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1
Milani, C., and J. Castillo. "HIV-associated peripheral T-cell lymphoma." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e19551-e19551. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e19551.
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e19551 Background: T-cell lymphomas (TCL) constitute 3% of all AIDS-related lymphomas. Over the past 2 decades numerous case reports have documented the emergence of TCL among HIV-infected individuals. These lymphomas comprise a diverse group of disease entities, including peripheral T-cell lymphomas (PTCL), which represent the most common subtype. The aim of this study was to investigate the clinical and pathological features of HIV-associated PTCL. Methods: A MEDLINE search for cases of HIV-associated PTCL was conducted through December 2008. Data regarding patient age, gender, HIV status (CD4 count, viral load, opportunistic infections), use of HAART, lymphoma features (B symptoms, stage, sites of involvement, immunophenotype, molecular studies), EBV coinfection, therapy, and outcome (survival, cause of death) were analyzed and reported descriptively. Results: A total of 34 cases were included. Patients had a median age of 36 years with a male:female ratio of 4:1. Median CD4+ count was 126 cells/mm3. Seventeen patients (50%) had an opportunistic infection, but only 7 patients (26%) were on HAART treatment; 4 patients on HAART (57%) were alive at time of publication. PTCL was extranodal in 75% of cases, affecting predominantly the oral cavity, lung, and GI tract. B symptoms were present in 60% of cases. Stage III and IV disease was found in 17 and 5 cases, respectively, accounting for 76% of the total cases. T-cell receptor gene rearrangement was positive in 10 out of 10 (100%) analyzed cases. EBV was identified in 6 of 12 cases (50%). Median LDH level was 269 IU/L. Therapy for PTCL was administered in 23 cases (68%), while 10 cases (30%) did not receive therapy; 9 of the treated patients (39%) received CHOP with a 33% remission rate. Twenty-two patients (69%) died complicated by infections in 57% and lymphoma progression in 36% of cases. The reported median survival was 12 months. Conclusions: HIV-associated PTCL tends to affect young male individuals with low CD4 counts. Apart from marked immunosuppression, the poor prognosis of HIV-associated PTCL appears to be related to advanced stage at presentation, presence of B symptoms, elevated LDH levels, prominent extranodal disease, and poor response to CHOP chemotherapy. The role of HAART and EBV in the development of PTCL needs further clarification. No significant financial relationships to disclose.
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Klameth, Andreas, Andreas Neubauer, Christian Keller, Christian Aepinus, Ulrich Kaiser, Jörg Hoffmann, and Cornelia Brendel. "Aberrant CD3-Positive, CD8-Low, CD7-Negative Lymphocytes May Appear During Viral Infections and Mimic Peripheral T-Cell Lymphoma." Diagnostics 10, no. 4 (April 7, 2020): 204. http://dx.doi.org/10.3390/diagnostics10040204.
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Flow cytometry (FC) facilitates diagnosis of peripheral T-cell non-Hodgkin lymphoma (T-NHL), but overlapping features between reactive and neoplastic T-cell proliferations often hamper a rapid assessment. One hundred forty peripheral blood samples submitted to diagnostic FC for T-cell immunophenotyping were retrospectively analyzed. A T-cell population with a conspicuous aberrant surface epitope expression pattern was observed in 18 cases and diagnostic follow up was performed. The aberrant T-cell population exhibited a low scatter profile, a CD7-negative/low, CD8-low and CD3-positive immunophenotype, and monoclonal T-cell receptor expansion. T-NHL was ruled out by follow up in all cases. Epstein-Barr virus infection was diagnosed in 12 cases, cytomegalovirus infection in three cases; one patient had been vaccinated. The irregular subpopulation disappeared spontaneously within days or weeks. We describe a novel peripheral blood T-cell subpopulation with a low light scatter and CD8-low, CD7-negative/low and CD3-positive marker expression profile, which indicates reactive T-cell expansion in patients who present with peripheral lymphadenopathy and/or B symptoms.
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Baaij, Laura R. de, Jolanda MW van de Water, Wieke HM Verbeek, Otto J. Visser, Dirk J. Kuik, Joost J. Oudejans, Chris JLM Meijer, Chris JJ Mulder, and Saskia AGM Cillessen. "Enteropathy-Associated T-Cell Lymphoma: a Clinical Prognostic Model to Identify High Risk Patients." Blood 116, no. 21 (November 19, 2010): 3092. http://dx.doi.org/10.1182/blood.v116.21.3092.3092.
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Abstract Abstract 3092 Enteropathy-associated T-cell lymphoma (EATL) is a rare intestinal lymphoma that arises from intraepithelial lymphocytes. In Western countries EATL accounts for 5% of all gastrointestinal lymphomas and in 80–90% of all cases this lymphoma is associated with celiac disease (CD). Based on clinical presentation, EATL can be divided into two subtypes: primary and secondary EATL. Primary EATL develops without a preceding history of CD. The first presentation is often perforation or obstruction, which leads to diagnosis of both EATL and CD. Secondary EATL is diagnosed in patients with well-established CD or refractory CD. These patients deteriorate and eventually develop EATL. The current standard treatment for both types of EATL consists of surgery and chemotherapy, but overall survival (OS) is poor and new therapeutic strategies are urgently needed. For risk-based selection of patients for new therapies and clinical trials, prognostic models as the International Prognostic Index (IPI) are generally used. Since IPI is not predictive for EATL, we determined a prognostic model specifically for EATL, which can identify high-risk patients who need more aggressive therapy. Forty-one patients were diagnosed with EATL and retrospectively analyzed. Two- and 5-years OS were 18% and 10% respectively (range: 0 – 97 months). In multivariate analysis, 3 risk factors were predictive for survival: serum LDH > normal (P < 0.001; RR 6.65; 95% CI 1.96 to 9.89), presence of B-symptoms (P < 0.001; RR 4.41; 95% CI 2.73 to 16.18) and subtype secondary EATL (P = 0.036; RR 2.33; 95% CI 1.06 to 5.13). A weighted point score was assigned to each of these 3 factors and a prognostic model was constructed. Four risk groups were identified (P < 0.0001). Group I showed most favorable outcome: 2- and 5-years OS were 55% and 30% respectively. Although survival rates in groups II, III and IV were significantly different, in none of these groups 2-years survival was achieved. Therefore, the model was simplified to a low risk and a high risk group (P < 0.0001, Figure 1). The low risk group represented patients with no risk factors, i.e. primary EATL with no B-symptoms and normal LDH. In the high risk group, patients had 1 or more of the risk factors elevated serum LDH, B-symptoms or subtype secondary EATL. The new prognostic model showed superior predictive capacity as compared to IPI. In conclusion, our new prognostic model clearly identifies a high and a low risk group. Patients with one or more of the risk factors serum LDH > normal, B-symptoms or subtype secondary EATL are at high risk, and therefore new therapies for this group are urgently needed. Figure 1: Survival in EATL. Low risk group = no risk factors. High risk group = presence of 1 or more of the following risk factors: serum LDH > normal, B-symptoms or subtype secondary EATL. Figure 1:. Survival in EATL. Low risk group = no risk factors. High risk group = presence of 1 or more of the following risk factors: serum LDH > normal, B-symptoms or subtype secondary EATL. Disclosures: No relevant conflicts of interest to declare.
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Federico, Massimo, Thomas Rudiger, Monica Bellei, Bharat N. Nathwani, Stefano Luminari, Bertrand Coiffier, Nancy L. Harris, et al. "Clinicopathologic Characteristics of Angioimmunoblastic T-Cell Lymphoma: Analysis of the International Peripheral T-Cell Lymphoma Project." Journal of Clinical Oncology 31, no. 2 (January 10, 2013): 240–46. http://dx.doi.org/10.1200/jco.2011.37.3647.
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PurposeThe International Peripheral T-Cell Lymphoma Project was undertaken to better understand the subtypes of T-cell and natural killer (NK) –cell lymphomas.Patients and MethodsAngioimmunoblastic T-cell lymphoma (AITL) was diagnosed according to the 2001 WHO criteria by a central review process consisting of panels of expert hematopathologists. Clinical, pathologic, immunophenotyping, treatment, and survival data were correlated.ResultsOf 1,314 patients, 243 (18.5%) were diagnosed with AITL. At presentation, generalized lymphadenopathy was noted in 76% of patients, and 89% had stages III to IV disease. Skin rash was observed in 21% of patients. Hemolytic anemia and hypergammoglobulinemia occurred in 13% and 30% of patients, respectively. Five-year overall and failure-free survivals were 33% and 18%, respectively. At presentation, prognostic models were evaluated, including the standard International Prognostic Index, which comprised the following factors: age ≥ 60 years, stages III to IV disease, lactic dehydrogenase (LDH) > normal, extranodal sites (ENSs) > one, and performance status (PS) ≥ 2; the Prognostic Index for Peripheral T-Cell Lymphoma, comprising: age ≥ 60 years, PS ≥ 2, LDH > normal, and bone marrow involvement; and the alternative Prognostic Index for AITL (PIAI), comprising: age > 60 years, PS ≥ 2, ENSs > one, B symptoms, and platelet count < 150 × 109/L. The simplified PIAI had a low-risk group (zero to one factors), with 5-year survival of 44%, and a high-risk group (two to five factors), with 5-year survival of 24% (P = .0065).ConclusionAITL is a rare clinicopathologic entity characterized by an aggressive course and dismal outcome with current therapies.
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Gerevini, Simonetta, Ruggero Capra, Diego Bertoli, Alessandra Sottini, and Luisa Imberti. "Immune profiling of a patient with alemtuzumab-associated progressive multifocal leukoencephalopathy." Multiple Sclerosis Journal 25, no. 8 (April 9, 2019): 1196–201. http://dx.doi.org/10.1177/1352458519832259.
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A 31-year-old woman affected by multiple sclerosis (MS) experienced generalized tonic–clonic seizures 2 months after the second alemtuzumab cycle. Positive JC virus (JCV)-DNA in cerebrospinal fluid (CSF) and lesion iconography at magnetic resonance imaging (MRI) were suggestive of progressive multifocal leukoencephalopathy (PML). After 1 month, during full-blown immune reconstitution inflammatory syndrome, JCV-DNA became negative and symptoms gradually improved. New T- and B-cell output and T- and B-cell diversity were low and lymphocytes poorly responded to stimulation. This is the first case of an alemtuzumab-treated patient with clinical symptoms and radiological features compatible with PML. The lack of large T- and B-cell diversity, necessary for JCV recognition, is likely to have concurred to PML insurgence.
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Endo, Tomonori, Daiya Asaka, Tsuguhisa Nakayama, Shota Saito, Hiroki Kodama, Ryoto Mitsuyoshi, Naoki Sugimoto, et al. "Long-term oral administration of transgenic rice containing cedar pollen T-cell epitopes potentially improves medication- and allergy-related quality-of-life scores." Allergy and Asthma Proceedings 42, no. 4 (July 1, 2021): 293–300. http://dx.doi.org/10.2500/aap.2021.42.210011.
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Background: We previously developed a transgenic rice that contains seven linked human predominant T-cell epitopes (7Crp) derived from Japanese cedar (JC) pollen allergens Cry j 1 and Cry j 2. Oral administration of 80 g of transgenic rice for 20 weeks suppressed allergen-specific T-cell proliferation in participants with JC pollinosis, but their clinical symptoms did not improve. Objective: We examined the clinical efficacy of low-dose (5 g and 20 g) intake of the transgenic rice administered for two successive seasons. Methods: In this randomized, double-blind, placebo controlled study, transgenic rice seeds (5 g or 20 g) were orally administered to the participants for 24 weeks in each of two successive JC pollen seasons. We analyzed T-cell proliferation and cytokine expression, and monitored symptom and medication scores during the pollen season. Quality of life (QOL) was evaluated by using the Japanese Allergic Rhinitis Quality of Life Standard Questionnaire (JRQLQ). Results: Specific T-cell proliferation after stimulation with 7Crp, Cry j 1, and Cry j 2 was significantly suppressed in the second JC pollen season. No significant differences were found among the three groups (5 g, 20 g, and placebo) with regard to clinical symptoms or medication scores in the first season. However, the medication scores and face scale for overall condition of JRQLQ improved in the 5-g transgenic rice group in the second season, although careful re-examination with a large sample size is necessary to confirm the results. Conclusion: Low-dose oral administration of transgenic rice that contains 7Crp significantly reduced allergen-specific T-cell responses and improved medication scores during the second season of administration. Thus, oral intake of the transgenic rice has the potential to induce immune tolerance to JC pollen allergens when administered for at least two successive seasons.
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Slovick, Anna, Abdel Douiri, Rachel Muir, Andrea Guerra, Konstantinos Tsioulos, Evie Haye, Emily PS Lam, et al. "A randomised placebo-controlled trial investigating efficacy and mechanisms of low-dose intradermal allergen immunotherapy in treatment of seasonal allergic rhinitis." Efficacy and Mechanism Evaluation 3, no. 10 (December 2016): 1–80. http://dx.doi.org/10.3310/eme03100.
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BackgroundWe previously reported that repeated low-dose grass pollen intradermal allergen injection suppresses allergen-induced cutaneous late-phase responses, comparable with conventional high-dose subcutaneous and sublingual immunotherapy.ObjectiveTo evaluate the efficacy and mechanism of grass pollen intradermal immunotherapy for treatment of allergic rhinitis.DesignA Phase II, double-blind, randomised controlled parallel-group trial.SettingSingle-centre UK study.ParticipantsAdults aged 18–65 years, with grass pollen-induced allergic rhinoconjunctivitis.InterventionsSeven 2-weekly intradermal injections were given into the forearm, containing eitherPhleum pratensesoluble grass pollen extract (7 ng of the major allergen Phl p 5) or histamine control.Main outcome measuresThe primary outcome was a combined symptom and medication score (CSMS) during the 2013 grass pollen season. Secondary clinical outcomes were overall symptom scores; individual symptoms scores for nose, mouth, eyes and lungs; overall medication scores; CSMSs during the peak season; visual analogue scale (VAS) scores for nose and eye symptoms; Mini Rhinitis Quality of Life Questionnaire scores; health-related quality-of-life scores (European Quality of Life-5 Dimensions, 5-levels); a global evaluation of symptoms, number of symptom-free and medication-free days; number of days when prednisolone was used; and adverse events. Mechanistic studies included measurement of late-phase skin response sizes, allergen-specific antibody titres, analysis of skin biopsies and basophil activation tests.ResultsThere was no significant difference in CSMSs between treatment arms [difference in median area under curve (AUC) 14, 95% confidence interval (CI) –172.5 to 215.1;p = 0.80]. Paradoxically, among the secondary outcomes, nasal symptoms measured with daily scores were higher in the active arm (difference in median AUC 35, 95% CI 4.0 to 67.5;p = 0.03), with a trend for higher nasal symptoms measured by VASs (difference in median AUC 53, 95% CI –11.6 to 125.2;p = 0.05). No differences were seen in other clinical outcomes in the main intention-to-treat analysis. In mechanistic studies, active treatment increasedP. pratense-, Phl p 1- and Phl p 5-specific immunoglobulin E (allp = 0.001) compared with the control. T cells cultured from skin biopsies of active intradermal immunotherapy subjects showed higher T helper type 2 cell (Th2) marker CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) expression (p < 0.05) and lower T helper type 1 cell marker CXCR3 [chemokine (C-X-C Motif) receptor 3] expression (p < 0.05), respectively. Interleukin 5 messenger ribonucleic acid, measured by microarray, was more highly expressed by cultured skin T cells in the active arm (p < 0.05). Late-phase skin responses to grass pollen were still inhibited up to 7 months after intradermal immunotherapy (p = 0.03), but not at 10–13 months’ time points.LimitationsGrass pollen doses were not increased during the course, as our proof-of-concept trial showed that repeating the same doses was sufficient to achieve almost complete late-response suppression. Injections were not continued throughout the season, as previous subcutaneous grass pollen immunotherapy trials have demonstrated preseasonal regimen efficacy.ConclusionsIntradermal immunotherapy suppressed late-phase skin responses to allergen, but was not clinically effective. The intervention appeared to have an immunological priming effect and exacerbated certain seasonal symptoms, notably in the nose.Future workFurther studies on low-dose intradermal grass pollen immunotherapy are not recommended because of our demonstrated worsening of allergic rhinitis symptoms and immunological priming. The findings are of great significance for other novel immunotherapies targeting the skin, such as epicutaneous techniques.Trial registrationCurrent Controlled Trials ISRCTN78413121.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.
