4 weeks after treatment and AIN recurrence at week 24, week 48, and week 72 after treatment. The primary analysis was done in a modified intention-to-treat population, including all patients who had received their assigned treatment at least once. The trial is registered at the Netherlands Trial Register , number NTR1236. Findings Between Aug 12, 2008, and Dec 1, 2010, we screened 388 HIV-positive MSM for AIN by high resolution anoscopy. Of the 246 (63%) patients who had AIN, 156 (63%) were randomly assigned to either receive imiquimod (54 patients), topical fluorouracil (48 patients), or electrocautery (46 patients) following withdrawing of consent by eight patients. Modified intention-to-treat analysis showed a complete response in 13 (24%, 95% CI 15–37) patients in the imiquimod group, eight (17%, 8–30) of patients in the fluorouracil group, and 18 (39%, 26–54) of patients in the electrocautery group (p=0·027). At week 24, 11 (22%) of 50 responders had recurrence; at week 48, 22 (46%) of 48 had recurred; and at week 72, 30 (67%) of 45 had recurred. Recurrence was observed at 72 weeks in 10 (71%) of 14 patients treated with imiquimod, seven (58%) of 12 patients treated with fluorouracil, and 13 (68%) of 19 patients treated with electrocautery. Grade 3–4 side-effects were noted in 23 (43%) of 53 patients in the imiquimod group, 13 (27%) of 48 patients in the fluorouracil group, and eight (18%) patients in the electrocautery group (p=0·019). The most common side-effects were pain, bleeding, and itching. Seven serious adverse events occurred, all not related to the study. Interpretation Electrocautery is better than imiquimod and fluorouracil in the treatment of AIN, but recurrence rates are substantial. Funding Anna Maurits de Cock foundation provided funding for the video colposcope.
Background
Circulating tumor DNA (ctDNA) has predictive and prognostic value in localized and metastatic cancer. This study analyzed the prognostic value of baseline and on-treatment ctDNA in ...metastatic gastroesophageal cancer (mGEC) using a region-specific next generation sequencing (NGS) panel.
Methods
Cell free DNA was isolated from plasma of patients before start of first-line palliative systemic treatment and after 9 and 18 weeks. Two NGS panels were designed comprising the most frequently mutated genes and targetable mutations in GEC. Tumor-derived mutations in matched metastatic biopsies were used to validate that the sequencing panels assessed true tumor-derived variants. Tumor volumes were calculated from baseline CT scans and correlated to variant allele frequency (VAF). Survival analyses were performed using univariable and multivariable Cox-regression analyses.
Results
ctDNA was detected in pretreatment plasma in 75% of 72 patients and correlated well with mutations in metastatic biopsies (86% accordance). The VAF correlated with baseline tumor volume (Pearson’s
R
0.53,
p
< 0.0001). Detection of multiple gene mutations at baseline in plasma was associated with worse overall survival (OS, HR 2.16, 95% CI 1.10–4.28;
p
= 0.027) and progression free survival (PFS, HR 2.71, 95% CI 1.28–5.73;
p
= 0.009). OS and PFS were inferior in patients with residual detectable ctDNA after 9 weeks of treatment (OS: HR 4.95, 95% CI 1.53–16.04;
p
= 0.008; PFS: HR 4.08, 95% CI 1.31–12.75;
p
= 0.016).
Conclusion
Based on our NGS panel, the number of ctDNA mutations before start of first-line chemotherapy has prognostic value. Moreover, residual ctDNA after three cycles of systemic treatment is associated with inferior survival.
Objective
Patients with Sjӧgren's syndrome (SS) have an increased risk of developing malignant B cell lymphomas, particularly mucosa‐associated lymphoid tissue (MALT)–type lymphomas. We have ...previously shown that a predominant proportion of patients with SS‐associated salivary gland MALT lymphoma express somatically hypermutated IgM with strong amino acid sequence homology with stereotypic rheumatoid factors (RFs). The present study was undertaken in a larger cohort of patients with SS‐associated MALT lymphoma to more firmly assess the frequency of RF reactivity and the significance of somatic IGV‐region mutations for RF reactivity.
Methods
B cell antigen receptors (BCRs) of 16 patients with SS‐associated salivary gland MALT lymphoma were analyzed. Soluble recombinant IgM was produced of 12 MALT lymphoma samples, including 1 MALT lymphoma sample that expressed an IgM antibody fitting in a novel IGHV3‐30–encoded stereotypic IGHV subset. For 4 of the 12 IgM antibodies from MALT lymphoma samples, the somatically mutated IGHV and IGKV gene sequences were reverted to germline configurations. Their RF activity and binding affinity were determined by enzyme‐linked immunosorbent assay and surface plasmon resonance, respectively.
Results
Nine (75%) of the 12 IgM antibodies identified in patients with SS‐associated salivary gland MALT lymphoma displayed strong monoreactive RF activity. Reversion of the IGHV and IGKV mutations to germline configuration resulted in RF affinities for IgG that were significantly lower for 3 of the 4 somatically mutated IgM antibodies. In stereotypic IGHV3‐7/IGKV3‐15–encoded RFs, a recurrent replacement mutation in the IGKV3‐15–third complementarity‐determining region was found to play a pivotal role in the affinity for IgG‐Fc.
