Persistent Cytotoxic T Lymphocyte Expansions after Allogeneic Hematopoietic Stem Cell Transplantation: Kinetics, Clinical Impact and Absence of STAT3 Mutations

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3153-3153
Author(s):  
Julia Muñoz-Ballester ◽  
Tzu Hua Chen-Liang ◽  
Ana María Hurtado ◽  
Pastora Iniesta ◽  
María Dolores García-Malo ◽  
...  

Abstract Thymic-independent peripheral expansion of CD8+ cells derived from the graft in the initial stage of post-HSCT immune recovery is a well-known physiological event. Nevertheless, the description of symptomatic LGL leukemias and aggressive malignant cases in this setting may generate uncertainty, mostly in those cases in which the cytotoxic T lymphocyte expansion CTLe persists beyond the early transplantation period. We aimed to assess the nature of CTLe in adults during the post-alloHSCT period in a series of 154 patients with a long term surveillance. We studied the longitudinal kinetics of those expansions, their relation to clinical events, and their phenotypic and molecular features, including recently reported CTL leukemia-STAT3 mutations. In our study, trying to adhere to the WHO annotation of T-LGL, we considered two definitions for a CTL expansion: an absolute increase (≥ 2000 x109/L), and a relative expansion (a CD8/CD4 ratio ≥ 1.5), persisting more than six months in both cases. Persistent relative CTLe cases are frequent (49%) and related with timoglobulin prophylaxis (p≤0.001), acute graft versus host disease (GVHD, p=0.02), reduced intensity conditioning (p=0.04) and fungal and viral infections in the early post-HSCT. No differences in the number of serious infectious events from day 180 was found. Absolute CTLe are scarce (9%), related with chronic GVHD and absence of relapses. TCR rearrangement was reported as clonal and oligoclonal in the majority of patients with CTLe. We studied in a cross sectional manner with an extended immunophenotypic panel 17 patients: 5 patients with an absolute CTLe and 12 cases with a relative CTLe. A similar cytotoxic T αβ-effector phenotype was observed in all cases, with slight differences in the expression of CD25, CD16 and 1a. One patient with a relative CTLe expressed CD56 intensely: his ratio normalized at day 730 and no immune-related events were recorded. DNA stored during the post-alloHSCT setting was available from 68/75 relative CTLe patients (14/14 absolute CTLe cases). All of them went through molecular TCR rearrangement and STAT3 exon 21 mutations determination. In the relative CTLe cohort, TCR rearrangement was described as clonal, oligoclonal or polyclonal in 77%, 16% and 7%, respectively. Regarding absolute CTLe patients, TCR rearrangement was described as clonal in all the patients (n=14) of this subset. To increase the sensibility of the Sanger PCR, it was performed on DNA from CD3+ sorted cells in 54 out of 68 cases. No STAT3 mutation could be found in the CD3+ sorted fraction of relative or absolute defined CTLe. Not using an absolute threshold would establish a diagnosis of a persistent CTL expansion in 49% of our cohort of allo-transplanted patients. Additional diagnostic tools, as an effector phenotype, the presence of a NK marker or a monoclonal TCR rearrangement would not reduce significantly that percentage: CD57 was invariably expressed in CTLe cases, and 80% of our patients with expansions showed a TCR monoclonal pattern. STAT3 mutations resulting in persistent proliferation of CTL clones are a frequent event in large granular lymphocytic leukemia, and those clones have also been described in autoimmunity-driven disorders as acquired aplastic anemia and hypocellular myelodysplastic syndromes. We establish in this study the absence of exon 21 STAT3 mutations in the persistent CTL expansions found in a large series of patients with a long-term post-alloHSCT surveillance. The absence of STAT3 mutations and the CD8/CD4 declining longitudinal kinetics in the late period, supports its benign nature, expressed clinically by the null detrimental impact of these expansions on post-transplant outcome and/or serious infectious events. Figure 1. Relative and absolute CTLe kinetics. A) Linear representation over time of the CD8/CD4 ratio in the 75 patients with relative CTLe. B) Trend linear plot of 25 patients with a relative CTLe and a follow up of, at least, 1440 days from transplantation. Each line depicts a patientxs longitudinally measured CD8/CD4 ratio. Patients are grouped by similar pattern of ratio behaviour through follow up. The line "slope" depicts the magnitude of the change between time points. C) Linear representation over time of the CD3/CD8 count in PB in the 14 patients with an absolute CTLe. D) Trend linear plot illustrating the CD8/CD4 ratio behaviour of the 14 patients with an absolute CTLe. Figure 1. Relative and absolute CTLe kinetics. A) Linear representation over time of the CD8/CD4 ratio in the 75 patients with relative CTLe. B) Trend linear plot of 25 patients with a relative CTLe and a follow up of, at least, 1440 days from transplantation. Each line depicts a patientxs longitudinally measured CD8/CD4 ratio. Patients are grouped by similar pattern of ratio behaviour through follow up. The line "slope" depicts the magnitude of the change between time points. C) Linear representation over time of the CD3/CD8 count in PB in the 14 patients with an absolute CTLe. D) Trend linear plot illustrating the CD8/CD4 ratio behaviour of the 14 patients with an absolute CTLe. Disclosures No relevant conflicts of interest to declare.

