The elderly immune system is characterized by reduced responses to infections and vaccines, and an increase in the incidence of autoimmune diseases and cancer. Age‐related deficits in the immune ...system may be caused by peripheral homeostatic pressures that limit bone marrow B‐cell production or migration to the peripheral lymphoid tissues. Studies of peripheral blood B‐cell receptor spectratypes have shown that those of the elderly are characterized by reduced diversity, which is correlated with poor health status. In the present study, we performed for the first time high‐throughput sequencing of immunoglobulin genes from archived biopsy samples of primary and secondary lymphoid tissues in old (74 ± 7 years old, range 61—89) versus young (24 ± 5 years old, range 18–45) individuals, analyzed repertoire diversities and compared these to results in peripheral blood. We found reduced repertoire diversity in peripheral blood and lymph node repertoires from old people, while in the old spleen samples the diversity was larger than in the young. There were no differences in somatic hypermutation characteristics between age groups. These results support the hypothesis that age‐related immune frailty stems from altered B‐cell homeostasis leading to narrower memory B‐cell repertoires, rather than changes in somatic hypermutation mechanisms.
Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity, and immunodeficiency. We here investigated 4 patients from unrelated ...families presenting with immunodeficiency, autoimmunity, and malignancy. We identified 4 distinct homozygous mutations in TNFRSF9 encoding the tumor necrosis factor receptor superfamily member CD137/4-1BB, leading to reduced, or loss of, protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, and differentiation, were impaired. Genetic reconstitution of CD137 reversed these defects. CD137 deficiency is a novel inborn error of human immunity characterized by lymphocytic defects with early-onset Epstein-Barr virus (EBV)-associated lymphoma. Our findings elucidate a functional role and relevance of CD137 in human immune homeostasis and antitumor responses.
•CD137 deficiency is a novel inborn error of immunity with immune dysregulation and EBV-associated lymphomagenesis.•Our study highlights the key role of CD137 for immune homeostasis with relevance to immunodeficiency and cancer immunotherapy.
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Mixed-phenotype acute leukemia is a rare subtype of leukemia in which both myeloid and lymphoid markers are co-expressed on the same malignant cells. The pathogenesis is largely unknown, and the ...treatment is challenging. We previously reported the specific association of the recurrent t(8;12)(q13;p13) chromosomal translocation that creates the ETV6-NCOA2 fusion with T/myeloid leukemias. Here we report that ETV6-NCOA2 initiates T/myeloid leukemia in preclinical models; ectopic expression of ETV6-NCOA2 in mouse bone marrow hematopoietic progenitors induced T/myeloid lymphoma accompanied by spontaneous Notch1-activating mutations. Similarly, cotransduction of human cord blood CD34+ progenitors with ETV6-NCOA2 and a nontransforming NOTCH1 mutant induced T/myeloid leukemia in immunodeficient mice; the immunophenotype and gene expression pattern were similar to those of patient-derived ETV6-NCOA2 leukemias. Mechanistically, we show that ETV6-NCOA2 forms a transcriptional complex with ETV6 and the histone acetyltransferase p300, leading to derepression of ETV6 target genes. The expression of ETV6-NCOA2 in human and mouse nonthymic hematopoietic progenitor cells induces transcriptional dysregulation, which activates a lymphoid program while failing to repress the expression of myeloid genes such as CSF1 and MEF2C. The ETV6-NCOA2 induced arrest at an early immature T-cell developmental stage. The additional acquisition of activating NOTCH1 mutations transforms the early immature ETV6-NCOA2 cells into T/myeloid leukemias. Here, we describe the first preclinical model to depict the initiation of T/myeloid leukemia by a specific somatic genetic aberration.
•Markers of pre-metastatic niche are present in metastasis-free cervical lymph nodes.•Cervical lymph nodes are primed before the arrival of the metastatic cells.•Priming of lymph nodes involves ...extensive remodeling of extracellular matrix.
To assess expression of some markers of the pre-metastatic niche (PMN) in lymph nodes (LNs) of oral cancer patients.