Conclusion
A majority of patients with SS‐associated salivary gland MALT lymphoma express somatically mutated BCRs that are selected for monoreactive, high‐affinity binding of IgG‐Fc. These data underscore the notion that soluble IgG, most likely in immune complexes in inflamed tissues, is the principal autoantigen in the pathogenesis of a variety of B cell lymphomas, particularly SS‐associated MALT lymphomas.
Defective B-cell memory in patients with Down syndrome Verstegen, Ruud H.J., MD; Driessen, Gertjan J., MD; Bartol, Sophinus J.W., BSc ...
Journal of allergy and clinical immunology,
12/2014, Letnik:
134, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Background Patients with Down syndrome carry immunologic defects, as evidenced by the increased risks for autoimmune diseases, hematologic malignancies, and respiratory tract infections. Moreover, ...the low numbers of circulating B cells suggest impaired humoral immunity. Objective We sought to study how immunodeficiency in patients with Down syndrome results from immunologic defects in the B-cell compartment. Methods We studied blood B-cell subset composition, replication history, somatic hypermutation status, and class-switch recombination in 17 children with Down syndrome. Germinal centers and plasma cells were studied in tonsils from 4 additional children with Down syndrome. Results Blood transitional B-cell numbers were normal, but naive mature and memory B-cell numbers were reduced despite slightly increased serum B cell–activating factor levels. Germinal centers and plasma cells in tonsils appeared normal, as were serum immunoglobulin levels. CD27+ IgD+ IgM+ “natural effector” B cells showed reduced proliferation and somatic hypermutation levels, whereas these were normal in CD27+ IgD− memory B cells. Furthermore, IgM+ and IgA+ , but not IgG+ , memory B cells showed impaired molecular signs for antigen selection. The B-cell pattern was highly similar to that of patients with common variable immunodeficiency and a defect in B-cell activation and proliferation. Conclusion Children with Down syndrome seem capable of normal germinal center and plasma cell formation. Still, blood memory B-cell numbers were reduced and showed impaired molecular maturation of IgA and IgM, which are important for mucosal immunity. The observed molecular defects in circulating IgA and IgM B-cell memory could reflect impaired local responses, which underlie the increased susceptibility to respiratory tract infections of patients with Down syndrome.
The pathogenesis of classical Hodgkin lymphoma (cHL), the most common lymphoma in the young, is still enigmatic, largely because its Hodgkin and Reed-Sternberg (HRS) tumor cells are rare in the ...involved lymph node and therefore difficult to analyze. Here, by overcoming this technical challenge and performing, for the first time, a genome-wide transcriptional analysis of microdissected HRS cells compared with other B-cell lymphomas, cHL lines, and normal B-cell subsets, we show that they differ extensively from the usually studied cHL cell lines, that the lost B-cell identity of cHLs is not linked to the acquisition of a plasma cell-like gene expression program, and that Epstein-Barr virus infection of HRS cells has a minor transcriptional influence on the established cHL clone. Moreover, although cHL appears a distinct lymphoma entity overall, HRS cells of its histologic subtypes diverged in their similarity to other related lymphomas. Unexpectedly, we identified 2 molecular subgroups of cHL associated with differential strengths of the transcription factor activity of the NOTCH1, MYC, and IRF4 proto-oncogenes. Finally, HRS cells display deregulated expression of several genes potentially highly relevant to lymphoma pathogenesis, including silencing of the apoptosis-inducer BIK and of INPP5D, an inhibitor of the PI3K-driven oncogenic pathway.
Background and aimsPatients with hyperplastic polyposis syndrome (HPS) receive endoscopic surveillance to prevent malignant progression of polyps. However, the optimal treatment and surveillance ...protocol for these patients is unknown. The aim of this study was to describe the clinical and pathological features of a large HPS cohort during multiple years of endoscopic surveillance.MethodsDatabases were searched for patients with HPS, who were analysed retrospectively. Endoscopy reports and histopathology reports were collected to evaluate frequency of endoscopic surveillance and to obtain information regarding polyp and the presence of colorectal cancer (CRC).ResultsIn 77 patients with HPS, 1984 polyps were identified during a mean follow-up period of 5.6 years (range: 0.5–26.6). In 27 (35%) patients CRC was detected of which 22 (28.5%) at initial endoscopy. CRC was detected during surveillance in five patients (cumulative incidence: 6.5%) after a median follow-up time of 1.3 years and a median interval of 11 months. Of these interval CRCs, 4/5 were detected in diminutive serrated polyps (range: 4–16 mm). The cumulative risk of CRC under surveillance was 7% at 5 years. At multivariate logistic regression, an increasing number of hyperplastic polyps (OR 1.05, p=0.013) and serrated adenomas (OR 1.09, p=0.048) was significantly associated with CRC presence.ConclusionsHPS patients undergoing endoscopic surveillance have an increased CRC risk. The number of serrated polyps is positively correlated with the presence of CRC in HPS, thus supporting a ‘serrated pathway’ to CRC. To prevent malignant progression, adequate detection and removal of all polyps seems advisable. If this is not feasible, surgical resection should be considered.
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