2018 ◽  
Vol 82 (3) ◽  
pp. 351-369 ◽  
Author(s):  
Iren Johnsen ◽  
Kari Dyregrov ◽  
Stig Berge Matthiesen ◽  
Jon Christian Laberg

This article presents results from one of the first longitudinal studies exploring the effects of losing a close friend to traumatic death, focusing on complicated grief over time and how this is affected by avoidant behavior and rumination about the loss. The sample consists of 88 persons (76% women and 24% men, mean age = 21) who lost a close friend in the Utøya killings in Norway on July 22, 2011.Quantitative data were collected at three time-points; 18, 28, and 40 months postloss. Main findings are that bereaved friends are heavily impacted by the loss and their grief reactions are affected negatively by avoidant behavior and rumination. This indicates that close bereaved friends are a group to be aware of and that there is a need for better strategies for identifying individuals in need for follow-up.


2010 ◽  
Vol 28 (15_suppl) ◽  
pp. 8544-8544 ◽  
Author(s):  
P. A. Prieto ◽  
J. C. Yang ◽  
R. M. Sherry ◽  
M. S. Hughes ◽  
U. S. Kammula ◽  
...  

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5881-5881
Author(s):  
Dave Nellesen ◽  
Qayyim Said ◽  
Nina Shak ◽  
Cody Patton ◽  
Sedge Lucas ◽  
...  