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Autio, Matias, Suvi-Katri Leivonen, Teijo Pellinen, and Sirpa Leppa. "Clinical Impact of Tumor-Associated Macrophage and T-Cell Contents in Diffuse Large B-Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 33. http://dx.doi.org/10.1182/blood-2020-142331.
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Background: Tumor infiltrating immune cells can modulate cancer progression and are attractive therapeutic targets. We have previously identified a tumor microenvironment (TME) immune cell signature in diffuse large B-cell lymphoma (DLBCL), which contains genes for cytolytic factors, immune checkpoint molecules, T-cells and macrophages, and separates the patients into immune cell high and low or T-cell inflamed and non-inflamed subgroups (Autio et al., 2020). As macrophages and T-cells are key components of the TME, our aim was to characterize their phenotypes and relationships in the tumor tissue and associate the findings to clinical outcome in patients with DLBCL. Methods: We used multiplex immunohistochemistry, gene expression data, and unsupervised computational approaches to characterize tumor associated T-cell and macrophage (TAM) phenotypes in 178 samples from DLBCL patients. We correlated the immune cell constitution with clinical data, and validated the findings utilizing gene expression data from three independent DLBCL cohorts (Reddy et al., 2017, Schmitz et al., 2018, Chapuy et al., 2018) and in silico immunophenotyping with CIBERSORT. Results: The proportions of TAMs and infiltrating T-cells varied significantly between the patients. Unsupervised hierarchical clustering divided the samples into T-cell inflamed and non-inflamed subgroups. The T-cell inflamed phenotype was rich in other immune cell subtypes such as TAMs, natural killer (NK) cells, and regulatory T-cells, thus characterizing an immune hot phenotype. Apart from B-symptoms being more common in the patients with T-cell inflamed phenotype, clinical characteristics were equally distributed between the subgroups, and no association with survival was observed. However, when we divided the T-cell inflamed group further into subgroups according to the TAM content, we identified a T-cell high/macrophage low group, which was characterized by clinically less aggressive disease and better survival as compared to the T-cell high/macrophage high or T-cell low groups. Using in silico deconvolution analyses, we validated the T-cell high/macrophage low subgroup, and its association with less aggressive disease and survival in an external dataset comprising 496 patients (Reddy et al., 2017). The prognostic impact of T-cell high/macrophage low subgroup on survival was independent of the IPI and molecular subtype. Differential gene expression analyses identified a gene signature corresponding to the T-cell high/macrophage low subgroup. This signature translated to better outcome, and was validated in two additional datasets (Schmitz et al. n=562, Chapuy et al. n=137). Finally, we studied the impact of immune checkpoint expressing TAMs on survival, and whether it differed between the T-cell inflamed and T-cell non-inflamed subgroups. In particular, a high proportion of PD-L1+, TIM3+, and PD-L1+TIM3+CD163- macrophages associated with poor outcome, independent from the IPI and molecular subtype. Furthermore, the impact of these TAM subtypes on survival was evident only in the patients with T-cell inflamed phenotype. Conclusions: Our data demonstrate that the proportions of different immune cell phenotypes in the DLBCL TME are clinically meaningful, and suggest that the high T-cell/macrophage ratio predicts favorable survival in patients with DLBCL. Disclosures Leppa: Novartis: Consultancy; Takeda: Consultancy; Celgene: Research Funding; Bayer: Research Funding; Incyte: Consultancy; Roche: Consultancy, Research Funding.
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Huang, Yenlin, Anne Moreau, Jehan Dupuis, Berthold Streubel, Barbara Petit, S. Legouill, Nadine Martin-Garcia, et al. "Peripheral T-Cell Lymphomas with Follicular Growth Patterns Are Derived from Follicular Helper T Cells (TFH): A Link with Angioimmunoblastic T-Cell Lymphomas?." Blood 110, no. 11 (November 16, 2007): 3568. http://dx.doi.org/10.1182/blood.v110.11.3568.3568.
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Abstract Nodal peripheral T-cell lymphomas represent a heterogeneous category, composed of three entities: anaplastic large cell lymphomas, peripheral T-cell lymphomas unspecified (PTCLu) and angioimmunoblastic T-cell lymphomas (AITL). The later entity has been recently recognized to derive from follicular helper T cells (TFH). Among PTCLu - which represents an ill-defined entity - a peculiar form with follicular growth pattern (PTCL-F) has been recently reported, and one article stated their association with t(5 ;9)(q33 ;q22) involving ITK and SYK (Leukemia2006; 20: 313–318). However, the origin of tumor cells and clinical aspects of this group of PTCL-F are still unknown. The aim of this study was to analyse a series of PTCL-F to describe their clinical and histopathological aspects, to identify their cell of origin, and their relationship with AITL. Fourty-two patients from 32 to 85 years of age with 51 biopsies were selected from three Departments of Pathology (Creteil, n=24, Nantes n=13, Vienna n=14). All patients showed histopathologic features of PTCL-F in at least one biopsy. Biopsies were classified into three categories according to predominant morphological features at low power magnification: follicular lymphoma-like (n=7), progressive transformation of germinal center-like (n=22), and AITL-like features with follicular colonization (n=19). Several cases have combinations of patterns. The neoplastic population is characterized by medium-sized cells with clear cytoplasm surrounded by IgD+ B-cells. Tumor cells are of helper T-cell immunophenotype [CD2+ (33/33 = 100%), CD3+ (45/48 = 93%), CD4+ (35/42 = 83%), CD5+ (39/39 = 100%), CD7+ (7/37 = 19%)], with frequent expression of CD10 (29/43 = 67%) and of TFH markers [PDCD-1 (32/36 = 88%), CXCL13+ (33/38 = 87%), BCL6+ (15/25 = 60%), CD57+ (9/16 = 56%)]. Scattered CD20+ B-immunoblasts (27/28 = 96%) and EBV+ cells (18/30 = 60%) are also frequently observed. Seven out of 31 patients (22%) in the 3 morphological patterns have t(5 ;9)(q33 ;q22) detected by fluorescent in situ hybridization. At prentation and/or at relapse, most patients had multiple lymphadenopathies (19/23 = 83%) and disseminated disease (stages III–IV, 22/28 = 79%). Skin lesions and B symptoms were present in 7/19 (37%) and 6/22 (27%) patients, respectively. In addition, 2 patients with sequential biopsies disclosed typical clinical & histopathological features of AITL in one episode. Our results show that this rare form of PTCL has an immunophenotype indicative of TFH origin, is associated with t(5 ;9) in a proportion of cases, shows some similarities in morphology and immunophenotype with AITL, suggesting a relationship, and generates diagnostic pitfalls, especially with atypical reactive lymphoid lesions and some B-cell lymphomas. The use of immunohistochemistry with TFH markers and molecular studies can help to make a correct diagnosis.
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Reimer, Peter, Thomas Ruediger, Florian Weissinger, Hans Konrad Mueller-Hermelink, Andreas Engert, Hermann Einsele, and Martin Wilhelm. "Different Outcome for Angioimmunoblastic T-Cell Lymphoma (AIL) and Peripheral T-Cell Lymphoma Unspecified (PTCL-U) Following Upfront Autologous Stem Cell Transplantation." Blood 108, no. 11 (November 16, 2006): 5431. http://dx.doi.org/10.1182/blood.v108.11.5431.5431.
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Abstract Introduction: Peripheral T-cell lymphomas (PTCL) are rare diseases and optimal treatment strategies still remain to be defined. With the exception of the ALK-positive anaplastic large cell lymphoma (ALCL) that shows a favourable outcome following conventional chemotherapy, PTCL are known for their poorer prognosis compared to aggressive B-cell lymphomas. However, the impact of the different PTCL-subtypes on treatment outcome has not been clearly demonstrated in prospective studies. PTCL unspecified (PTCL-U) and angioimmunoblastic T-cell lymphoma (AIL) represent the most common subtypes of PTCL in Western countries, accounting for approximately 70% of PTCL. We therefore analysed the data of our study on myeloablative radiochemotherapy followed by autologous stem cell transplantation (ASCT) in primary diagnosed PTCL with regard to the main histologic subtypes. Material and Methods: From 06/00 to 06/06 92 patients with confirmed diagnosis of PTCL entered the study. Primary cutaneous PTCL and ALK+ ALCL were excluded from the trial. Main subtypes were PTCL-U (n= 37) and AIL (n= 28) accounting for 65 of the 92 patients (71%). 0f these patients 53 (PTCL, n= 31; AIL, n= 22) were evaluable for the analysis (82%). Results: Median age was 50 years in the PTCL-U and 47.5 years in the AIL group, respectively. The International Prognostic Index (IPI) did not differ in both groups. In the PTCL-U and the AIL group a low/intermediate-low risk was found in 35% and 36%, respectively and a high/intermediate-high risk in 65% and 64%, respectively. There were slightly more patients in stage IV in the AIL group compared to the PTCL-U group (64% versus 53%). In addition, more patients in the AIL group complained of B-symptoms and had bone marrow involvement compared to the PTCL-U group (86% versus 66% and 48% versus 39%, respectively). However, in an intent-to treat analysis only 58% in the PTCL-U group compared to 82% in the AIL group underwent ASCT mainly due to a higher rate of patients with progressive disease in the PTCL-U group. The median overall survival (OS) was 11 months in the PTCL-NOS and 20 months in the AIL group. Regarding only patients undergoing ASCT, the median OS was 13.5 months in the PTCL-U and 25.5 months in the AIL group. Conclusion: Our analysis suggests that patients with AIL, although showing a slightly more unfavourable risk profile at diagnosis, benefit more from upfront autotransplantation than patients with PTCL-U in our study.
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Naji Rad, Sara, Behnam Rafiee, Gagan Raju, Mahdis Solhjoo, and Prachi Anand. "T-Cell Large Granular Lymphocyte Leukemia in a Patient With Rheumatoid Arthritis." Journal of Investigative Medicine High Impact Case Reports 8 (January 2020): 232470962094130. http://dx.doi.org/10.1177/2324709620941303.
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Large granular lymphocyte leukemia (LGL) is a clonal, lymphoproliferative disorder with an indolent disease course. T-cell LGL (T-LGL) is the most common type of LGL driven from T-cell lineage (85%). The coexistence of T-LGL with several types of autoimmune disorders, mostly rheumatoid arthritis (RA), has been reported. Felty’s syndrome (FS) is defined by splenomegaly, low neutrophil count, and destructive arthritis and is usually seen in <1% of patients with RA. About 30% to 40% of patients with FS have been reported to have an expansion of large granulated lymphocytes in the circulation. FS and T-LGL are similar in terms of clinical manifestations, response to immunosuppressive therapy, their smoldering course, and immunogenetic findings, proposing FS and T-LGL with RA might be different aspects of a single disease spectrum. In this article, we present a case with long-standing RA who had never been on DMARD (Disease Modifying Anti-Rheumatic Drugs) treatment found to have constitutional symptoms, neutropenia, and splenomegaly, and the patient was diagnosed with T-LGL.
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Hojo, Akihisa, Hisashi Nakayama, Osamu Aramaki, Tokio Higaki, Masamichi Moriguchi, Masahiko Sugitani, Katsuhiro Miura, et al. "Diagnostic Value of Open Biopsy for Malignant T-Cell Lymphoma of the Liver." International Surgery 98, no. 1 (February 1, 2013): 13–18. http://dx.doi.org/10.9738/cc162.1.
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Abstract A 62-year-old man was referred to our hospital because of pain in the right upper quadrant. Laboratory tests revealed normal levels of tumor markers. Abdominal ultrasonography showed a hypoechoic mass of approximately 9 cm in diameter in the right lobe of the liver. Computed tomography revealed a low-density mass with peripheral enhancement in the posterior segment of the right lobe. Magnetic resonance imaging showed a low-intensity mass on T1-weighted images and a high-intensity mass on T2-weighted images. Abdominal angiography showed enhanced staining only at the periphery of the tumor. An open biopsy was performed and intraoperative examination of frozen sections indicated malignant lymphoma. The histopathologic diagnosis was malignant T-cell lymphoma. After combined chemotherapy, the tumor shrank to 4 cm in diameter. To our knowledge, only 15 cases of malignant T-cell lymphoma have been reported previously. Diagnosis is particularly challenging because this type of tumor has no distinctive imaging characteristics or signs or symptoms. This case emphasizes the need to include malignant T-cell lymphoma in the differential diagnosis and demonstrates the importance of open biopsy in patients with a suspected liver tumor.
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Bi, Xi-wen, Liang Wang, Wen-wen Zhang, Shu-mei Yan, Peng Sun, Yi Xia, Zhi-ming Li, and Wen-qi Jiang. "The pretreatment albumin to globulin ratio predicts survival in patients with natural killer/T-cell lymphoma." PeerJ 4 (March 3, 2016): e1742. http://dx.doi.org/10.7717/peerj.1742.
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Background.The pretreatment albumin to globulin ratio (AGR) has been reported to be a predictor of survival in several types of cancer. The aim of this study was to evaluate the prognostic impact of AGR in patients with natural killer/T-cell lymphoma (NKTCL).Methods.We retrospectively reviewed the available serum biochemistry results for 331 NKTCL patients before treatment. AGR was calculated as albumin/(total protein—albumin), and a cut-off value of 1.3 was used to define AGR as low or high. Survival analysis was used to assess the prognostic value of AGR.Results.A low AGR (<1.3) was associated with significantly more adverse clinical features, including old age, poor performance status, advanced stage, elevated lactate dehydrogenase, B symptoms, and high International Prognostic Index (IPI) and natural killer/T-cell lymphoma prognostic index (NKPI) scores. Patients with a low AGR had a significantly lower 5-year overall survival (44.5 vs. 65.2%,P< 0.001) and progression-free survival (33.1 vs. 57.4%,P< 0.001). In the multivariate analysis, a low AGR remained an independent predictor of poorer survival. Additionally, AGR distinguished patients with different outcomes in the IPI low-risk group and in the NKPI high-risk group.Discussion.Pretreatment AGR may serve as a simple and effective predictor of prognosis in patients with NKTCL.
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Xiao, J., C. Guo, L. Zhai, H. Li, X. Fu, Y. Huang, Y. Huang, et al. "Prognostic value of different B symptoms in upper aerodigestive tract NK/T-cell lymphoma." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e19544-e19544. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e19544.