LNs from metastatic-free neck dissections (LN0/N0, N = 43) and metastatic-free LNs in the vicinity of metastasis-containing LNs (LN0/N+, N = 30) were immuno-histochemically stained for lysyl oxidase (LOX), fibronectin (FN), vascular-endothelial growth factor receptor (VEGFR)-1 and matrix metalloproteinase (MMP)-9. Staining was assessed as 0 (no or weak staining), 1 (strong stain in 25% cells or extracellular area), 2 (same as 1 but in up to 50%) and 3 (same as 1 but in > than 50% of cells/area). Assessment was performed in the lymph node capsule (CAP), sub-capsular sinus (SCS) and medullary sinus (MS). In addition, sections were stained with picrosirius red and examined with polarized microscopy for assessing the distribution of polarization colors of the collagen fibers in the LN capsular area.
All examined LNs were positive for markers of the PMN. In general, the distribution and intensity of the immunoreactivity was similar between the LN0/N0 and LN0/N+, with only a few differences regarding expression of LOX in the capsule (p = 0.002) and VEGFR1 and MMP9 in the SCS (p = 0.023 and p < 0.001, respectively). Picrosirius red stain and polarized microscopy revealed a disrupted arrangement and distribution of the collagen fibers in both LN0/N0 and LN0/N + .
Markers for PMN were shown for the first time to be expressed in cervical LN0/N0 from patients with oral cancer, suggesting the increased permissive pathway remotely paved by the primary oral tumor for the incoming metastatic cells.
Background
The SRP54 (signal recognition protein 54) is a conserved component of the ribonucleoprotein complex that mediates cotranslational targeting and translocation of proteins to the endoplasmic ...reticulum. In 2017, mutations in the gene have been described as a cause of congenital neutropenia with or without pancreatic insufficiency, and since then, only limited cases were added to the literature.
Methods
Two patients with neutropenia underwent hematological, immunological, and genetic work‐up, including lymphocyte phenotyping, immunoglobulins, and complement levels, antineutrophil and antinuclear antibodies, bone marrow FISH panel for myelodysplastic syndrome, whole‐exome sequencing, and in silico proteomic analysis.
Results
Clinical findings in the two families revealed a wide spectrum of immunological and clinical manifestations, ranging from mild asymptomatic neutropenia during febrile illnesses to severe neutropenia and life‐threatening infection requiring leg amputation. Immunological and hematological work‐up showed isolated neutropenia with normal lymphocyte subpopulations, immunoglobulin and complement levels, and negative autoimmune tests. Bone marrow aspirations showed variability ranging from normal myelopoiesis to myeloid maturation arrest at the promyelocytic stage, with normal FISH panel for myelodysplastic syndrome. Genetic analysis identified a novel, de novo, in‐frame deletion in the SRP54 gene, c.342‐344delAAC, p.T115del. In silico proteomic analysis suggested impaired SRP54 protein function due to reduced GTP activity and stability.
Conclusions
We describe congenital neutropenia with variable clinical presentation in novel mutation of the SRP54 gene.
Background: Ibrutinib is an orally-administered inhibitor of Bruton's tyrosine kinase. It is an effective agent in diffuse large B cell lymphoma (DLBCL), specifically of the Activated (ABC) type ...(Younes A et al, Lancet Oncol 2014). The combination of ibrutinib, bendamustine, and rituximab (IBR) was reported to be potent for B cell lymphomas, including DLBCL, in a phase I clinical trial (Maddocks et al, Blood 2015). We aimed to explore the efficacy of the IBR regimen in patients with relapsed & refractory (RR) aggressive B cell lymphoma (ABCL), who were either transplant ineligible or in relapse post autologous stem cell transplantation (ASCT). We report here, the interim analysis of a phase II clinical trial.
Methods: Patients with RR ABCL of all subtypes as well as transformed low-grade lymphoma and grade 3B follicular lymphoma were eligible. Patients with CNS lymphoma, inadequate bone marrow function or previous exposure to bendamustine or ibrutinib were excluded. All diagnostic biopsies were centrally reviewed or repeated. PET scans were interpreted according to the Lugano criteria 2014. Rituximab and bendamustine were given for a six 28 days cycles in their standard dose (rituximab 375 mg/m2 in day 1 and bendamustine 90/70 mg/m2 day 1 and 2). Ibrutinib 560 mg orally, was administered continuously from day 1. PET scans were repeated after 3 and 6 cycles of therapy and then every 16 weeks up to 3 years. Patients that achieved a response after 3 cycles and who were eligible, could undergo either allogeneic or autologous stem cell transplantation. For the interim analysis, 34 patients were screened, and 32 of them were treated.