Abstract Introduction: Chronic immune thrombocytopenia (cITP) is an autoimmune disorder defined by low platelet count (<100 x 109/L) lasting ≥12 months in the absence of other causes of thrombocytopenia. Splenectomy is an option for patients with cITP who fail to respond to oral corticosteroids and/or intravenous immunoglobulin or relapse after treatment is discontinued. A systematic literature review (SLR) conducted in 2004 (Kojouri et al) identified articles describing outcomes associated with splenectomy in patients with cITP. The objective of this study was to update this SLR with a focus on contemporary data on long-term outcomes (≥12 months of follow-up). Methods: MEDLINE, Embase, Cochrane CENTRAL and recent congresses were searched in June 2018. Results were screened against predefined criteria by two independent researchers. Included studies assessed patients with cITP (N≥15) who underwent splenectomy; studies of patients with secondary ITP, newly diagnosed ITP, and/or persistent ITP were excluded unless separate outcomes were reported for cITP subgroups. Outcomes of interest were clinical efficacy (response and relapse rates), safety (rates of complications), mortality, and health-related quality of life (HRQoL). Prospective or retrospective clinical studies or real-world study types were included. English-language studies published during or after 2000 were included, with no geographic restrictions. Results: The literature search identified 3140 records for title-abstract screening. Of these, 159 full-text studies were evaluated and 108 were included in the analysis. Most studies (93) were retrospective. Fifteen prospective studies (9 interventional, 6 observational) but no randomized controlled trials were identified. Nine studies were comparative (all retrospective): splenectomy vs rituximab (3), splenectomy vs rituximab vs romiplostim (1), and splenectomy vs non-splenectomy (5). Reports of the long-term efficacy of splenectomy varied widely, with multiple definitions of response and remission across the heterogeneous study types. Among 40 studies, the mean complete response (CR) rate within 12 months of surgery was 77% (median: 81%; range: 26-97%). Relapse rates varied widely, ranging from 0-94% among 47 studies with ≥12 months of follow up. Five of 7 studies reporting remission rates at multiple time points at ≥1 year noted a decrease in clinical remission over time. Mortality generally increased with length of follow up: in studies with ≤1 month of follow-up (28 studies) the mean mortality rate was 1% (range: 0-5%), while in studies with 1-5 years of follow-up (20 studies) and ≥5 years of follow-up (15 studies), the mean mortality rate was 2% (range: 0-17%) and 11% (range: 0-30%), respectively. Four studies reported that long-term response rates were higher with splenectomy than rituximab; all other efficacy comparisons were inconclusive. Although 11 of 15 prospective studies and 61 of 93 retrospective studies reported some safety information, there were very limited data on the long-term safety of splenectomy. Commonly reported complications were bleeding (mean: 14%; median: 12% range: 0-50%; 22 studies), infections (mean: 8%; median: 4% range: 0-33%; 38 studies), venous thromboembolism (VTE) (mean: 5%; median: 3% range: 0-21%; 27 studies) and sepsis/septic shock (mean: 2%; median: 0%; range: 0-11%; 18 studies). Rates of postoperative complications (≤30 days) ranged from 3-50% (mean: 13%; 31 studies), and 2 studies suggested that older age may be associated with higher rates of postoperative complications. HRQoL data were rarely reported (3 studies). Rates of remission, relapse, and infections for studies reporting at least 1 of these outcomes at 1 or more discrete time points are shown in Figure 1. Conclusions: Although more than 100 studies reported long-term outcomes for patients with cITP treated with splenectomy, available evidence on the durability of response and long term safety are limited. In general, most measures of efficacy declined over time, while complications (infections, bleeding, VTE) and mortality increased over time. The extent to which the outcomes for splenectomy differ from currently available treatments is unclear. Additional data are needed to understand the long-term benefits and risks of splenectomy in patients with cITP. Disclosures Nellesen: Analysis Group, Inc.: Employment; Novartis Pharmaceuticals Corporation: Consultancy. Said:Novartis: Employment. Shak:Analysis Group, Inc.: Employment; Novartis Pharmaceuticals Corporation: Consultancy. Patton:Novartis Pharmaceuticals Corporation: Consultancy; Analysis Group, Inc.: Employment. Lucas:Novartis Pharmaceuticals Corporation: Consultancy; Analysis Group, Inc.: Employment. Graves:Novartis: Employment. Nezami:Novartis Pharmaceuticals: Employment. Cuker:Kedrion: Membership on an entity's Board of Directors or advisory committees; Spark Therapeutics: Research Funding; Synergy: Consultancy; Genzyme: Consultancy.


2021 ◽  
Vol 42 (Supplement_1) ◽  
pp. S2-S3
Author(s):  
Callie Abouzeid ◽  
Audrey E Wolfe ◽  
Gretchen J Carrougher ◽  
Nicole S Gibran ◽  
Radha K Holavanahalli ◽  
...  

Abstract Introduction Burn survivors often face many long-term physical and psychological symptoms associated with their injury. To date, however, few studies have examined the impact of burn injuries on quality of life beyond 2 years post-injury. The purpose of this study is to examine the physical and mental well-being of burn survivors up to 20 years after injury. Methods Data from the Burn Model System National Database (1997–2020) were analyzed. Patient-reported outcome measures were collected at discharge with a recall of preinjury status, and then at 5, 10, 15, and 20 years after injury. Outcomes examined were the Physical Component Summary (PCS) and Mental Component Summary (MCS) of the Short Form-12. Trajectories were developed using linear mixed methods model with repeated measures of PCS and MCS scores over time and controlling for demographic and clinical variables. The model fitted score trajectory was generated with 95% confidence intervals to demonstrate score changes over time and associations with covariates. Results The study population included 420 adult burn survivors with a mean age of 42.4 years. The population was mainly male (66%) and white (76.4%) with a mean burn size of 21.5% and length of hospital stay of 31.3 days. Higher PCS scores were associated with follow-up time points closer to injury, shorter hospital stay, and younger age. Similarly, higher MCS scores were associated with earlier follow-up time points, shorter hospital stay, female gender, and non-perineal burns. MCS trajectories are demonstrated in the Figure. Conclusions Burn survivors’ physical and mental health worsened over time. Such a trend is different from previous reported results for mental health in the general population. Demographic and clinical predictors of recovery over time are identified.