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e19544 Background: Extranodal NK/T-cell lymphoma (ENKL) is a rare disease originated from NK or toxic T cells. ENKL arising from the upper aerodigestive tract (UNKTL) is a newly recognized subtype and commonly presents with B symptoms. This study is to investigate the prognostic value of different B symptoms in UNKTL. Methods: UNKTL cases with detailed clinical, pathological and prognostic data in our center since 2001 to 2007 were retrospectively analyzed with the major study endpoint of overall survival (OS). Central pathological review was performed. Survival curves were estimated by Kaplan-Meier method and tested by Log Rank method. Statistically significant factors in univariate analysis were then included in multivariate analysis. B symptoms were defined as fever, night sweat and weight loss according to the Ann Arbor Cotswolds meeting. The predictive values of survival for each type of B symptoms were studied independently. Results: 172 cases of UNKTL with a median follow-up duration of 27.4 months were included. 45 ladies and 127 gentlemen had a median age of 43 years. 98 cases were Ann Arbor stage I, 54 were stage II and the remaining 20 cases were stage III or IV. About half of the patients present B symptoms: 82 had fever, 5 had night sweat and 6 present weight loss. Totally 18 patients had ECOG PS larger than 1. The 5-year OS rate of the whole group is 41.8%. Patients with persistent fever before treatment indicated a poor outcome in the univariate analysis (p=.033) and its prognostic value was also confirmed by the Cox regression (p=.030) whereas those of night sweat and weight loss were not (p= .960 and .824 respectively). Conclusions: B symptoms were common in UNKTL patients. Our data suggested that only fever among the three types of B symptoms was independent prognostic factor for UNKTL but it still needs further confirmation. No significant financial relationships to disclose.
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Turner, Jackson S., Tingting Lei, Aaron J. Schmitz, Aaron Day, José Alberto Choreño-Parra, Luis Jiménez-Alvarez, Alfredo Cruz-Lagunas, et al. "Impaired Cellular Immune Responses During the First Week of Severe Acute Influenza Infection." Journal of Infectious Diseases 222, no. 7 (May 5, 2020): 1235–44. http://dx.doi.org/10.1093/infdis/jiaa226.
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Abstract Background Cellular immune responses are not well characterized during the initial days of acute symptomatic influenza infection. Methods We developed a prospective cohort of human subjects with confirmed influenza illness of varying severity who presented within a week after symptom onset. We characterized lymphocyte and monocyte populations as well as antigen-specific CD8+ T-cell and B-cell responses from peripheral blood mononuclear cells using flow cytometry and enzyme-linked immunospot assays. Results We recruited 68 influenza-infected individuals on average 3.5 days after the onset of symptoms. Three patients required mechanical ventilation. Influenza-specific CD8+ T-cell responses expanded before the appearance of plasmablast B cells. However, the influenza-specific CD8+ T-cell response was lower in infected subjects than responses seen in uninfected control subjects. Circulating populations of inflammatory monocytes were increased in most subjects compared with healthy controls. Inflammatory monocytes were significantly reduced in the 3 subjects requiring mechanical ventilation. Inflammatory monocytes were also reduced in a separate validation cohort of mechanically ventilated patients. Conclusions Antigen-specific CD8+ T cells respond early during acute influenza infection at magnitudes that are lower than responses seen in uninfected individuals. Circulating inflammatory monocytes increase during acute illness and low absolute numbers are associated with very severe disease.
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Qian, Shenxian, Pengfen Shi, DaQian Gao, Kuang Chen, Junfeng Tan, LiRong Liu, and Yaping Xie. "Nasal-Type NK/T Cell Lymphoma: Clinical Features, Immunophenotype and Treatment Outcome." Blood 112, no. 11 (November 16, 2008): 5296. http://dx.doi.org/10.1182/blood.v112.11.5296.5296.
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Abstract The clinical characteristics and prognosis remain unclear for nasal-type NK/T-cell lymphoma. The aim of this study is to determine the clinical features and outcome. 26 patients diagnosed as nasal-type NK/T cell lymphoma were included in the analysis. Immunophenotype was analyzed by immunohistochemical staining for LCA, CD79α, CD20, CD56, CD3, CD45RO, All the cases of nasal NK/T cell lymphoma were LCA, The positivity rates of CD45RO and CD56 were 89.8%, and 66%, respectively. Tumor cells didn’t express antigens of B and histiocyte, According to Ann Arbor system, 2, 7, 12, and 5 patients had stage I, II, III, and IV. 24 patients received combined chemotherapy(CHOP plus Ara-c) and radiotherapy, and 2 patients received chemotherapy alone. The disease is characterized by predominant young males, a propensity for nodal involvement, frequent stage II–III diseases, low frequency of elevated LDH, low-risk international prognostic index (IPI), high sensitivity to radiotherapy, and intermediate sensitivity to chemotherapy. The 3-year overall survival and progression-free survival for all patients were 88% and 71%, respectively The age, B symptoms, stage, and IPI were important prognostic factors. Combined chemotherapy(CHOP plus Ara-c) and radiotherapy tended to improve the survival for patients with stage and II or III diseases. The distant extranodal dissemination were the primary failure patterns. nasal-type NK/T-cell lymphoma appears to have distinct clinical characteristics and favorable outcomes.
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Choi, Yong Won, Jung Il Park, Jae Ho Jung, Sung Heun Jeong, Hyun Woo Lee, Jae Ho Han, Seon Yong Jeong, et al. "Extranodal NK/T-Cell Lymphoma: A Comparative Clinicopathological Study According to Survival Outcome." Blood 110, no. 11 (November 16, 2007): 4413. http://dx.doi.org/10.1182/blood.v110.11.4413.4413.
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Abstract BACKGROUND Extranodal NK/T-cell lymphoma is notable for its unique behavior; Many patients die before 1 year from the diagnosis. However, the patients who survive the first year from the diagnosis live for longer period. Known prognostic factors were insufficient to explain this unique pattern. The objective of this study was to investigate clinicopathological features according to survival outcome(OS<1 yr vs OS ≥1 yrs). METHODS We reviewed 28 patients who diagnosed as extranodal NK/T cell lymphoma from March, 1995 to July, 2006. Patients were treated with chemotherapy alone or chemoradiotherapy. Real-time PCR was done from the tissue of the biopsy specimen to quantify the Epstein-Barr virus load. RESULTS Of the 28 patients, 14 patients(50%) achieved a complete remission(CR). Median survival was 46 months(range, 1–114 months). The B symptoms, IPI score, stage, ECOG status, first treatment response was significant prognostic factor (P<0.05). However ECOG status the only significant prognostic factor by using mutivariate analysis (P=0.001). Seventeen patients (61%) expired; 12 of those patients died during the first year of diagnosis. Thus we divided them into 2 groups; who lived more than 1 year and who lived less than 1 year. The ECOG status, first treatment response rate was different between the two groups significantly(p<0.05). All patients showed positive EBV by PCR. However, there was no significant difference in EBV load between these two groups. (p=0.113) CONCLUSION The ECOG status, and response to the first treatment related to the survival of first year from the diagnosis. For the patients with poor performance status, and failure to achieve CR after the first treatment, more aggressive treatment should be considered to improve survival. In our study, EBV load measured on the paraffin tissue failed to correlate with survival. Univariate Analysis of Overall survival Prognostic Factors Median OS(months) P value Age >60yrs 33 <60yrs 10 0.783 Type Nasal 33 Nasal type 5 0.225 B symptom Yes 5 No 42 0.021 IPI Low/Low-intermediate 42 High-intermediate/High 2 0.002 Stage I/II 42 III/IV 2 0.001 ECOG 0,1 45 2,3,4 2 0.001 LDH Normal 33 High 17 0.720 EBV load(copies/ug DNA)(n=22) 46 0.228 Treatment C/T alone 5 C/T and R/T 42 0.196 treatment response CR 45 No-CR 14 0.0127 Multivariate Analysis of Overall survival Prognostic Factors Hazad Ratio 95% CI P B symptom No 1.00 Yes 0.97 0.11–8.58 0.980 IPI score Low/Low-inermediate 1.00 High-intermediate/High 1.35 0.25–7.26 0.730 Stage I,II 1.00 III,IV 0.60 0.06–6.12 0.668 ECOG 0,1 1.00 2,3,4 6.94 2.23–21.55 0.001 Treatment response CR 1.00 No-CR 1.98 0.56–6.96 0.287 Fig. 2 Overall survival according to survival outcome (OS<1 year vs OS ≥ 1 years). The patients who survive more than 1 year showed relativily good prognosis. Fig. 2. Overall survival according to survival outcome (OS<1 year vs OS ≥ 1 years). The patients who survive more than 1 year showed relativily good prognosis.
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Kwiatkowska-Borowczyk, Eliza P., Anna Kozłowska, Klaudia Maruszak, Luiza Kańczuga-Koda, Mariusz Koda, Monika Dajnowiec, Andrzej Mackiewicz, and Dariusz W. Kowalczyk. "Adoptive transfer of tumor specific T cells from allogeneic donors is feasible, effective and safe alternative to autologous T cell based tumor immunotherapy." Journal of Medical Science 83, no. 1 (March 30, 2014): 21–28. http://dx.doi.org/10.20883/medical.e39.
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Donor lymphocyte infusion is used to increase the graft versus tumor (GVT) effect after allogeneic hematopoietic cell transplant. The limited spectrum of activity and high risk of graft versus host disease (GVHD) remain major limitations of this approach. The finding of new cell populations for adoptive immunotherapy, with the ability to separate GVT from GVHD, would be useful. In the present manuscript, we tested in mouse model the use of allogeneic MHC partially matched effector cells for adoptive T cell immunotherapy of cancer. We sought to maximize graft-versus-tumor effect while minimizing GVHD using tumor-specific allogeneic effector T cells rather than open-repertoire T cells. A F1 hybrid (Balb/c x C57BL/6) -MethA-EGFP–bearing mice received a preparative regimen of nonmyeloablating cyclophosphamide lymphodepletion followed by adoptive transfer of bulk Balb/c derived allogeneic T cells specific for the MethA-EGFP tumor cells. Adoptively transferred allogeneic tumor-specific T lymphocytes prevented tumor formation without graft versus host disease – like symptoms. We found that the risk of GVHD was low even with high number of transferred tumor-specific T cells. These data indicate that the use of tumor-specific allogeneic T cells is feasible, effective and safe alternative to autologous T cell based tumor immunotherapy.
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Rivas-Vera, Silvia, Mabel Oropeza-Borges, and Pedro Sobrevilla-Calvo. "T- Cell Non-Hodgkin's Lymphoma, Data From a Mexican Tertiary Health Center.." Blood 114, no. 22 (November 20, 2009): 5030. http://dx.doi.org/10.1182/blood.v114.22.5030.5030.
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Abstract Abstract 5030 Introduction T cell Non/Hodgkin's lymphomas (TCNHL) are a group of lymphomas characterized by an aggressive clinical course and resistance to the usual chemotherapy agents. Due to the limited availability of immunochemistry techniques the frequency and clinical presentation of these lymphomas are not well described in underdeveloped countries. Here we describe the experience with these diseases in a tertiary referral health center. Patients and methods We reviewed 520 cases with diagnosis of Non-Hodgkin's Lymphoma from the records of the Pathology Department of the Hospital General de Mexico, seen from January 2002 to July 2006. Results We found 80 cases with TCNHL (15.3%). In 62 cases the clinical information was available for review. We found a 1.45:1 male/female ratio, median age 32 years (range 17 to 83). Symptoms were present for a median of 6 months (range 1 to 120 months) before diagnosis. Regarding the pathological classification the Unspecified Peripheral T-cell lymphomas were more common (56%), followed by the anaplastic lymphoma (23%), T/NK (16%), Cutaneous lymphoma (3%) and angioimmunoblastic lymphoma (2%). In 56% the initial presentation was nodal and in 44% extranodal. The extranodal sites were: Nasal (34%), bone marrow (22%), pleura and lung (14%), parotid (5%), colon (5%), and liver (5%). Sixty seven percent of the patients had advanced clinical stages and 73% had at least 3 B symptoms. One quarter of patients had bulky disease at their first visit to our Hospital; the most frequent site was retroperitoneal (19%). The lactic dehydrogenase (LDH) was elevated in 89% of cases (range:97 U/L -3017 IU L, median 418 U/L); patients with anaplastic NHL had the highest values and NHL-TNK patients the lowest. HIV serology was performed in 41 of 62 patients. Ninety four percent of the patients had an ECOG between 1 and 3. We calculated the International Prognostic Index (IPI); it was low in 23 patients (37%), low-intermediate in 18 (29%), intermediate-high in 16 (26%) and high in just 5 patients (8%). When we classified the patients with the Prognostic Index for non-specific peripheral T-NHL (PIT or PTCL-L), we found that 79.4% of cases were in the high-risk group in contrast with 73.6% low group according to IPI. All patients were treated with CHOP chemotherapy. A complete response (CR) was achieved in 10 patients (16%); 13 patients (21%) were still on treatment at the end of the study, 4 patients (6.45%) did not respond to treatment and 14 patients (24.1%) had progressive disease. Ten patients discontinued treatment (16%) and 5 died (8.06%). At the end of the observation period 8 patients were alive without tumor activity, 2 patients were lost without tumor activity, 7 patients were alive with disease, 24 patients were missing with tumor activity, 9 patients were on treatment and 12 patients had died. Conclusions This study shows that in Mexico as in other populations, the TCNHL are less frequent than the B-cell lymphomas. It also confirms the poor response of the T-Cell lymphomas to CHOP. The population that attends our hospital is of a low socioeconomic stratum, and this fact explains the large abandonment of medical care. It is desirable the development of new drugs for these neoplasia. Disclosures No relevant conflicts of interest to declare.
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Inoue, Norihito, Noriko Nishimura, Anna Takahashi, Hirofumi Yamauchi, Yoshiharu Kusano, Kyoko Ueda, Yuko Mishima, Masahiro Yokoyama, Yasuhito Terui, and Kiyohiko Hatake. "Retrospective Analysis of NK/T Cell Lymphoma Prognostic Index (NKPI), EBV-DNA and Soluble IL-2 Receptor (sIL2R) for Extranodal NK/T-Cell Lymphoma, Nasal Type." Blood 128, no. 22 (December 2, 2016): 5360. http://dx.doi.org/10.1182/blood.v128.22.5360.5360.