Results: Seventeen male (53%) and 15 (47%) female patients, median age 69 (28-94) were treated. All patients received at least one prior line of rituximab-containing therapy mostly RCHOP (n=28, 87%). Ten (31%) participants received the IBR therapy as a second line and 22 (69%) as a third-line regimen, 6 (19%) received prior ASCT. Eight (25%) patients had relapsed disease, and 24 (75%) were refractory. Twenty-nine patients had denovo aggressive B cell lymphoma, including 12 (37%) ABC-DLBCL, 5 (16%) GCB-DLBCL, 6 (19%) undefined DLBCL, 2 (6%) primary mediastinal lymphoma and 4 (12%) double hit high grade lymphoma. Two patients had transformed low grade and 1 grade 3B follicular lymphoma.
We recorded 258 adverse events (AEs); 11 (4%) were Serious Adverse Events (SAEs) and 3 (1%) adverse events were of particular interest. SAEs that were related to ibrutinib were documented in 4 patients one time each (1.6%) and included atrial flutter/fibrillation, fatigue, and thrombopenia.
Of the 32 patients 27 were evaluable for response, the additional 5 patients had early clinical progression. Complete response (CR) was documented in 8 (30%), partial response in 4 (15%) and stable disease in 2 (7%) translating to overall response rate (ORR) of 45%. On an intention to treat analysis ORR was 38%. There were no statistically significant differences in response rates between relapsed vs. refractory patients as well as ABC type vs. others.
Four patients were referred to transplant after achieving CR or PR, 2 to ASCT and 2 to allogeneic stem cell transplantation. With a median follow-up of 14 months, all 4 patients remained alive and in remission. Median PFS and OS for the entire cohort (n=32) was 2.7 and 7.1 months, respectively. Both PFS and OS were significantly better for patients who achieved CR. Median PFS for patients with no CR was 2.5 months and was significantly different from patients with CR (p=0.008, log-rank test, figure 1a). Median OS for patients without a CR was 5.9 months; no deaths occurred among patients who achieved CR (p=0.032, log-rank test, figure 1b).
There were no significant differences in OS or PFS between relapsed and refractory patients as well as between the different histological subtypes.
Conclusions: We demonstrated that the IBR regimen is both safe and effective for patients with RR ABCL. Our patient population was of advanced age and mostly refractory, and despite that, we were able to show 45% ORR. Four of the patients that were chemorefractory and therefore transplant ineligible were able to undergo transplants after achieving remissions with this regimen, all of them are alive and in remission. We conclude that this regimen has promising results as a salvage regimen for RR ABCL patients both as a sole therapy or as a bridge to transplant, and it should be investigated in further clinical trials.
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No relevant conflicts of interest to declare.
Extreme swing of phosphor from severe hyperphosphatemia to severe hypophosphatemia in a patient with blast crisis of myeloid origin was the result of imbalance between massive apoptosis of leukemic ...cells in the context of spontaneous tumor lysis syndrome and massive production of leukemic cells with only 1% of blast in peripheral blood. The mutated p53 protein suggested acting as oncogene in the presented case and possibly affecting phosphor status.
