A 4-base deletion has been identified in the coding region of the gene for gastric intrinsic factor (IF) in an 11-year-old girl with severe anemia and cobalamin (Cbl) deficiency. The bone marrow showed frank megaloblastic morphology, and the Schilling test indicated a failure to absorb Cbl that was corrected by coadministration of IF. Pentagastrin administration induced acid secretion, but the gastric juice lacked IF as determined by CbI binding, by fractionation of protein-bound CbI, and by immunoprecipitation with anti-IF antiserum. Individual exons were amplified by the polymerase chain reaction by using primers to the flanking intronic regions, and the nucleotide sequence analysis identified a 4-base deletion (c183_186delGAAT) spanning positions 104 to 107 in exon 2, resulting in premature termination of translation. This mutation also eliminates a site for Bst XI endonuclease and introduces a site for BsaBI for identifying this deletion in hereditary IF deficiency.
LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency caused by a mutation in the LRBA gene. Affected individuals present with a variety of clinical symptoms including hypogammaglobulinemia, recurrent infections, splenomegaly, hepatomegaly, and autoimmune cytopenias. Except for hypogammaglobulinemia, the remaining features resemble autoimmune lymphoproliferative syndrome (ALPS). Here, we report the case of a 14-year-old boy with the ALPS phenotype, eventually diagnosed with LRBA deficiency. He presented with lymphadenopathy and hepatosplenomegaly, along with autoimmune cytopenia. Due to recurrent infections and worsening gastrointestinal symptoms, whole-exome sequencing was conducted and revealed a novel homozygous pathogenic variant in the LRBA gene (c.534del; p.9Asp179IIef*16). The patient recently suffered from clinical deterioration due to SARS-COV-2 which appears to have triggered an acute worsening of his existing Cytomegalovirus colitis leading to an eventual demise. A literature search for reported LRBA deficient patients with ALPS-like phenotype revealed 11 patients. The most common clinical presentations in LRBA patients with ALPS-like phenotype included autoimmunity (100%), splenomegaly (91%), lymphadenopathy (36.4%), and respiratory tract infections (63.6%). LRBA deficiency is unique in the fact that it encompasses immune deficiency, autoimmunity, and lymphoproliferation. In children with multiple symptoms related to these domains, a genetic diagnosis is necessary to ensure tailored and precise medical therapy.
Several clinical characteristics-age, initial white blood cell (WBC) count, involvement of the central nervous system (CNS) disease at diagnosis, involvement of testis at diagnosis, immunophenotype, cytogenetics abnormalities-have been found to be associated with disease prognosis and outcomes. Patients with favorable prognosis are treated with less toxic regimen, while more aggressive regimens are offered to those with poor prognosis. The main components of treatment based on multidrug chemotherapy regimen to avoid drug resistance includes-remission induction, consolidation, interim maintenance, delayed intensification, maintenance chemotherapy, and CNS directed therapy (Cooper and Brown, 2015). With the incremental advances in therapy more than 80% survival (98% in certain subset) has been achieved in the developed countries (Gaynon et al., 1997).
Background:The frequency of pathogenic/likely pathogenic (P/LP) germline mutations in cancerrelated genes among children with cancer in highly consanguineous populations is not well studied.
Introduction : The outcome of Hodgkin lymphoma (HL) has improved over the past 20 years. However, the probability of relapse after response to initial treatment is currently approximately 10 to 15 percent for localized HL (i.e. stage I and II) and 20 to 40 percent for advanced stages (i.e. IIIB and IV), dependent on prognostic factors [1]. In young patients eligible for dose intensive chemotherapy, salvage chemotherapy with autologous stem cell transplantation (ASCT) is a frequently used therapy option and can be considered as standard [2, 3]. Patients who relapse following ASCT and those not eligible for myeloablative therapy are being treated with conventional chemotherapy or new novel agents such brentuximab vedotin (BV). Since approval of BV several study groups published the results of their experience in treating refractory/relapsed HL patients with BV. Patients and methods: The purpose of this study was to evaluate the impact of BV on outcome of patients with refractory and relapsed HL. In this systematic review we analyzed the published data on refractory / relapsed Hodgkin lymphoma patients who received BV as single agent. A systematic literature search was performed and included studies published from 1st January 2000 to 1st July 2015 in PubMed, electronic databases EMBASE (Dialog), Cochrane Library, DIMDI-Recherche and MEDPILOT. We used the key words brentuximab, brentuximab vedotein, adcetris, CD30 antibody and SGN-35. Recent conference abstracts from the American Society for Clinical Oncology (ASCO) (2012-2015) and American Society of Hematology (ASH) (2012-2014) were also included. Serial reports of 5 patients and more were included. If several publications from same author and group were published, the publications were re-scanned whether the reported patients' cohorts are the same. We included patients treated with BV pre- and post-transplantation as well as those not eligible for transplantation. Publications reporting about experience with BV in several diseases, e.g. T cell lymphoma and HL, underwent special analysis in order to extract only the HL data. Studies using BV in combination with radiation were disqualified for our analysis. Results: 51 out of 5369 screened records met the eligibility criteria. After exclusion of duplicates and serial reports with <5 patients total of 22 records (17 full articles and 5 abstracts) were included. Data of 903 patients treated with BV as salvage treatment was collected. The median age of the cohort was 31 year (range: 26-45). The patients received in median 4 lines (range: 1-9) of chemotherapy prior to BV. Median follow up was 16.1 months (range: 4.5-45.1). Most patients were heavily pretreated, 529/903 and 232/903 underwent high dose chemotherapy and autologous stem transplantation or received allogeneic stem transplantation prior of BV respectively. The response rate was 62.7% (range: 30-100%). The complete remission, partial remission, stable disease and progressive disease rates were 31.8%, 35.1%, 19.5% and 11.7% respectively. The one year progression free survival and estimated one year overall survival were 47.7% and 70% respectively. Conclusion: Significant number of the cohort received autologous and/or allogeneic stem cell transplantation prior BV. Response rate of 62.7% and complete remission rate of 31.8% are supporting results of the pivotal study [4] and establish the solid basis for using BV in heavily pretreated HL patients. Litreature: 1. Josting, A., et al., New prognostic score based on treatment outcome of patients with relapsed Hodgkin's lymphoma registered in the database of the German Hodgkin's lymphoma study group. J Clin Oncol, 2002. 20 (1): p. 221-30. 2. Sirohi, B., et al., Long-term outcome of autologous stem-cell transplantation in relapsed or refractory Hodgkin's lymphoma. Ann Oncol, 2008. 19 (7): p. 1312-9. 3. Rancea, M., et al., High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma. Cochrane Database Syst Rev, 2013. 6: p. CD009411. 4. Younes, A., et al., Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol, 2012. 30 (18): p. 2183-9. Disclosures No relevant conflicts of interest to declare.
Introduction: Patients with Hodgkin lymphoma (HL) relapsing after ASCT and those not eligible for myeloablative therapy can be salvaged with conventional chemotherapy or new novel agents such the immunotoxin brentuximab vedotin and the recently FDA approved anti-PD-1 inhibitor nivolumab. Other options include the mTOR inhibitor everolimus (1) for which, the data in literature is scarce. Moreover, there is no data on the efficacy of everolimus after failure of brentuximab vedotin. Patients and methods: In this study, we retrospectively analyzed the outcome of patients with relapsed/ refractory HL treated with single agent everolimus at our center between July 2015 and July 2016. All patients were started on everolimus 10 mg daily. Response to treatment was assessed every 2 months. Primary endpoint was the response rate of everolimus as single agent in patients with relapsed/refractory HL. Results: We identified 5 patients with heavily pretreated HL who received single agent everolimus. Mean age was 24.4 years (range, 20-30). Mean lines of previous treatment was 6.4 (range, 5-8). All patients failed brentuximab vedotin. Two patients failed previous autologous stem cell transplantation. Prior treatments included ABVD, radiation, ICE, ESHAP, miniBEAM, GVD, brentuximab vedotin, gemzar plus brentuximab vedotin, bendamustine, and ASCT. Mean duration of everolimus treatment was 5 months (range 4-7). One patient showed complete metabolic remission after 5 months of treatment. This remarkable response was achieved after failure of 6 lines. Partial remission and stable disease each were documented in 40%. Grade 1 neutropenia was reported in 80%. Grade 2 anemia, thrombocytopenia, fatigue and stomatitis were observed in 60%, 80%, 20% and 20% respectively. Everolimus dose reduction (5 mg) was required in two cases (one patient had grade 2 thrombocytopenia and other one had grade 3 fatigue). The latter discontinued the treatment after 4 months and is still in complete remission 5 months after discontinuation. No pulmonary toxicity was observed. Conclusion:The presented data suggest that everolimus is effective in heavily pretreated HL patients who failed conventional treatment including ASCT and new novel agents with 60% ORR. This result is the first of its kind showing efficacy of everolimus after failure of brentuximab vedotin. Literature: Johnston PB et al. A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. Am J Hematol. 2010 May;85(5):320-4. Disclosures No relevant conflicts of interest to declare.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.