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Abstract Introduction Extranodal NK/T cell lymphoma (ENKTL) is a rare aggressive lymphoma, and more prevalent in Asians, Mexico, Central America, and South America. ENKTL relates to Epstein-Barr Virus (EBV) reactivation, and occurs most often in adults. The prognosis of ENKTL relates to NK/T Cell Lymphoma Prognostic Index (NKPI), which includes presence of B symptom, elevated serum lactate dehydrogenase (LDH), stageⅢ or Ⅳ, and regional lymph node involvement. Recently, EBV-DNA level is known to be an important prognosis factor of ENKTL. We retrospectively analyzed relationship among NKPI, EBV-DNA level and other factors in patients with ENKTL. Patients and methods We analyzed the data of ENKTL patients who were diagnosed and treated at our hospital from April 2007 to July 2016, retrospectively. Data of the blood test and EBV-DNA level, when we diagnosed were also analyzed. PET-CT examination was performed for staging of ENKTL before treatment. The event-free survival (EFS) and overall survival (OS) were estimated using Kaplan-Meier method. Results A total of 26 ENKTL patients (14 male, 12 female) were analyzed. All patients were treated with radiation therapy (RT) and 2/3DeVIC (dexamethasone 40mg/body days 1 through 3, ifosfamide 1000mg/m² days 1 through 3, carboplatin 200mg/m² day 1, etoposide 67mg/m² days 1 through 3). Median age was 58 years old (range; 18-77 years old). Median OS was 17 months (range; 1-105 months), and EFS was 12 months (range 1-105 months). Seven patients had B symptoms, and serum LDH level (median 192.5 U/L, range 153-540 U/L) was elevated in 10 patients at diagnosis. The patients with stage Ⅰ, Ⅱand Ⅳ were 19, 5, and 2 patients, respectively. The patients with stage Ⅳ were treated with RT and 2/3DeVIC, because patient's performance status, age or other factor is not good. According to the NKPI, the patients were stratified into low score (10 patients), low intermediate (13 patients), and high intermediate (3 patients). In our analysis, 2 year-EFS (p=0.125) was not changed among all score groups o However,, low score group was associated with better 2 year-OS (p=0.0734) than intermediate and high score groups. Twenty patients were tested EBV-DNA level at diagnosis. Median EBV-DNA at diagnosis was 113.5 copies/10⁶WBC (range; 0-38000 copies/10⁶WBC). We analyzed relationship between the prognosis and EBV-DNA level. However, EBV-DNA level (EBV-DNA cut-off; 140 copies/10⁶WBC ) was not related to 2 year-OS (p=0.838) and 2 year-EFS (p=0.686). Twenty-six patients were tested serumβ2-microglobulin (β2MG) and soluble IL-2 receptor (sIL2R). Serum β2MG level (median; 2.035 mg/l , range; 1.10-4.95 mg/l) was increased in 13 patients, and serum sIL2R level (median; 543 U/ml, range; 264-2490 U/ml) was increased in 14 patients. β2MG level was not related to 2 year-OS (p=0.152) and 2 year-EFS (p=0.181). Low sIL2R level was associated with better OS (p=0.0445) and EFS (p=0.0793) than high level. Discussion NKPI score and serum sIL2R were related to the prognosis of patients with ENKTL with early stage, although EBV-DNA copies were not related to the prognosis. Disclosures Nishimura: Chugai: Consultancy. Mishima:Chugai: Consultancy. Yokoyama:Chugai: Consultancy. Terui:Yanssen: Honoraria. Hatake:Chugai: Research Funding; Meiji-Seika: Consultancy; Otsuka: Consultancy; Kyowa Kirin: Honoraria, Research Funding.
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Broussais, Florence, Diane Coso, Vadim Ivanov, Thérèse Aurran, Anne-Marie Stoppa, and Reda Bouabdallah. "A Restrospective Review of Peripheral T-Cell Lymphoma in a Single Institution Between 2000 and 2010." Blood 118, no. 21 (November 18, 2011): 1623. http://dx.doi.org/10.1182/blood.v118.21.1623.1623.
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Abstract Abstract 1623 Background: Peripheral T-cell non-hodgkin lymphomas (NHL) comprise a heterogeneous group of malignancies, characterized by an aggressive disease course and a poor clinical outcome. T-cell lymphomas present in lymph nodes and they also frequently involve extra nodal sites. The first line treatment consists in CHOP-like regimen. Consolidation treatment in first line or in relapse is autologous stem cell transplantation (ASCT) or allogenic stem cell transplantation (SCT). Patients and methods: We retrospectively analysed the data of 189 adults who had received chemotherapy in our institution between 2000 and 2010. Results: Median age at time of presentation was 55 (range 17–89) years, 76% were <65 years. 50% had B symptoms and 50% serum elevated LDH. ECOG was 0–1 in 60% and 2–4 in 40%. According to the Ann Arbor classification, 15% were stage I-II and 85% were stage III-IV. 50% had low IPI (0-1-2) and 50% had elevated IPI (3-4-5). The histologic subtypes were 42% peripheral T-cell NHL unspecified (PTCL-U), anaplastic large cell lymphoma (ALCL), 8% had ALK+ and 10% had ALK-, 24% angioimmunoblastic lymphoma (AILT), 3% transformed mycosis fungoide, 2% instestinal T-cell lymphoma, 2% hepatosplenic γδ T-cell lymphoma and 1% adult T-cell lymphoma/leukemia. Primary extranodal lymphoma represented 17% and 8% were diagnosed with hemophagocytosis. Five-year overall survival (OS) was 28.3% (21.8–36.8%), and five-year progression free survival (PFS) was 18.4% (13.1–25.7%). On multivariate analysis, ALCL-ALK+ (p=0.008), AILT (p<0.001), extranodal involvement (p=0.01), PS>1 (p<0.001), LDH>N (p=0.003) were independent adverse factors for OS. Moreover B symptoms (p<0.01) was a significant factor for PFS. 86% received CHOP-like induction treatment. The median number of chemotherapy was 2 (1–7). 59% experienced a complete response during the therapeutic procedure, while 22% were primary refractory. 44% had ASCT and 14% allogenic SCT. Only 28% of patients referred for allogenic SCT received this treatment. Conclusions: This 10-year review of patients treated in a single institution with initial conventional chemotherapy followed by more intensive treatments confirms the poor OS and PFS in the case of T-cell lymphoma. Despite a low incidence, T-cell lymphoma could be a priority area of research for new treatments with a potential to improve OS and PFS. Disclosures: No relevant conflicts of interest to declare.
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Lee, Thomas C., Saurabh Mehandru, Okebugwu Kamalu, Lisa Malter, Martin Markowitz, and Michael A. Poles. "W1203 Despite Mucosal CD4+ T Cell Depletion, the Prevalence of GI Symptoms Is Low During Acute and Early HIV-1 Infection." Gastroenterology 134, no. 4 (April 2008): A—654. http://dx.doi.org/10.1016/s0016-5085(08)63053-x.
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dos Santos Virgilio, Fernando, Camila Pontes, Mariana Ribeiro Dominguez, Jonatan Ersching, Mauricio Martins Rodrigues, and José Ronnie Vasconcelos. "CD8+T Cell-Mediated Immunity duringTrypanosoma cruziInfection: A Path for Vaccine Development?" Mediators of Inflammation 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/243786.
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MHC-restrictedCD8+T cells are important during infection with the intracellular protozoan parasiteTrypanosoma cruzi, the causative agent of Chagas disease. Experimental studies performed in the past 25 years have elucidated a number of features related to the immune response mediated by these T cells, which are important for establishing the parasite/host equilibrium leading to chronic infection.CD8+T cells are specific for highly immunodominant antigens expressed by members of thetrans-sialidase family. After infection, their activation is delayed, and the cells display a high proliferative activity associated with high apoptotic rates. Although they participate in parasite control and elimination, they are unable to clear the infection due to their low fitness, allowing the parasite to establish the chronic phase when these cells then play an active role in the induction of heart immunopathology. Vaccination with a number of subunit recombinant vaccines aimed at eliciting specificCD8+T cells can reverse this path, thereby generating a productive immune response that will lead to the control of infection, reduction of symptoms, and reduction of disease transmission. Due to these attributes, activation ofCD8+T lymphocytes may constitute a path for the development of a veterinarian or human vaccine.
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Singh, Anju, Anne Flörcken, Antje van Lessen, Bernd Dörken, Antonio Pezzutto, and Jörg Westermann. "CD3-Negative CD4+ T-Cells: A Useful Diagnostic Tool with High Specificity in Angioimmunoblastic Lymphadenopathy (AILD)-Type T-Cell Lymphoma." Blood 112, no. 11 (November 16, 2008): 5311. http://dx.doi.org/10.1182/blood.v112.11.5311.5311.
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Abstract Angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma is one of the common T cell lymphomas in Western countries. Many patients present with symptoms of a systemic disease and diagnosis can often be challenging. Particularly in cases in which histological confirmation cannot be easily achieved flowcytometry of peripheral blood can give important clues for the differential diagnosis of AILD. We have previously reported that CD4-negative CD3+ T-cells in peripheral blood are a characteristic immunophenotypic finding in AILD patients. Gene scan analysis for the TCR gamma chain and intracellular CD3 expression clearly showed that these CD3-negative CD4+ cells are of T cell origin. In this study we further evaluated the phenotype of the CD4− CD3+ T cells and we compared their frequency in AILD patients with the frequency in patients with other histologically confirmed leukemic T cell lymphomas. 14 patients with AILD (clinical stage III/IV) were compared with 26 patients with other subtypes of leukemic T cell lymphomas (6 T-large granular lymphocyte leukemias (T-LGL), 4 T-chronic lymphocytic leukemias/prolymphocytic leukemias (T-CLL/PLL), 5 anaplastic large cell lymphomas (ALCL), 1 adult T-cell leukemia/lymphoma (ATLL), 1 mycosis fungoides and 9 peripheral T-cell lymphomas. Flowcytometric analysis of peripheral blood was performed in a lymphocyte gate using fluorochrome-labeled antibodies against CD3, CD2, CD4, CD5, CD7, CD8, CD16, CD56, CD57 and TCR. In 14/14 AILD patients a small but distinct population of CD3-negative CD4+ T cells was found (mean percentage of CD3-negative CD4+ T cells in the gate: 12,0 ± 17,6 %, range 0,05 – 51,8 %). In contrast, CD3-negative CD4+ T cells could be detected in only 1/26 patients with other leukemic T cell lymphomas. This patient had been diagnosed with mycosis fungoides. Further immunophenotypic analysis showed that the aberrant T cells in AILD also express pan T cell markers, such as CD2, CD5 and partially CD7, surface TCR expression could not be detected. In conclusion our comparative study shows that flowcytometric detection of CD3-negative CD4+ T cells in peripheral blood is a characteristic feature of AILD with a high specificity. Therefore, flowcytometry is particulary useful in the differential diagnosis of AILD, even if the aberrant T cell population has a very low frequency. Although AILD is mostly CD3+ on immunohistochemistry, the presence of low numbers of CD3-negative CD4+ T cells in peripheral blood appears to be a typical feature of AILD. Cytoplasmic CD3-expression is one possible explanation for this discrepancy. Since complete or partial loss of pan T cell antigens is a characteristic feature of many T cell lymphomas, the aberrant CD3-negative CD4+ T cells might also represent just a subfraction of lymphoma cells in AILD. Further biological characterization of this subpopulation should be performed.
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Beltran, B. E., D. Morales, P. Quiñones, R. Salas, and J. Castillo. "Analysis of prognostic factors in patients with adult T-cell leukemia/lymphoma." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 8575. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.8575.
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8575 Background: Adult T-cell leukemia/lymphoma (ATLL) is associated with human T-cell lymphotropic virus type-I (HTLV-1) described in Southern Japan, Europe, Caribbean and South America. Risk-stratification tools for ATLL have not been adequately evaluated. This study attempts to define prognostic factors for patients with ATLL. Methods: A total of 102 cases from our Institution were collected between January 1997 and September 2008. Diagnosis was based on clinical history and histological findings consistent with ATLL and either positive HTLV-1 serology or evidence of HTLV-1 integration. Survival curves were estimated using the Kaplan-Meier method. Univariate and multivariate analyses were evaluated using log-rank and Cox regression tests, respectively. Results: Median age was 61 years with a female:male ratio of 1.15:1. Clinical types were acute (n=45), lymphomatous (n=43), cutaneous (n=10), smoldering (n=3) and chronic (n=1). Median OS for acute, lymphomatous, smoldering and cutaneous subtype were 2, 11, 17 and 39 months, respectively (log-rank 28.5, p<0.00001). In the univariate analysis, presence of B symptoms, ECOG performance status 2, clinical stage II or higher, elevated LDH level and bone marrow (BM) involvement were independent factors for survival with p<0.05. The IPI score was available in 92 patients; 13 (14%), 12 (13%), 29 (32%) and 38 (41%) patients were low, low-intermediate, high-intermediate and high-risk, respectively. Median OS by IPI risk group was 40, 13, 6 and 2 months, respectively (p<0.005). The prognostic index for T-cell lymphoma (PIT) score was determined in 80 patients; 20 (25%), 17 (21%), 33 (41%) and 10 (13%) patients had scores of 0–1, 2, 3 and 4, respectively. Median OS by PIT risk group was 19, 5, 3 and 2 months, respectively (p<0.005). In multivariate analysis, BM involvement and elevated LDH were significant for survival. Conclusions: This retrospective series represents the largest Latin-American experience on ATLL, which is a heterogeneous disease with distinct clinical features and outcomes. The IPI ant PIT scores, used for risk-stratification of aggressive B-cell and peripheral T-cell lymphomas, respectively, appear as good prognostic indicators for ATLL as well. Further research is needed to better risk-stratify this unique lymphoma. No significant financial relationships to disclose.
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Nogueira, Daniel Silva, Marcia Torresan Delamain, Eliana Cristina Miranda, Yung Bruno de Melo Gonzaga, Juliana Pereira, Renata Lyrio, Marcelo Bellesso, et al. "Adult T-Cell Leukemia/Lymphoma: A Cohort of 41 Cases Recorded in the Brazilian T-Cell Project." Blood 136, Supplement 1 (November 5, 2020): 35–36. http://dx.doi.org/10.1182/blood-2020-142818.
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Introduction:Adult T cell Leukemia/Lymphoma (ATLL) is a mature T-Cell-neoplasm related to human T-cell lymphotropic virus type 1 (HTLV-1) infection that shows variable clinical presentation and adverse prognosis with shorter overall survival (OS) when compared to other peripheral T-cell lymphomas (PTCL). Previous epidemiological studies estimated cumulative incidence in endemic regions around the world. In Brazil, mainly due to its vast dimension, data collection has limitations and is subject to bias. In April 2015 theBrazilianT-cell longitudinal project initiative was launched. One of the primary purposes was the collection of epidemiological and clinical data from the most frequent subtypes of newly diagnosed PTCL. Among them, 41 cases of ATLL were recorded. Objectives:The aim of this study is to describe clinical features, frequency and overall survival (OS) of 41 cases of ATLL registered in the ongoingBrazilianT-Cell Project. Methods:This is an ambispective observational study design collecting baseline characteristics, clinical features including date of diagnosis, clinical subtypes, B symptoms, performance status, Ann-Arbor staging, HTLV-1 status, number of sites, nodal and extra nodal presentation and types of skin lesions, peripheral blood counts and biochemical tests, front-line treatment and best response after first-line treatment. REDcap Platform has been used to collect and store data and for descriptive analysis the IBM-SPSS version 24 was applied. Kaplan-Meier method estimated the OS, whereas Log-Rank tests to compare its curves. OS period was calculated from diagnosis date until death or last seen date, and event was death by any cause. Results:Out of 281 cases of PTCL registered so far, 41 were ATLL cases. The median age was 50 years (34-88), 25 (64%) female; a higher incidence of lymphoma subtype was observed (46%), followed by acute (29%), chronic (17%) and smoldering (8%). Most of the patients (85%) had advanced-stage disease (III-IV, Ann-Arbor) and 56% had B symptoms (Table 1); 73% received chemotherapy with anthracycline-based regimens (46.5% CHOEP; 33.5% CHOP; 20% others) whereas 17% were managed with immunotherapy and antiviral therapy. The overall response rate was 30%; no response or progression 46%; stable disease 9% and 15% no data available yet (Table 2). Median follow-up was 13 months and 25 months for 41% of alive patients. Two year OS was 39% (95%CI: 23-55%) (Figure 1). Smoldering and Chronic subtypes showed better OS when compared with acute and lymphoma (100% smoldering, 86% chronic; 30% lymphoma type and 13% acuteP=0.04) (Figure 2). The multivariate Cox Regression analysis found male gender (HR 10.9 95%CI: 3.0-39.7, P<0.0001) and albumin (HR 0.23 Beta -1.45 95%CI: 0.10-0.55, P=0.001) as significant prognostic factors for OS. Discussion:ATLL prognosis remains poor regardless of the type of treatment regimen and may be associated with the high incidence of lymphoma and acute subtypes, as well as advanced stage disease presentation. Despite the high number of cases seen in southeastern region of Brazil, it is important to emphasize there are still limited data from other regions. Albeit the sample size is small, these findings confirmed literature review data so far, with poor overall survival in a short time and gender and albumin as predictors of OS in the multivariate analysis. Conclusion:This study highlights the poor prognosis associated with ATLL. Moreover, it seems relevant to expand this study to all Brazilian regions. Hence, the need for early diagnosis and new treatment strategies, able to reduce mortality is warranted, that could possibly change the nature and spectrum of disease. Disclosures Federico: Spectrum:Consultancy, Membership on an entity's Board of Directors or advisory committees;Sandoz:Consultancy, Membership on an entity's Board of Directors or advisory committees;Cephalon/Teva:Research Funding;Mundipharma s.r.l.:Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Millennium/Takeda:Research Funding;Roche:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda:Consultancy, Membership on an entity's Board of Directors or advisory committees.