2015 ◽  
Vol 51 (17) ◽  
pp. 2689-2697 ◽  
Author(s):  
Zeynep Eroglu ◽  
Dae Won Kim ◽  
Xiaoyan Wang ◽  
Luis H. Camacho ◽  
Bartosz Chmielowski ◽  
...  

2022 ◽  
Author(s):  
Steinunn Arnardóttir ◽  
Jacob Järås ◽  
Pia Burman ◽  
Katarina Berinder ◽  
Per Dahlqvist ◽  
...  

Objective: To describe treatment and long-term outcomes of patients with acromegaly from all health-care regions in Sweden. Design and Methods: Analysis of prospectively reported data from the Swedish Pituitary Register of 698 patients (51% females) with acromegaly diagnosed from 1991-2011. The latest clinical follow-up date was December, 2012, while mortality data were collected for 28.5 years until June, 2019. Results: The annual incidence was 3.7/million; 71% of patients had a macroadenoma, 18% had visual field defects, and 25% had at least one pituitary hormone deficiency. Eighty-two percent had pituitary surgery, 10% radiotherapy and 39% medical treatment. At the 5- and 10-year follow-ups, IGF-I levels were within the reference range in 69% and 78% of patients, respectively. In linear regression the proportion of patients with biochemical control including adjuvant therapy at 10 year follow-up increased over time with 1.23 % per year. The SMR (95% CI) for all patients was 1.29 (1.11-1.49). For patients with biochemical control at the latest follow-up, SMR was not increased, neither among patients diagnosed 1991-2000, SMR 1.06 (0.85-1.33) or 2001-2011, SMR 0.87 (0.61-1.24). In contrast, non- controlled patients at the latest follow up from both decades had elevated SMR, 1.90 (1.33-2.72) and 1.98 (1.24-3.14), respectively. Conclusions: The proportion of patients with biochemical control increased over time. Patients with biochemically controlled acromegaly have normal life expectancy while non-controlled patients still have increased mortality. The high rate of macroadenomas and unchanged age at diagnosis illustrates the need for improvements in the management of patients with acromegaly.


2015 ◽  
Vol 28 (1) ◽  
pp. 71-81 ◽  
Author(s):  
Jane McCusker ◽  
Martin G. Cole ◽  
Philippe Voyer ◽  
Johanne Monette ◽  
Nathalie Champoux ◽  
...  

ABSTRACTBackground:Depression is a common problem in long-term care (LTC) settings. We sought to characterize depression symptom trajectories over six months among older residents, and to identify resident characteristics at baseline that predict symptom trajectory.Methods:This study was a secondary analysis of data from a six-month prospective, observational, and multi-site study. Severity of depressive symptoms was assessed with the 15-item Geriatric Depression Scale (GDS) at baseline and with up to six monthly follow-up assessments. Participants were 130 residents with a Mini-Mental State Examination score of 15 or more at baseline and of at least two of the six monthly follow-up assessments. Individual resident GDS trajectories were grouped using hierarchical clustering. The baseline predictors of a more severe trajectory were identified using the Proportional Odds Model.Results:Three clusters of depression symptom trajectory were found that described “lower,” “intermediate,” and “higher” levels of depressive symptoms over time (mean GDS scores for three clusters at baseline were 2.2, 4.9, and 9.0 respectively). The GDS scores in all groups were generally stable over time. Baseline predictors of a more severe trajectory were as follows: Initial GDS score of 7 or more, female sex, LTC residence for less than 12 months, and corrected visual impairment.Conclusions:The six-month course of depressive symptoms in LTC is generally stable. Most residents who experience a more severe symptom trajectory can be identified at baseline.


2018 ◽  
Vol 130 (1) ◽  
pp. 84-89 ◽  
Author(s):  
Shiro Horisawa ◽  
Taku Ochiai ◽  
Shinichi Goto ◽  
Takeshi Nakajima ◽  
Nobuhiko Takeda ◽  
...  