In industrialized societies atherosclerosis is still a major cause of morbidity and mortality, in spite of advances in development of cholesterol lowering drugs such as statins and ezetimibe. The ...detection of procoagulant proteases within atherosclerotic plaques, and the observation that patients with severe factor XI (FXI) deficiency have a reduced tendency to develop ischemic stroke, lead us to investigate whether absence of FXI would affect the process of atherogenesis. For this purpose, we created mice that are homozygous for null alleles for apolipoprotein E (apoE) and FXI (Double knock out DKO mice), and compared development of atherosclerosis in these animals to mice lacking apoE alone. At 24 weeks of age, there was a 32% reduction in atherosclerotic plaque area in the aortic sinus in apoE/FXI DKO mice compared to apoEKOmice (p=0.004). At age 42 weeks, apoE/FXI DKO mice had 25% smaller atherosclerotic plaque area in the aortic sinus compared to apoEKO mice (p=0.024), and aortic plaque area was reduced by 49% (p=0.028). Plasma cholesterol and triglycerides levels and lipoprotein profiles were similar in apoE/FXI DKO and apoE KO mice. In some murine infection models, FXI deficiency or FXI inhibition is associated with reduced markers of inflammation and improved survival. Based on this observation, we explored the possibility that reduced atherogenesis in apoE/FXI DKO mice is associated with reduced inflammation. There was a significant reduction in macrophages within atherosclerotic plaque in apoE/FXI DKO mice compared to apoE KO mice as determined by CD68 immunostaining. In conclusion, this work indicates for the first time that factor XI deficiency significantly reduces early, as well as advanced, atherosclerotic burden in an established animal model. We hypothesize that the effect of FXI on atherosclerosis is related to a proinflammatory effect within the atherosclerotic plaque. and propose that therapeutic targeting of FXI may have a role in preventing development of atherosclerosis. As FXI serves a minor role in hemostasis, treatment directed at this protein should not be associated with a high risk of major bleeding.
No relevant conflicts of interest to declare.
Introduction: End of treatment FDG-PET/CT activity is a powerful predictor of survival outcome in patients with Hodgkin, Diffuse large B cell and Follicular lymphomas. The predictive value of interim ...PET/CT scan on survival in Hodgkin lymphoma is also well established. To date, there are limited data regarding the prognostic significance of interim and end of treatment FDG-PET/scan results in adult patients with Burkitt lymphoma (BL), mainly due to the rarity of this entity. In this single-center retrospective study we analyzed the survival outcomes of patients with BL according to the findings on interim and end of treatment FDG-PET/CT scans using the Deauville criteria.
Methods: We thoroughly reviewed the clinical records of all BL patients who were treated in our medical center between 2005-2014. Thirty three patients and 104 scans were included in our final analysis. Interim PET/CT scan was performed before starting the 3rd cycle of the therapy. PET/CT scans were scored as positive or negative based on the five-point scale: scores 1-3 represented complete metabolic response (CMR) and scores 4-5 defined persistent or progressive disease. Response and survival outcomes were defined according to the Lugano Classification. Survival was calculated with the Kaplan-Meier method and survival comparison was analyzed with the Log-Rank test.
Results: Twenty four (73 %) were males and median age was 48 years (22-78). Two patients were HIV positive. Twenty four patients (73%) had stage 3 or 4 disease and 25 patients (76%) had high-intermediate or high risk disease according to the International Prognostic Index. All patients received intensive regimens, and the majority of them (78%) were treated according to the GMALL-B-ALL/NHL2002 protocol. Rituximab was part of treatment in 28 (85%) patients. After a median follow-up of 1.92 years (yrs) (0.08-9.58), 7 patients (21%) have died: six due to advanced BL and one from treatment related toxicity. The overall (OS) and progression-free survival (PFS) at 3-yrs for all patients were 76% and 70%, respectively. Importantly, OS was predicted by the results of end of treatment PET/CT scans: patients in CMR (n=21) had OS of 90% while those with positive PET/CT (n=5) had OS of 30% at 3 years (Figure 1, p=0.001). Early-interim PET/CT results did not predict either PFS or OS at 3 years (OS - 85% for patients in CMR and 60% for patients with positive PET, p=0.27).
Conclusions: The current retrospective study indicates that adult patients with BL, who receive rituximab-based intensive regimens, such as the GMALL-B-ALL/NHL2002 protocol, have a favorable outcome. End of treatment PET activity strongly predicted survival outcomes while interim PET result did not correlate with prognosis. Based on our data, it appears that changing treatment in adult patients with BL only on the basis of interim PET/CT results is not advised, unless there is clear evidence of progression.
*Authors EP, MK & TD equally contributed to this study.
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No relevant conflicts of interest to declare.
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