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Li, Ye-Xiong, Hui Fang, Qing-Feng Liu, Jiade Lu, Shu-Nan Qi, Hua Wang, Jing Jin, et al. "Clinical features and treatment outcome of nasal-type NK/T-cell lymphoma of Waldeyer ring." Blood 112, no. 8 (October 15, 2008): 3057–64. http://dx.doi.org/10.1182/blood-2008-05-160176.
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Abstract The clinical characteristics and prognosis remain unclear for nasal-type NK/T-cell lymphoma of Waldeyer ring (WR-NKTL). The aim of this study is to determine the clinical features and outcome. Ninety-one patients with WR-NKTL were reviewed. According to the Ann Arbor system, 15, 56, 12, and 8 patients had stage I, II, III, and IV. Of patients with stage I and II, 54 received combined chemotherapy and radiotherapy (CMT), 13 received radiotherapy alone, and 4 patients received chemotherapy alone. All 20 patients with stage III/IV received primary chemotherapy. The disease is characterized by predominance in young males, good performance, a propensity for nodal involvement, frequent stage II through IV diseases, low frequency of elevated LDH, low-risk international prognostic index (IPI), high sensitivity to radiotherapy, and intermediate sensitivity to chemotherapy. The 5-year overall survival and progression-free survival for all patients were 65% and 51%, respectively. The age, B symptoms, stage, and IPI were important prognostic factors. CMT tended to improve the survival compared with radiotherapy alone for patients with stage I and II diseases. Both nodal involvement and distant extranodal dissemination were the primary failure patterns. WR-NKTL appears to have distinct clinical characteristics and favorable outcomes.
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Beltran, Brady, Domingo Morales, Pilar Quinones, Carlos Desposorio, Lubomir Sokol, and Jorge Castillo. "Prognostic Factors in Aggressive, Non-Primary Cutaneous Peripheral T-Cell Lymphoma in Peru: A Study of 227 Cases." Blood 114, no. 22 (November 20, 2009): 5021. http://dx.doi.org/10.1182/blood.v114.22.5021.5021.
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Abstract Abstract 5021 Background Peripheral T-cell lymphoma (PTCL) is a heterogeneous family of entities with a worse prognosis, stage by stage, than their B-cell counterparts. We have previously reported that Peruvian population has a higher incidence of PTCL, akin to the Asian population. The goal of this study is to therefore investigate the clinical characteristics and prognostic factors in patients with PTCL in a reference center in Peru. Methods A total of 227 cases of aggressive, non-primary cutaneous PTCL diagnosed between January 1997 and December 2008 were reviewed, reappraised according to their morphological, immunological and clinical characteristics, and reclassified according to the new WHO classification of lymphoid neoplasms. Kaplan-Meier method was used to estimate survival curves, which were compared using the log-rank test. The multivariate analysis was performed using the Cox proportional-hazard regression test. Results The mean age at diagnosis was 57 years (range 14 – 92 years) with a male-to-female ratio of 1:1. According to the new WHO classification of lymphoid neoplasms, 97 cases (43%) were classified as adult T-cell leukemia/lymphoma (ATLL), 84 cases (37%) as PTCL, unspecified (PTCLU), 28 cases (12%) as anaplastic large cell lymphoma (ALCL), 10 cases (4%) as extranodal NK/T lymphoma, nasal type, 4 cases (2%) as angioimmunoblastic lymphoma and 3 cases (1%) were diagnosed with more rare PTCL subtypes. Fifteen percent were stage I, 12% stage II, 16% stage III and 56% stage IV. Distribution based on the International Prognostic Index (IPI) score was: low 24%, low-intermediate 24.5%, intermediate-high 26% and high 25.5%. B symptoms were present in 64% of patients. The median overall survival (OS) for the whole group was 8.4 months, the 2-year OS was 34% and the 5-year OS was 27%. ATLL patients showed a median overall survival of 6.1 months, PTCL of 11.4 months, ALCL of 12.4 months and extranodal NK/T cell lymphoma of 7.8 months. The IPI score, the Prognostic Index for PTCLU (PIT) score and the presence of B symptoms showed statistical significance in both the univariate and the multivariate survival analysis (p=0.001, p=0.005 and p=0.005, respectively). Conclusions The distribution of PTCL subtypes in Peru is comparable to the series of patients reported in Asian countries. ATLL and PTCL-U are the most frequent aggressive, non-primary cutaneous PTCL subtypes found. PTCL tends to present with advanced stages and has a poor prognosis, with a 5-year OS of less than 30%. In the multivariate analysis, the IPI score, the PIT score and presence of B symptoms were independent prognostic factors for survival in PTCL. Disclosures No relevant conflicts of interest to declare.
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Pinter-Brown, Lauren, and Anna Kozlovski. "Effect of Denileukin Diftitox on Pruritus and Other Skin-Related Symptoms Vs Placebo In Patients with Cutaneous T-Cell Lymphoma." Blood 116, no. 21 (November 19, 2010): 4922. http://dx.doi.org/10.1182/blood.v116.21.4922.4922.
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Abstract Abstract 4922 Introduction. Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin's lymphomas (NHLs) that develop primarily in the skin but may progress to involve lymph nodes, blood, and visceral organs. CTCL is characterized by skin patches, plaques, tumors, and erythroderma. Pruritus is frequently associated with skin lesions in CTCL and may be severe. Some treatments have been noted to produce improvements in pruritus that appears to be independent of the response rate. Denileukin diftitox (DD, Ontak), a recombinant fusion protein targeting IL-2-receptor-expressing T lymphocytes, has demonstrated a significant effect on overall response rate with minimal immunosuppression in patients with CD25 assay-positive CTCL. For this post-hoc analysis, we used data from a randomized, double-blind, placebo-controlled, phase III clinical trial to assess the effect of DD on pruritus and overall skin condition in patients with CTCL. Patients and methods. Patients with CD25 assay-positive, stage Ia to III CTCL were randomized to receive 9 μg/kg/d DD (n=45), 18 μg/kg/d DD (n=55), or placebo (n=45). Study medications were administered on the first 5 days of a 21-day cycle for up to 8 cycles. Four grading scales were used to assess clinical signs and symptoms (Table 1). Results. Higher percentages of DD-treated patients experienced clinically significant improvements in skin-related symptoms than did patients on placebo during treatment and follow-up (Table 2). The differences between the proportions of patients in the placebo group experiencing clinically significant improvement and the proportions of those in the 18 μg/kg/d and combined DD dose groups were statistically significant for all 4 assessments. Substantially more DD-treated patients had ≥20% and ≥50% improvement in pruritus (relative to baseline) at any time than those receiving placebo; improvements were maintained for ≥6 weeks. The global skin score improvement and pruritus score improvement in both high dose and low dose groups were significantly correlated, with higher correlation in high dose group compared to low dose group (p=0.0004 vs p=0.0381). There is no correlation in placebo group for the two scores (p=0.3798). Improvement in pruritis was to some extent independent of response, as demonstrated by the proportion of agreement between tumor response and significant pruritus improvement (27% and 19% for high dose and low dose, respectively, in DD groups), based on Kappa concordance coefficient. Conclusion. Patients treated with DD, particularly at the 18-μg/kg/d dose, were more likely to experience clinically significant improvements in pruritus and other skin-related symptoms than were patients receiving placebo. DD was observed to improve pruritus independent of response. Disclosures: Kozlovski: Eisai Inc.: Employment.
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Greer, J. P., W. R. Macon, R. E. Lamar, S. N. Wolff, R. S. Stein, J. M. Flexner, R. D. Collins, and J. B. Cousar. "T-cell-rich B-cell lymphomas: diagnosis and response to therapy of 44 patients." Journal of Clinical Oncology 13, no. 7 (July 1995): 1742–50. http://dx.doi.org/10.1200/jco.1995.13.7.1742.
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PURPOSE Clinicopathologic features of 44 patients with well-documented T-cell-rich B-cell lymphomas (TCRBCLs) were reviewed to determine if there were distinguishing clinical characteristics and to evaluate the responsiveness to therapy. PATIENTS AND METHODS Forty-one patients had de novo TCRBCL, while three patients had a prior diagnosis of diffuse large B-cell lymphoma. Seventeen TCRBCLs were identified from a retrospective analysis of 176 lymphomas diagnosed before 1988 as peripheral T-cell lymphoma (PTCLs). The initial pathologic diagnosis was incorrect in 36 of 44 cases (82%), usually due to the absence of adequate immunophenotypic and/or genotypic studies at the initial study. RESULTS The median age of patients was 53 years (range, 17 to 92), and the male-to-female ratio was 1.4:1. B symptoms were present in 22 of 41 patients (54%); splenomegaly was detected in 11 patients (25%). Clinical stage at diagnosis was as follows: I (n = 8), II (n = 6), III (n = 15), IV (n = 14), and unstaged (n = 1). Although therapy was heterogeneous, the disease-free survival (DFS) and overall survival (OS) rates at 3 years for patients with de novo TCRBCL were 29% and 46%, respectively. A complete response (CR) to combination chemotherapy for intermediate-grade lymphomas was observed in 16 of 26 patients (62%); 11 of these patients (42%) had a continuous CR, compared with one of 14 patients (7%) who received radiation therapy or therapy for low-grade lymphoma or Hodgkin's disease (HD) (P < .05). However, there was no difference in OS between patients who received chemotherapy for intermediate-grade lymphoma versus other therapies (49% v 48%) due to a high response rate to salvage therapies, including seven patients without disease after marrow transplantation. CONCLUSION TCRBCLs are difficult to recognize without immunoperoxidase studies. Patients with TCRBCL have clinical features similar to patients with other large B-cell lymphomas, except they may have more splenomegaly and advanced-stage disease; they should receive combination chemotherapy directed at large-cell lymphomas.
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Jim, Heather S. L., Aasha I. Hoogland, Aaron Collier, Margaret Booth-Jones, Michael D. Jain, and Frederick L. Locke. "Patient-Reported and Neurocognitive Outcomes in Patients Treated with Axicabtagene Ciloleucel." Blood 132, Supplement 1 (November 29, 2018): 2289. http://dx.doi.org/10.1182/blood-2018-99-111711.
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Abstract Background: Axicabtagene ciloleucel (axi-cel) is a CD19 targeted chimeric antigen receptor (CAR) T-cell therapy that may induce durable responses in relapsed/refractory lymphoma patients whose survival prospects are otherwise poor. Recent FDA approval of axi-cel and other CAR T-cell therapies is expected to lead to a growing population of cancer survivors treated with these therapies. Little is known about patient-reported outcomes (PROs) such as symptomatology and quality of life (QOL) in these patients. The goal of the current observational study was to examine PROs and neurocognitive functioning in adult patients in the first 90 days after treatment with axi-cel. Methods: Patients who were scheduled to undergo axi-cel therapy as part of a clinical trial or standard of care at Moffitt Cancer Center were recruited prior to conditioning chemotherapy. Patients completed items from the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) at enrollment and 14, 30, 60, and 90 days post-CART. A total of 20 symptoms were selected for inclusion based on clinician-rated toxicity of CART reported on clinical trials as well as symptoms likely to be of concern to cancer patients (e.g., fatigue, insomnia, diarrhea, constipation, nausea, decreased appetite). Patients also completed the Medical Outcomes Study Short Form 36 (SF-36) QOL measure at baseline and 90 days. Neurocognitive assessments were completed at baseline and 30 days using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Means, SDs, frequencies, and Wilcoxon signed rank tests were used to characterize outcomes and change over time. Results: Participants were 29 patients (28% female; mean age=58, SD=13; 52% treated on an interventional trial). Participants were diagnosed with diffuse large B-cell lymphoma (76%), follicular lymphoma or transformed follicular lymphoma (10%), mediastinal large b cell lymphoma (3%), or other indications (11%). Of these, 11 completed neurocognitive testing at baseline and 30 days. Patient-reported symptoms spiked at 14 days post-CAR-T before returning to levels similar to baseline. The most common symptoms at 14 days post-CAR-T were decreased appetite (95% any severity, 48% moderate to severe), fatigue (95% any severity, 43% moderate to severe), and dry mouth (85% any severity, 38% moderate to severe). By 90 days post-CAR-T, the most common symptoms were fatigue (82% any severity), insomnia (55% any severity), and joint pain (45% any severity); no patients reported moderate to severe symptoms at this time. Non-significant improvements were observed in physical health QOL (mean increase=1.43; p=0.37) and mental health QOL (mean increase=2.66, p=0.07) from baseline to 90 days. Patients demonstrated non-significant declines in total RBANS percentile score from baseline to day 30 (mean decrease=-8.18, p=0.32). Updated results will be presented at the meeting. Conclusions: This study is the first to our knowledge to report on both PROs and neurocognitive outcomes in patients treated with CAR T-cell therapy. Results indicate that moderate-to-severe patient-reported symptoms were transient following axi-cel, although a majority of patients reported ongoing, low-grade symptoms at 90 days post-treatment. Quality of life and neurocognition did not significantly change over time. These preliminary findings warrant larger future studies with longer follow-up to better understand changes in PROs and neurocognition in cancer survivors treated with CAR-T. Disclosures Jim: Janssen: Consultancy; RedHill Biopharma: Consultancy. Locke:Kite Pharma: Other: Scientific Advisor; Novartis Pharmaceuticals: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy.
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Kim, Seok Jin, Soo-Young Yoon, Byung Soo Kim, Chul Won Choi, Jungwoo Choi, In Sun Kim, Young-Hen Lee, and Jun Suk Kim. "Prognostic Significance of Ki-67 Expression in Extranodal NK/T Cell Lymphoma, Nasal Type: A Proposed Prognostic Index, KLABS Index." Blood 108, no. 11 (November 1, 2006): 2055. http://dx.doi.org/10.1182/blood.v108.11.2055.2055.