OBJECTIVEMeige syndrome is characterized by blepharospasm and varied subphenotypes of craniocervical dystonia. Current literature on pallidal surgery for Meige syndrome is limited to case reports and a few small-scale studies. The authors investigated the clinical outcomes of deep brain stimulation (DBS) of the globus pallidus internus (GPi) in patients with Meige syndrome.METHODSSixteen patients who underwent GPi DBS at the Tokyo Women’s Medical University Hospital between 2002 and 2015 were included in this study. Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) movement subscale (BFMDRS-M) scores (range 0–120) obtained at the following 3 time points were included in this analysis: before surgery, 3 months after surgery, and at the most recent follow-up evaluation.RESULTSThe patients’ mean age (± SD) at symptom onset was 46.7 ± 10.1 years, and the mean disease duration at the time of the authors’ initial evaluation was 5.9 ± 4.1 years. In 12 patients, the initial symptom was blepharospasm, and the other 4 patients presented with cervical dystonia. The mean postoperative follow-up period was 66.6 ± 40.7 months (range 13–150 months). The mean total BFMDRS-M scores at the 3 time points were 16.3 ± 5.5, 5.5 ± 5.6 (66.3% improvement, p < 0.001), and 6.7 ± 7.3 (58.9% improvement, p < 0.001).CONCLUSIONSThe results indicate long-term efficacy for GPi DBS for the majority of patients with Meige syndrome.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6568-6568
Author(s):  
Robert J. Motzer ◽  
Toni K. Choueiri ◽  
Jessica May ◽  
Youngmin Kwon ◽  
Nifasha Rusibamayila ◽  
...  

6568 Background: After a minimum follow-up of 48 months (mos), the CheckMate 214 trial (phase 3, NCT02231749) continued to demonstrate a significant overall (OS) and progression-free (PFS) survival benefit for N+I vs. SUN in aRCC patients (pts) with intermediate (I) or poor (P) International Metastatic RCC Database Consortium (IMDC) risk factors (median OS: 48.1 vs. 26.6 mos, HR: 0.65, 95% confidence interval [95% CI]: 0.54, 0.78; 48-mos PFS: 32.7% vs. 12.3%, HR: 0.74, 95% CI: 0.62, 0.88) (Albiges et al. ESMO Open 2020). To further understand the clinical benefits and risks of N+I vs. SUN, we evaluated the Q-TWiST over time using up to 57 mos of follow-up in CheckMate 214. Methods: OS was partitioned into 3 states: time with any grade 3 or 4 adverse events (TOX), time without symptoms of disease or toxicity (TWiST), and time after progression (REL). The Q-TWiST is a metric that combines the quantity and quality (i.e., “utility”) of time spent in each of the 3 states TWiST, TOX, and REL. Prior research (Revicki et al, Qual Life Res, 2006) has established that relative gains in Q-TWiST (i.e., Q-TWiST gain divided by OS in SUN) of ≥ 10% and ≥ 15% can be considered as “clinically important” and “clearly clinically important”, respectively. Non-parametric bootstrapping was used to generate 95% CIs. To observe changes in quality-adjusted survival gains over time, absolute and relative Q-TWiST were calculated up to 57 mos at intervals of 12-mos. Results: With 57-mos follow-up, compared to SUN pts, N+I pts (N = 847) had significantly longer time in TWiST state (+7.1 mos [95% CI: 4.2, 10.4]). The between-group differences in TOX state (0.3 mos [95% CI: -0.2, 0.8]) and REL state (-1.2 mos [95% CI: -4.1, 1.5]) were not statistically significant. The Q-TWiST gain in the N+I vs. SUN arms was 6.6 mos (95% CI: 4.1, 9.4), resulting in a 21.2% relative gain. Q-TWiST gains progressively increased over the follow-up period and exceeded the “clinically important” threshold around 27 mos (Table). These gains were driven by steady increases in TWiST gains from 0.4 mos (after 12 mos) to 7.1 mos (after 57 mos). Conclusions: In CheckMate 214, N+I resulted in a statistically significant and “clearly clinically important (≥ 15%)” longer quality-adjusted survival vs. SUN, which increased over the longer follow-up time. Q-TWiST gains were primarily driven by time in “good” health (i.e., TWiST), which largely resulted from the long-term PFS benefits seen for N+I vs. SUN. Clinical trial information: NCT02231749. [Table: see text]


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