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Abstract Ki-67 is a nuclear antigen expressed by dividing cells, therefore, the percentage of Ki-67-positive cells reflects the proportion of tumor cells actively proliferating. However, the prognostic value of Ki-67 expression is still controversial in non-Hodgkin’s lymphoma. Although a recent study in peripheral T-cell lymphoma showed a positive correlation with poor prognosis, the prognostic value of Ki-67 has never been studied in patients with extranodal NK/T cell lymphoma. Therefore, we performed this study to determine the value of Ki-67 expression in predicting prognosis and to propose a new prognostic model involving Ki-67 expression in patients with extranodal NK/T cell lymphoma. We studied 65 patients who were diagnosed with extranodal NK/T cell lymphoma from 1999 to 2005. All patients were treated with combination chemotherapy alone or followed by radiotherapy. We analyzed the percentage of Ki-67 expressing cells and determined its prognostic significance in terms of overall survival (OS) and disease-free survival (DFS). The immunohistochemical staining of Ki-67 was available for this study in fifty-five patients. The median age was 41 (range: 19 – 74 years), 89.1 percent of the patients (49/55) had an ambulatory performance status: Eastern Cooperative Oncology Group (ECOG) 0–1. Fifty-one patients presented as a localized disease: Ann Arbor stage I or II, and elevated level of serum lactate dehydrogenase (LDH) was observed in 14 patients. Thus, most patients showed the low or low-intermediate international prognostic index (IPI): low risk (74.5%, 41/55) or low intermediate risk (18.2%, 10/55). The percentage of Ki-67 expressing tumor cells was ranged from 5% to 95%, and the patients were separated into two groups: low Ki-67 (< 50%) versus high (≥ 50%). The patients in the high Ki-67 group had a shorter OS (95% CI 1.0-6.3, P = 0.046) and DFS (95% CI 1.1-5.5, P = 0.024) while the IPI failed to predict worse OS. Ki-67 expression could also predict the group with worse prognosis in 51 patients of low and low-intermediate IPI risk. Age, serum LDH, B symptoms, and tumor size were also associated with worse OS or DFS. Thus, based on the univariate and mutivariate analysis, we proposed a new prognostic index (KLABS index) with high Ki-67 expression, increased serum LDH, Age (≥ 60 years), presence of B symptoms, and bulky Size of tumors (≥ 10cm2) as follows: low risk, none or one of the above-mentioned factors; intermediate risk, presence of two factors; high risk, presence of three or more factors. This new index showed a high degree of correlation with survival outcomes in terms of OS and DFS (Figure A, B). This study demonstrated the prognostic significance of Ki-67 expression, and our new prognostic index may become a useful tool for predicting prognosis in extranodal NK/T cell lymphoma, nasal type. Figure Figure
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Iwao, Noriaki, Junji Tanaka, Naoko Kato, Takeshi Kondo, Yoko Miura, Tomomi Toubai, Akio Shigematsu, et al. "Analysis of TREC (T Cell Receptor Excision Circles) Levels in CD94 Expressing CD8 T Cells in Chronic GVHD." Blood 106, no. 11 (November 16, 2005): 5367. http://dx.doi.org/10.1182/blood.v106.11.5367.5367.
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Abstract CD94 is one of the C-type lectin family members, forms a heterodimer with NKG2 gene family, and CD94 /NKG2A are inhibitory receptors. Not only NK cells but a subset of T cells express CD94/NKG2A, and previously we revealed the proportion of CD94/NKG2A expressing CD8 T cells were higher in patients with chronic graft versus host disease (GVHD), and CD94 expressing T cells have suppressive effects on mixed lymphocyte culture(MLC). We focus on CD94 positive T cell during T cell reconstitution after allogeneic hematopietic stem cell transplantation (allo-HSCT). T cell receptor excision circles (TREC) are suggested to be a useful marker of recent thymic output. In this study, we attempt to study TREC-containing CD8 T cell subset expressing CD94, and to examine the relation of TREC DNA level in CD94 expressing CD8 T cell and GVHD. We analyzed peripheral blood mononuclear cells (PBMCs) isolated from 24 patients (82 samples) undergone allo-HSCT including 15 patients with bone marrow transplantation and 9 patients with non-myeloablative stem cell transplantation. Informed consent was obtained from all patients. CD4 positive T cells were separated from PBMCs by magnetic cell sorting, and CD4 negative cell population was divided into CD94 positive CD8 T cells and CD94 negative CD8 T cells by fluorescence activated cell sorter. Genomic DNA was extracted from these separated T cell subsets. TREC DNA copy numbers per 105 isolated T cells (TREC level) were quantified by real time PCR. We investigated TREC levels in clinical status with pre-allo-HSCT, no episodes of GVHD or before manifestation of GVHD (No GVHD), chronic GVHD on disease (C-GVHD), and no symptoms and remission status of GVHD after immunosuppressive therapy (R-GVHD). Statical analyses were carried out by Mann-Whitney U test. There were no significant differences in TREC level of sorted CD4 positive T cells in C-GVHD compared with No GVHD (p=0.75) and R-GVHD (p=0.61), and also CD94 negative CD8 T cells in C-GVHD compared with No GVHD (p=0.79) and R-GVHD (p=0.20). On the other hand, TREC level of CD94 positive CD8 T cells in C-GVHD decreased in comparison with No GVHD (p=0.015) and R-GVHD (p=0.0019). The reduction of TREC level is thought to be induced not only by low thymic output but also by dilution of TREC concentration due to peripheral T cell expansion without duplications of TREC. These results may suggest that CD94 positive T cells play a role in modulation of GVHD, and proliferate during chronic GVHD with dilution of TREC in CD94 positive CD8 T cells. It is suggested that TREC level of CD94 expressing CD8 T cells may be useful markers of chronic GVHD.
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Narendra, S. K., N. C. Sahani, Upendra Das, and S. Tripathy. "Low current Cd4+T cell count: prediction, for persistent herpetic gingivostomatitis in HIV-positive patients under antiretroviral therapy." International Journal of Basic & Clinical Pharmacology 6, no. 10 (September 23, 2017): 2446. http://dx.doi.org/10.18203/2319-2003.ijbcp20174374.
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Background: Oral viral lesions associated with HIV infection are important since they affect the quality of life of the patient and are useful markers of disease progression and immunosuppression. The purpose of this study was to correlate the persistence of herpetic gingivostomatitis lesions with the current CD4+ T cell count for adherence of HIV-infected individuals to anti retroviral therapy (ART) and antiviral therapy.Methods: 302 HIV +ve patients developing oral ulcers were included in this study. The herpes simplex viral infections associated with the oral manifestations were detected through Immuno histochemical staining. The quantitative analysis of oral ulceration was done by using mucositis index.CD4T cell count was correlated with clinical manifestations of extensiveness of oral ulcers, acute febrile condition and other constitutional symptoms during follow up of cases for the treatment with anti viral therapies.Results: Association of herpes simplex viral infections was found in 72 out of 302 HIV+ ve cases. All the HSV +ve patients developed extensive oral mucsal lesions during the 1st week. Extensive lesions developed within 7 days in patients with CD4 count <200 due to HSV infection, remained more or less unchanged in the oral cavity up to 90 days although they were receiving antiretroviral and antiviral therapies. In HIV + patients with CD4 count >500, manifestation of mucosal ulcers due to acute herpetic gingivostomatitis was limited to a period of 1 to 2 weeks. Patients with CD4 count >200 <500 did not follow a definite pattern.Conclusions: Persistent oropharyngeal mucosal ulcers along with acute febrile condition due to herpes simplex virus infection are associated with low CD4 T cell count in HIV + patients under antiretroviral therapy.
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Qian, Meihua, Wensong Wang, Manling Wang, Meijuan Wu, Zhongsheng Zhao, Tianxin Yang, Weiqun Jin, et al. "The Treatment of ECVP Plus G-Csf on Epstein–Barr Virus-Associated T Lymphoproliferative Disease (EBV+ T-LPD) in Adult." Blood 118, no. 21 (November 18, 2011): 4384. http://dx.doi.org/10.1182/blood.v118.21.4384.4384.
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Abstract Abstract 4384 Epstein–Barr virus-associated T lymphoproliferative disease (EBV+ T-LPD, non-immunocompromised hosts) is rare on adults. Normally it is only found on children. This disease, according to recent pathological categorization, can be categorized into following subtypes: (i) category A1, polymorphic LPD without clonal proliferation of EBV-infected cells; (ii) category A2, polymorphic LPD with clonality; (iii) category A3, monomorphic LPD (T-cell or NK cell lymphoma/leukemia) with clonality; and (iv) category B, monomorphic LPD (T-cell lymphoma) with clonality and fulminant clinical course; Clinical symptoms of systemic EBV+ T-LPD include fever, liver, spleen and lymph nodes enlargement, jaundice of bile stasis, liver failure, pancytopenia. Based on degree of pathological changes, there are three groups of EBV+ T-LPD: I) polyclonal II) oligoclonal III) monoclonal (neoplasm). EBER, CD2 and are all positive. Usually drugs for treatment of EBV+ T-LPD include Glucocorticoid, CiclosporinA, and Etoposide. An adult patient of systemic EBV+ T-LPD (non-immunocompromised hosts) (neoplasm) had been diagnosis and treatment recently by us. The patient is a 46-years-old male, fever, abdominal pain, hypocytosis and lymph nodes enlargement, 2 weeks of jaundice, vomiting and nausea. Physical examination: T: 37–39°C; marasmus, sclera and jaundice, upper left clavicle lymph node enlargement, apparent abdominal distention, upper abdominal pain, severe spleen enlargement. Blood Routine WBC 1.88×109/L; HB 87g/L; PLT 1.7×109/L. SGPT 163 U/L, SGOT 179μmol/L, STB 309μmol/L, CB 178μmol/L, STP43.8 g/L, ALB27.1 g/L, LDH905U /L. KPTT, PT, TT prolonged by a little. No abnormal cells were found in Bone Marrow examination. CT: 1. multiple enlarged lymph nodes were found in upper left clavicle area, inside mediastinum, and at right hilus of lung (diameter up to 1.4cm, with some nodes fusing together). 2. Pleural effusion in both thoraxes. 3. Severe spleen enlargement with several low-concentration nodes found inside. 4. Multiple enlarged lymph nodes found inside abdominal cavity and behind peritoneum. Pathological examination (upper left clavicle lymph node): lymph node normal structure disappears; many heteromorphic lymph-like cells were found, clear nucleus abnormality; Immunophenotype: CD3 +(mostly positive); CD5+(Partially positive); CD7+ (minor positive); CD4,CD8: a few cells positive;. EBER are positive. Pathological diagnosis: Epstein–Barr virus-associated T lymphoproliferative disease, EBV+ T-LPD, (III group, neoplasm stage) Treatment: adult patient was treated by many drugs including liver-protection, antibiotics, G –CSF and others. Because many symptoms such as abdominal pain, jaundice and high fever aggravated, plus severe liver and respiratory failure, the patient was infused DXM 10mg/d1-7. After treatment of DXM, many symptoms of the patient mitigated. Then the patient was treated by ECVP (Etoposide 0.1/D1 ~ D4, CTX 0.6/d1, VCR 2mg/D1, D8, Methylprednisolone 160mg/D1 ~ D7,) plus G-CSF (150 ~ 400mg/D). The minimum of WBC was 0.07 ×109/L. During treatment the patient suffered from pneumonia, therefore antibiotics were used. After treating, the temperature of patient returned and stayed normal; abdominal pain, jaundice, and vomiting symptoms alleviated, and eventually disappeared; spleen size was reduced. Among all enlarged superficial lymph nodes and enlarged lymph nodes inside the mediastinum, inside the abdominal cavity, and behind peritoneum, some reduced sizes and some eventually returned to normal sizes. Pleural effusion disappeared. Liver function: SGPT, SGOT and bilirubin index returned to normal. Coagulation function returned to normal. The patient has now finished treatment in hospital and is currently home, waiting for next cycle of treatment. This case of adult patient of systemic EBV+ T-LPD(non-immunocompromised hosts) (neoplasm) indicate that the treated method of ECVP plus G-csf is safe and effective in adult patient of systemic EBV+ T-LPD (neoplasm); no significant toxicity was found during treatment; the early diagnosis and early treatment of adult EBV+ T-LPD is very important. Further study and clinical research on more effective method of treatment on adult EBV+ T-LPD is still desired. Disclosures: No relevant conflicts of interest to declare.
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Kyriakou, Charalampia, Ayoma Attygalle, David Linch, Anthony Goldstone, Paul Smith, and Ahmet Dogan. "Angioimmunoblastic T-Cell Lymphoma: A Large Series Outcome Analysis." Blood 106, no. 11 (November 16, 2005): 2810. http://dx.doi.org/10.1182/blood.v106.11.2810.2810.
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Abstract Angioimmunoblastic T-cell Lymphoma (AITL) is a rare Peripheral T-cell lymphoma that primarily affects the elderly, presenting as advanced disease characterized by aggressive behaviour and very poor outcome. Despite the unfavourable prognosis, the best approach for treating patients with AITL is still unknown. We report a retrospective multicentre study of 64 AITL patients (37 male, 27 female) who were diagnosed as AITL in our institution based on typical histology and molecular clonality analysis between 1995 and 2004. The median age at diagnosis was 60 years (range 25 to 87). Fifty-two patients (81%) presented with advanced stage III–IV disease, 41 (64%) had B symptoms and 49 (76%) elevated LDH. ECOG performance status was 1 for 40%, 2 for 53% and 3 for 9% of the patients. Based on IPI risk factors 12% of the patients were classified as low risk, 17% low intermediate, 29% high intermediate and 42% as high risk. Six patients developed autoimmune haemolytic anaemia. Therapeutic approach varied from no treatment to high dose therapy (HDT). The majority of the patients had received CHOP chemotherapy. Overall 19 patients (30%) had received 1 treatment line, 20 (31%) had 2, 19 (30%) 3, 4 patients (6%) were treated with ≥4 and 2 (3%) were not eligible for any treatment. Twenty patients (31%) proceeded to an autologous and 2 to allogeneic transplantation after achieving CR (n=12), PR (n=7) while 3 had progressive disease. Following first line therapy 37 patients (58%) achieved CR, 15 (23%) PR and 10 (16%) had primary refractory disease. Median time to relapse or progression was 6 months (1 to 89). Interestingly three patients relapsed as EBV driven DLBCL, 1as DLBCL and 2 as EBV driven Hodgkin’s lymphoma. With a median follow-up of 19 months (1 to 119) twenty-six patients (41%) were alive. Eighteen (28%) of these patients were in CR, and 8 in PR (13%). Thirty-seven patients (58%) died, 29 (45%) from disease progression. Twelve patients developed toxic complications -infectious complications (n=8), haemorrhage (n=1), thrombosis (n=1) myocardial infarction (n=2). The estimated PFS rates at 1 and 2 years were 33% and 27% respectively. Overall survival rates were estimated at 55% and 28% at 2 and 4 years. By univariate and multivariate analyses, no response to first line therapy (p=0.035) and male sex (p=0.0161), were significantly associated with higher relapse rate. Application of HDT resulted to significantly superior PFS (p=0.002). Poor performance status at presentation was the only factor found to be significant for the OS (p= 0.0317). In conclusion analysis of the results of this large cohort of AITL patients showed that although the initial overall response rate was 73% this was short lived. It is estimated that less than 30% of the patients will survive and remain disease free at 4 years. Considering the dismal outcome with current therapeutic approaches, new strategies using novel agents to improve further and most importantly maintain initial response are needed. The role of frontline HDT either autologous or allogeneic for eligible AITL patients is worth exploring in prospective collaborative studies.
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Bigouret, Valérie, Till Hoffmann, Lionel Arlettaz, Jean Villard, Marco Colonna, André Ticheli, Alois Gratwohl, et al. "Monoclonal T-cell expansions in asymptomatic individuals and in patients with large granular leukemia consist of cytotoxic effector T cells expressing the activating CD94:NKG2C/E and NKD2D killer cell receptors." Blood 101, no. 8 (April 15, 2003): 3198–204. http://dx.doi.org/10.1182/blood-2002-08-2408.
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Abstract We have analyzed the phenotype, cytokine profile, and mitotic history (telomere length) of monoclonal T-cell expansions in 5 CD3+ T-cell large granular lymphocyte (TLGL) leukemia patients by fluorescence activated cell sorting (FACS) and single-cell polymerase chain reaction (PCR). We confirm that the common phenotype of TLGL leukemia is CD3+CD8+CD45RA+CD27−CD94+(CD57+). Interestingly, the C-type lectin-like type killer cell receptor CD94 was invariably associated with the activating form of its signal-transducing molecule NKG2. Furthermore, when judged by criteria such as interferon gamma (IFN-γ)/tumor necrosis factor (TNF) production, expression of granzyme, FasL, and NKG2D, the TLGL cells had all the features of a cytotoxic effector T cell. Telomere shortening in TLGL cells was in the normal range for CD8+ T cells, indicating that they had not divided significantly more than chronically stimulated CD8+ T cells in healthy individuals. In 25 of 27 controls, cells with a TLGL phenotype occurred at low (1%-3%) frequencies. However, in the other 2 individuals (ages 28-36 years), large stable (> 3 years) monoclonal expansions of CD3+CD8+CD45RA+CD27−CD57+CD94+ NKG2C+ were found which rendered these controls phenotypically indistinguishable from TLGL leukemia patients. We believe that the TLGL clonopathy, rather than being of a neoplastic nature, is more likely an extreme manifestation of the large and stable clonal size characteristic of CD8+ effector cells. Such a TLGL clone consisting of cells without any particular pathologic trait might exist in a considerable number of individuals. Clinical symptoms may occur in individuals in whom the TLGL clone encounters antigen and is triggered to produce large amounts of effector molecules that dysregulate the immune system, which could manifest itself as autoimmunity or as a FasL-mediated neutropenia.
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Senol, Vesile, Demet Unalan, Raziye Peksen Akca, and Mustafa Basturk. "Prevalence of attention-deficit/hyperactivity and other disruptive behaviour disorder symptoms among primary school-age children in Kayseri, Turkey." Journal of International Medical Research 46, no. 1 (July 21, 2017): 122–34. http://dx.doi.org/10.1177/0300060517712865.
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Objectives This study aimed to determine the prevalence of attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD), and their influencing factors on primary school-age children. Methods This cross-sectional study was conducted among 2045 students, 7–15 years old, who were randomly selected from seven schools in Kayseri, Turkey, in 2012. Participants were stratified by socioeconomic status. Data were collected using the Turgay DSM-IV-Based Child and Adolescent Behavioural Disorders Screening and Rating Scale (T-DSM-IV-S). For statistical analyses, the t-test and analysis of variance were used. Results Rates of disruptive behaviour disorders (DBDs) among children were as follows: ADHD, 6.2%; CD, 14.4%; and ODD, 6.7%. The prevalence of ADHD was higher in boys and children whose mothers were homemakers and from poorly-educated and low-income families, compared with their peers. CD was more prevalent among boys and children 13–15 years old, whose parents had low income levels and were separated. ODD was higher in boys and children whose mothers were homemakers. Conclusions Our findings suggest that the overall prevalence of DBDs in our study area is 27.4%, which is similar to the pooled worldwide prevalence. Adverse family factors are closely associated with the prevalence of DBDs.
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El Costa, Hicham, Jordi Gouilly, Florence Abravanel, Elmostafa Bahraoui, Jean-Marie Peron, Nassim Kamar, Nabila Jabrane-Ferrat, and Jacques Izopet. "Effector memory CD8 T cell response elicits Hepatitis E Virus genotype 3 pathogenesis in the elderly." PLOS Pathogens 17, no. 2 (February 22, 2021): e1009367. http://dx.doi.org/10.1371/journal.ppat.1009367.
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Genotype 3 Hepatitis E virus (HEV-3) is an emerging threat for aging population. More than one third of older infected patients develops clinical symptoms with severe liver damage, while others remain asymptomatic. The origin of this discrepancy is still elusive although HEV-3 pathogenesis appears to be immune-mediated. Therefore, we investigated the role of CD8 T cells in the outcome of the infection in immunocompetent elderly subjects. We enrolled twenty two HEV-3-infected patients displaying similar viral determinants and fifteen healthy donors. Among the infected group, sixteen patients experienced clinical symptoms related to liver disease while six remained asymptomatic. Here we report that symptomatic infection is characterized by an expansion of highly activated effector memory CD8 T (EM) cells, regardless of antigen specificity. This robust activation is associated with key features of early T cell exhaustion including a loss in polyfunctional type-1 cytokine production and partial commitment to type-2 cells. In addition, we show that bystander activation of EM cells seems to be dependent on the inflammatory cytokines IL-15 and IL-18, and is supported by an upregulation of the activating receptor NKG2D and an exuberant expression of T-Bet and T-Bet-regulated genes including granzyme B and CXCR3. We also show that the inflammatory chemokines CXCL9-10 are increased in symptomatic patients thereby fostering the recruitment of highly cytotoxic EM cells into the liver in a CXCR3-dependent manner. Finally, we find that the EM-biased immune response returns to homeostasis following viral clearance and disease resolution, further linking the EM cells response to viral burden. Conversely, asymptomatic patients are endowed with low-to-moderate EM cell response. In summary, our findings define immune correlates that contribute to HEV-3 pathogenesis and emphasize the central role of EM cells in governing the outcome of the infection.
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Launois, Pascal, Annie Drowart, Eliane Bourreau, Pierre Couppie, Claire-Michèle Farber, Jean-Paul Van Vooren, and Kris Huygen. "T Cell Reactivity against Mycolyl Transferase Antigen 85 ofM. tuberculosisin HIV-TB Coinfected Subjects and in AIDS Patients Suffering from Tuberculosis and Nontuberculous Mycobacterial Infections." Clinical and Developmental Immunology 2011 (2011): 1–10. http://dx.doi.org/10.1155/2011/640309.
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The mycolyl transferase antigen 85 complex is a major secreted protein family from mycobacterial culture filtrate, demonstrating powerful T cell stimulatory properties in most HIV-negative, tuberculin-positive volunteers with latentM.tuberculosisinfection and only weak responses in HIV-negative tuberculosis patients. Here, we have analyzed T cell reactivity against PPD and Ag85 in HIV-infected individuals, without or with clinical symptoms of tuberculosis, and in AIDS patients with disease caused by nontuberculous mycobacteria. Whereas responses to PPD were not significantly different in HIV-negative and HIV-positive tuberculin-positive volunteers, responses to Ag85 were significantly decreased in the HIV-positive (CDC-A and CDC-B) group. Tuberculosis patients demonstrated low T cell reactivity against Ag85, irrespective of HIV infection, and finally AIDS patients suffering from NTM infections were completely nonreactive to Ag85. A one-year follow-up of twelve HIV-positive tuberculin-positive individuals indicated a decreased reactivity against Ag85 in patients developing clinical tuberculosis, highlighting the protective potential of this antigen.
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Troszok, Agnieszka, Ludmiła Kolek, Joanna Szczygieł, Tomasz Ostrowski, Mikołaj Adamek, and Ilgiz Irnazarow. "Anti-CyHV-3 effect of fluorescent, tricyclic derivative of acyclovir 6-(4-MeOPh)-TACV in vitro." Journal of Veterinary Research 63, no. 4 (October 24, 2019): 513–18. http://dx.doi.org/10.2478/jvetres-2019-0065.
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AbstractIntroductionCyprinid herpesvirus 3 (CyHV-3) is a virus infecting carp with disease symptoms of gill necrosis, fish discoloration, sunken eyes, and mortality reaching 90%. Several research groups have examined how to potentially abate the consequences of viral activity. Recently we showed that acyclovir inhibits CyHV-3 replication in vitro and in the present study we examined the anti-CyHV-3 activity of the tricyclic derivative of acyclovir 6-(4-MeOPh)-TACV (T-ACV), a fluorescent molecule known for higher lipophilicity than acyclovir, and therefore potentially better candidate for application in vivo.Material and MethodsCCB and KF1 cell lines were incubated with T-ACV at concentrations of 0, 66.67, and 133.33 μM for three days and toxicity examined with MTT and CV assays. To investigate the antiviral activity of T-ACV, the lines were infected with CyHV-3 or mock infected and incubated for three days with the drug at concentrations of 0 or 66.67 μM. The activity of T-ACV was evaluated by plaque assay and TaqMan qPCR.ResultsT-ACV at a concentration of 66.67 μM displayed low toxicity and inhibited CyHV-3 activity by 13–29%, varying by cell line and method.ConclusionThe low anti-CyHV-3 activity of T-ACV indicates that it would be reasonable to screen several tricyclic derivatives of acyclovir for such activity.
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Eberhardt, Kirsten Alexandra, Fred Stephen Sarfo, Eva-Maria Klupp, Albert Dompreh, Veronica Di Cristanziano, Edmund Osei Kuffour, Richard Boateng, et al. "Intestinal Colonization with Tropheryma whipplei—Clinical and Immunological Implications for HIV Positive Adults in Ghana." Microorganisms 9, no. 8 (August 22, 2021): 1781. http://dx.doi.org/10.3390/microorganisms9081781.
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Background: Recent studies demonstrated higher prevalence rates of Tropheryma whipplei (T. whipplei) in HIV positive than in HIV negative subjects. However, associations with the immune status in HIV positive participants were conflicting. Methods: For this cross-sectional study, stool samples of 906 HIV positive and 98 HIV negative individuals in Ghana were tested for T. whipplei. Additionally, sociodemographic parameters, clinical symptoms, medical drug intake, and laboratory parameters were assessed. Results: The prevalence of T. whipplei was 5.85% in HIV positive and 2.04% in HIV negative participants. Within the group of HIV positive participants, the prevalence reached 7.18% in patients without co-trimoxazole prophylaxis, 10.26% in subjects with ART intake, and 12.31% in obese participants. Frequencies of clinical symptoms were not found to be higher in HIV positive T. whipplei carriers compared to T. whipplei negative participants. Markers of immune activation were lower in patients colonized with T. whipplei. Multivariate regression models demonstrated an independent relationship of a high CD4+ T cell count, a low HIV-1 viral load, and an obese body weight with the presence of T. whipplei. Conclusions: Among HIV positive individuals, T. whipplei colonization was associated with a better immune status but not with clinical consequences. Our data suggest that the withdrawal of co-trimoxazole chemoprophylaxis among people living with HIV on stable cART regimen may inadvertently increase the propensity towards colonization with T. whipplei.
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Espinoza-Jiménez, Arlett, Irma Rivera-Montoya, Roberto Cárdenas-Arreola, Liborio Morán, and Luis I. Terrazas. "Taenia crassicepsInfection Attenuates Multiple Low-Dose Streptozotocin-Induced Diabetes." Journal of Biomedicine and Biotechnology 2010 (2010): 1–11. http://dx.doi.org/10.1155/2010/850541.
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Taenia crassiceps, like other helminths, can exert regulatory effects on the immune system of its host. This study investigates the effect of chronicT. crassicepsinfection on the outcome of Multiple Low Dose Streptozotocin-Induced Diabetes (MLDS). Healthy or previouslyT. crassiceps-infected mice received MLDS and type 1 diabetes (T1D) symptoms were evaluated for 6 weeks following the induction of MLDS.T. crassiceps-infected mice displayed lower blood glucose levels throughout the study. A significantly lower percentage ofT. crassiceps-infected mice (40%) developed T1D compared to the uninfected group (100%). Insulitis was remarkably absent inT. crassiceps-infected mice, which had normal pancreatic insulin content, whereas uninfected mice showed a dramatic reduction in pancreatic insulin. Infected mice that received MLDS did not show an increase in their regulatory T cell population, however, they had a greater number of alternatively activated macrophages, higher levels of the cytokine IL-4, and lower levels of TNF-α. Therefore, infection withT. crassicepscauses an immunomodulation that modifies the incidence and development of MLDS-induced autoimmune diabetes.
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Lee, Jeeyun, Cheolwon Suh, Yeon Hee Park, Young H. Ko, Soo Mee Bang, Jae Hoon Lee, Dae Ho Lee, et al. "Extranodal Natural Killer T-Cell Lymphoma, Nasal-Type: A Prognostic Model From a Retrospective Multicenter Study." Journal of Clinical Oncology 24, no. 4 (February 1, 2006): 612–18. http://dx.doi.org/10.1200/jco.2005.04.1384.
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Purpose Patients with natural killer T (NK/T) -cell lymphomas have poor survival outcome, and for this condition there is no optimal therapy. The purpose of this study was to design a prognostic model specifically for extranodal NK/T-cell lymphoma, which can identify high-risk patients who need more aggressive therapy. Patients and Methods This multicenter retrospective study was comprised of 262 patients who were diagnosed with NK/T-cell lymphoma. Results After a median follow-up duration of 51.2 months, 5-year overall survival rate in 262 patients was 49.5%. Prognostic factors for survival were “B” symptoms (P = .0003; relative risk, 2.202; 95% CI, 1.446 to 3.353), stage (P = .0006; relative risk, 2.366; 95% CI, 1.462 to 3.828), lactate dehydrogenase (LDH) level (P = .0005; relative risk, 2.278; 95% CI, 1.442 to 3.598), and regional lymph nodes (P = .0044; relative risk, 1.546; 95% CI, 1.009 to 2.367). Of 262 patients, 219 had complete information on four parameters. We identified four different risk groups: group 1, no adverse factor; group 2, one factor; group 3, two factors; and group 4, three or four factors. The new model showed a superior prognostic discrimination as compared with the International Prognostic Index (IPI). Notably, the distribution of patients was balanced when a new model was adopted (group 1, 27%; group 2, 31%; group 3, 20%; group 4, 22%), whereas 81% of patients were categorized as low or low-intermediate risks using IPI. Conclusion The newly proposed model for extranodal NK/T-cell lymphoma demonstrated a more balanced distribution of patients into four groups with better prognostic discrimination as compared with the IPI.
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Kadia, Tapan, Luis Fayad, Maria Alma Rodriguez, Peter Mclaughlin, and Barbara Pro. "Retrospective Review of Angiommunoblastic T-Cell Lymphoma: The MD Anderson Cancer Center Experience." Blood 108, no. 11 (November 16, 2006): 4690. http://dx.doi.org/10.1182/blood.v108.11.4690.4690.
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Abstract Angioimmunoblastic T-cell Lymphoma (AITL) represents about 4–6% of all lymphomas, but up to 15–20% of all T-cell lymphomas. AITL usually presents in the 6th to 7th decade of life as an advanced stage, systemic disease with B-symptoms, lymphadenopathy, bone marrow involvement, rash, and autoimmune abnormalities. The disease follows an aggressive course and typically portends a poor prognosis. Nevertheless, there are no widely accepted treatment guidelines that have shown significant efficacy or improved benefit in this disease.We report our single institution experience with AITL over the past 10 years. We identified 33 cases of AITL seen at MDACC from 1996–2006. We retrospectively reviewed these cases to analyze clinicopathologic characteristics, treatment regimens, and response rates. The median age at diagnosis was 67 years (43–79), and there was a male to female ratio of 2:1. Thirty-two patients (97%) presented with stage 3 or 4 disease, 16 patients (49%) had bone marrow involvement, and 23 patients (70%) had B symptoms at presentation. Stratifying 32 patients by IPI, 12.5% were classified as low risk, 43.8% as low-intermediate, 28% as high-intermediate, and 15.6% as high risk. A skin rash was present in 16 patients (49%), while 4 patients (12%) had significant inflammatory arthralgias, and 5 patients (15%) had an autoimmune hematologic disorder. Interestingly, 6 patients (18%) had known exposure to industrial chemicals, 8 patients (24%) had a preceding or concurrent second malignancy, and 13 out of the 15 cases (87%) tested for EBV were positive for EBV RNA. Most patients were treated with an anthracycline based regimen. Of these, 6 patients were treated with an intense, alternating triple therapy regimen, 4 patients received a hyperfractionated cyclophosphamide based regimen, and 16 patients received a CHOP-like regimen. Of these 16 patients, 4 also received rituximab in combination with CHOP. Out of 25 evaluable patients after 1st line therapy, 17 patients (68%) achieved CR, 6 patients (24%) achieved PR, and 2 patients (8%) were found to be primary refractory. In those patients with CR, the median duration of 1st remission was 30.5 months (1–96), with a median follow up of 37.6 months (2–101). The probabilities of 1,2, and 3 year survival were 80%, 67%, and 57% respectively. The duration of remission by type of therapy was found to be higher in patients receiving the more intense chemotherapy regimens when compared to CHOP alone. Overall survival of patients treated with CHOP vs. non-CHOP regimens is shown in figure 1. Although the length of followup is still short, notably, only 1 out of 4 patients treated with rituximab have relapsed. The one case had skin-only relapse and has achieved a 2nd remission. The one patient who was treated with upfront high dose chemotherapy and autologous transplant continues to maintain one of the longest durations of remission in our series. Overall response rate and duration of remission in our series was slightly higher than that reported in the literature. Strategies such as early referral to transplant and addition of rituximab to CHOP-like regimens need to be investigated further, as we work to improve the outcome of this disease. Overall Survival by Treatment Overall Survival by Treatment
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Squiban, P. J., E. Bompas, J. Bennouna, V. Levy, H. Sicard, S. Lafaye de Micheaux, E. Viey, S. Salot, J. Tiollier, and F. Calvo. "Vγ9Vδ2 T (γδ) lymphocytes: a promising approach for immunotherapy of solid tumors." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 3064. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.3064.
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3064 Background: The Vγ9Vd2 T (γd) blood lymphocyte subset has a strong cytotoxic potential and can be selectively activated with chemically-synthesized, structural analogues of non-conventional antigens like BrHPP (IPH1101). Their proliferation requires low dose of Interleukin-2 (IL-2). Methods: We developed several in vitro and in vivo models to assess the immunotherapeutic potential of IPH1101-activated γd cells: - Direct cytotoxicity assays on patient-derived primary tumor cell lines - Extensive pharmacodynamics in the non human primate (NHP) - Small scale in vitro amplification assays for IPH1101-sensitive patient pre-selection Then, two Phase I clinical trials were performed in solid tumor patients: - Autologous cell therapy with ex vivo IPH1101- expanded γd cells (1, 4 or 8.109 cells) - Direct administration of IPH1101 (200 to 1800 mg/m2 i.v.) and low dose IL-2 (106 U/m2 s.c.). Results: In NHP, IPH1101 and low dose IL-2 induce early pro-inflammatory cytokine release and dose-dependent γd cell amplification in peripheral blood. In vitro, mRCC tumor cells are efficiently and selectively killed by autologous γd cells. In Phase I clinical trials, both ex vivo expanded γd cells and IPH1101 were well tolerated. - Cell therapy-related AEs included mainly gastrointestinal disorders, flu-like symptoms and hypotension. Six patients showed stabilized disease. Median duration of stabilization was 25.7 weeks. 2 pts treated with 4.109 or 8.109 cells showed substantial tumor shrinkage at the 14-week evaluation (-22% and -48%, respectively). - When IPH1101 was administered with low dose of IL-2, a significant increase of blood γd T cells was observed (up to 240 times the basal values) and in terms of clinical activity assessment, among the evaluable mRCC population (n=15), 8 patients presented disease stabilization for more than 35 weeks, including 6 for more than 51 weeks. Conclusions: For the first time, a specific γd immunotherapy was fully developed and led to Phase I clinical trials. It has been found well tolerated. Encouraging signs of disease stabilisation in mRCC patients suggest that γd may have a role in the treatment of cancers resistant to conventional therapies. A phase 2 is ongoing in mRCC patients. No significant financial relationships to disclose.
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Storek, Jan, Rob Woolson, Paul K. Wallace, Gregory Sempowski, Peter A. McSweeney, Maureen Mayes, Leslie Crofford, Sharon LeClercq, Richard A. Nash, and Keith M. Sullivan. "Low Blood Counts of Memory/Effector CD8 T Cells, Gamma/Delta T Cells, Memory B Cells and Plasmacytoid Dendritic Cells and High Counts of Th2 Cells in Systemic Sclerosis." Blood 118, no. 21 (November 18, 2011): 4917. http://dx.doi.org/10.1182/blood.v118.21.4917.4917.
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Abstract Abstract 4917 Introduction: Systemic sclerosis (SSc) is presumed to result from aberrant activation of autoreactive T cells. However, the exact pathogenesis of SSc is not known. Patients and Methods: To contribute to the understanding of the immunopathology of systemic sclerosis (SSc), we compared blood counts of multiple lymphocyte subsets between 20 adult SSc patients not treated with immunomodulatory drugs and healthy controls. The patients had to fit entry criteria for SCOT trial (Scleroderma – Cyclophosphamide or Transplantation?, www.sclerodermatrial.org), i.e, 1. symptoms for no longer than 5 years (except for Raynaud's phenomenon), 2. diffuse scleroderma, and 3. either moderate lung involvement (forced vital capacity (FVC) or diffusion of carbon monoxide (DLCO) between 45 and 70% predicted) or moderate kidney involvement (history of hypertensive renal crisis, but normal renal function at study entry). Multiparameter flow cytometry was used for the determination of the lymphocyte subset counts. Results: Counts of the following subsets were significantly lower in the patients compared to the controls: total T cells (median 1316 vs 2088/ul, p=0.015), total CD8 T cells (273 vs 580/ul, p<0.001), central memory CD8 T cells (23 vs 87/ul, p<0.001), effector memory CD8 T cells (17 vs 39/ul, p=0.015), effector CD8 T cells (28 vs 68/ul, p=0.001), gamma/delta T cells (31 vs 77/ul, p<0.001), switched (IgM/DàIgG/A isotype switched) memory B cells (6 vs 26/ul, p<0.001), non-switched memory B cells (7 vs 17/ul, p=0.004), and plasmacytoid dendritic cells (2 vs 6/ul, p=0.002). Counts of Th2-biased (producing interleukin-4 upon polyclonal stimulation) CD4 as well as CD8 T cells were significantly higher in the patients compared to the controls (248 vs 139/ul for CD4, p=0.002, and 259 vs 164/ul for CD8, p<0.001). Conclusion: Immunopathology of SSc is complex. Low blood counts of memory/effector CD8 T cells, gamma/delta T cells, memory B cells and plasmacytoid dendritic cells and Th2-biased T cells may play a role in the pathogenesis of SSc. However, cause and effect relations need to be established. Given previous reports of increased numbers of CD8 and gamma/delta T cells in the affected tissues of patients with systemic sclerosis and increased numbers of plasmacytoid dendritic cells in the affected tissues of patients with autoimmune diseases (compared to healthy individuals) (Prescott RJ et al: J Pathol 166 (1992) 255–63, Atamas SP et al: Arthritis Rheum 42 (1999) 1168–78, Giacomelli R et al: Arthritis Rheum 41 (1998) 327–34, Yurovski VV et al: J Immunol 153 (1994) 881–91, Nestle FO et al: J Exp Med 202 (2005) 35–43, Farkas L et al: Am J Pathol 159 (2001) 237–43), it is possible that the low blood counts of CD8 T cells, gamma/delta T cells and plasmacytoid dendritic cells result from redistribution of these cells from blood to affected tissues. Disclosures: No relevant conflicts of interest to declare.
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Till, Brian G., Michael C. Jensen, Jinjuan Wang, Xiaojun Qian, Ajay K. Gopal, David G. Maloney, Catherine G. Lindgren, et al. "CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results." Blood 119, no. 17 (April 26, 2012): 3940–50. http://dx.doi.org/10.1182/blood-2011-10-387969.
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Abstract Cellular immune responses have the potential to elicit dramatic and sustained clinical remissions in lymphoma patients. Recent clinical trial data demonstrate that modification of T cells with chimeric antigen receptors (CARs) is a promising strategy. T cells containing CARs with costimulatory domains exhibit improved activity against tumors. We conducted a pilot clinical trial testing a “third-generation” CD20-specific CAR with CD28 and 4-1BB costimulatory domains in patients with relapsed indolent B-cell and mantle cell lymphomas. Four patients were enrolled, and 3 received T-cell infusions after cyclophosphamide lymphodepletion. Treatment was well tolerated, although one patient developed transient infusional symptoms. Two patients without evaluable disease remained progression-free for 12 and 24 months. The third patient had an objective partial remission and relapsed at 12 months after infusions. Modified T cells were detected by quantitative PCR at tumor sites and up to 1 year in peripheral blood, albeit at low levels. No evidence of host immune responses against infused cells was detected. In conclusion, adoptive immunotherapy with CD20-specific T cells was well tolerated and was associated with antitumor activity. We will pursue alternative gene transfer technologies and culture conditions in future studies to improve CAR expression and cell production efficiency. This study is registered at www.clinicaltrials.gov as NCT00621452.
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Rank, Andreas, Athanasia Tzortzini, Elisabeth Kling, Christoph Schmid, Rainer Claus, Eva Löll, Roswitha Burger, et al. "One Year after Mild COVID-19: The Majority of Patients Maintain Specific Immunity, But One in Four Still Suffer from Long-Term Symptoms." Journal of Clinical Medicine 10, no. 15 (July 27, 2021): 3305. http://dx.doi.org/10.3390/jcm10153305.
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After COVID-19, some patients develop long-term symptoms. Whether such symptoms correlate with immune responses, and how long immunity persists, is not yet clear. This study focused on mild COVID-19 and investigated correlations of immunity with persistent symptoms and immune longevity. Persistent complications, including headache, concentration difficulties and loss of smell/taste, were reported by 51 of 83 (61%) participants and decreased over time to 28% one year after COVID-19. Specific IgA and IgG antibodies were detectable in 78% and 66% of participants, respectively, at a 12-month follow-up. Median antibody levels decreased by approximately 50% within the first 6 months but remained stable up to 12 months. Neutralizing antibodies could be found in 50% of participants; specific INFgamma-producing T-cells were present in two thirds one year after COVID-19. Activation-induced marker assays identified specific T-helper cells and central memory T-cells in 80% of participants at a 12-month follow-up. In correlative analyses, older age and a longer duration of the acute phase of COVID-19 were associated with higher humoral and T-cell responses. A weak correlation between long-term loss of taste/smell and low IgA levels was found at early time points. These data indicate a long-lasting immunological memory against SARS-CoV-2 after mild COVID-19.
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Levy, Ronald, Patrick M. Reagan, Jonathan W. Friedberg, Nancy L. Bartlett, Leo I. Gordon, Abraham Leung, Joanna Peterkin, et al. "SD-101, a Novel Class C CpG-Oligodeoxynucleotide (ODN) Toll-like Receptor 9 (TLR9) Agonist, Given with Low Dose Radiation for Untreated Low Grade B-Cell Lymphoma: Interim Results of a Phase 1/2 Trial." Blood 128, no. 22 (December 2, 2016): 2974. http://dx.doi.org/10.1182/blood.v128.22.2974.2974.
Full textAbstract:
Abstract Introduction: Prior studies have shown preliminary clinical efficacy in combining CpG-ODN with radiation therapy (XRT) to patients with indolent B-cell lymphoma. We report interim Phase 1/2 data of combination XRT and SD-101, a synthetic class C CpG-ODN TLR9 agonist, selected for the strong induction of type I interferon. Methods: This dose-escalation Phase 1/2 trial enrolled patients with untreated indolent B-cell lymphoma having at least 2 measurable lesions (one palpable). The primary endpoints were safety and alpha-interferon-gene induction. Secondary endpoints included efficacy assessment using Cheson (1999) criteria and quantification of changes in tumor-infiltrating lymphocytes. A single lesion was treated with XRT (2 Gy daily X 2 days) followed by a single intratumoral dose of SD-101 (same lesion). 4 additional doses of intratumoral SD-101 were given weekly over next 4 weeks. The treated lesion and distal lesions were monitored during the study. Pharmacodynamic assessment included flow cytometry analysis of immune infiltrates in an FNA sample of the treated tumor and RT-PCR RNA assay of whole blood to assess induction of alpha-interferon genes. Efficacy assessment included imaging (CT at 3, 6, and every 6 months thereafter). Results: As of 01 Aug 2016, 13 patients were treated with escalating doses of SD-101 at 1, 2, 4 or 8 mg/dose. There were no dose limiting toxicities. The majority of related adverse events (AEs) were Grade 1 (mild). The most common were flu-like symptoms (chills, headache, malaise, myalgia), typically resolving within ≤ 48 hours without requiring intervention (e.g., acetaminophen). An induction of alpha-interferon genes occurred at all dose levels with a similar level of induction. For the dose expansion phase, 15 patients were enrolled at 1 mg (6) and 8 mg dose group (9). Similar to dose escalation phase, the most common related events were again flu-like symptoms, typically resolving within ≤ 48 hours mitigated with acetaminophen. There was one dose delay for Grade 3 neutropenia in one patient (1 mg) that resolved following drug interruption. Twenty-nine Grade 3 transient flu-like symptoms were reported for four patients (44%) who received the 8 mg dose (e.g., chills headache, malaise, myalgia, and fatigue). Only one of the four patients experienced all 5 Grade 3 flu-like symptoms after intratumoral injection. There were no grade 4 or serious events reported, and no patient discontinued due to an adverse event. A reduction in tumor sizes was observed in the study over time (see Figure 1). At Day 90 the median changes in the product of diameters from baseline were -46.1% and -10.2% for treated tumor and distal tumors, respectively. At Day 540, the median changes were -68.6% and -24.1%, respectively. In patients with follicular lymphoma (largest subgroup), preliminary data suggest a higher percentage of CD8+ T cells in the treated lesion (FNA at day 8) correlated with an increased abscopal response. Conclusions: Intratumoral SD-101 following radiation therapy has been well tolerated and preliminary efficacy, promising. Abscopal anti-tumor activity was observed with preliminary data suggesting that a higher percentage of CD8+ T cells in the treated lesion correlated with an increased abscopal response seen in follicular lymphoma. Enrollment is ongoing with an option for cycle 2 retreatment. Disclosures Levy: Kite Pharma: Consultancy; Five Prime Therapeutics: Consultancy; Innate Pharma: Consultancy; Beigene: Consultancy; Corvus: Consultancy; Dynavax: Research Funding; Pharmacyclics: Research Funding. Reagan:Seattle Genetics: Research Funding. Friedberg:Bayer: Other: Data Safety Monitoring Committee. Bartlett:Gilead: Consultancy. Leung:Dynavax: Employment. Peterkin:Dynavax: Consultancy. Xing:Dynavax: Employment. Coffman:Dynavax: Employment. Janssen:Dynavax: Employment. Candia:Dynavax: Employment.