Development Of Lymphopenia Research Articles

Lymphopenia Predicts Poor Outcomes in Newly Diagnosed Multiple Myeloma

Bone marrow microenvironment plays an important role in promoting growth and survival of multiple myeloma (MM) cells. The tumor-promoting immune microenvironment is augmented while anti-tumor immune responses are inhibited. Although clinical and genomic markers of high-risk MM have been described, the immune status is just being recognized as a potential mediator of disease behavior. This is even more important with the development of a number of immune-based therapies. Based on these considerations, we evaluated peripheral blood absolute lymphocyte count (ALC) as an easily accessible marker representing immune microenvironment at diagnosis and following treatment of MM. We retrospectively evaluated 11,427 patients diagnosed with MM between 2000 and 2019 at Veteran’s Administration hospitals using ALC obtained closest to diagnosis and up to 2.5 years thereafter. Patients were stratified into 3 ALC categories: severely low, low, and normal (<1, 1-1.5, and >1.5 x 103/mm3, respectively). Lymphopenia (including severely low and low ALC) was present in 53% of patients at MM diagnosis and was associated with inferior overall survival (OS). Median OS of patients with severely low, low, and normal ALC at diagnosis was 2.7, 3.3, and 4.2 years (P < .001), respectively. Moreover, persistent or new development of lymphopenia during treatment and follow-up was also associated with inferior OS. Our findings support the use of ALC as a biomarker for risk stratification in MM.

Lymphopenia associated with whole-brain radiotherapy and its effects on clinical outcomes of patients with brain metastases

There is increasing awareness of radiotherapy’s potential side effects, such as lymphopenia. Therefore, this study aimed to establish the association between WBRT and the development of lymphopenia in patients with brain metastases undergoing brain radiotherapy (RT), along with evaluating the corresponding clinical outcomes. Including 116 patients with brain metastases undergoing brain radiotherapy, the study collected the absolute lymphocyte counts (ALC) within 2 weeks before brain radiotherapy (pre-radiotherapy, pre-RT), as well as ones at 1 and 2 months after completing RT (post-RT). Univariate and multivariate analyses were performed to identify associations between radiation modality and post-RT ALC. The relationships between post-RT ALC and overall survival were evaluated with Kaplan–Meier analysis and a multivariate Cox regression model. The median ALC definitely decreased at 1 month post-RT, but at 2 months post-RT, gradually rose but not to the pre-RT ALC. The multivariate analysis identified WBRT and lower pre-RT ALC as independent risk factors associated with the decrease in post-RT ALC at 1 month. It also revealed more than 4 brain metastases, G3-4 lymphopenia at 1 month and lower post-RT ALC at 2 months exhibited significantly worse prognosis regardless of the radiation modality. However, there was indeed an independent correlation between radiation modality and the outcome of intracranial progression-free survival (PFS). To approach the feasibility and reasonableness of treatment, clinicians should carefully consider various factors to achieve long-term survival of patients.

Lymphocyte Nadir Following Radiation for Soft-Tissue Sarcoma: Defining Key Dosimetric Parameters and Outlining Clinical Significance

<h3>Purpose/Objective(s)</h3> Lymphopenia following radiotherapy (RT) is associated with worse oncologic outcomes in numerous cancers, but its incidence and effects are unknown in soft-tissue sarcomas (STS). Our goals were to determine the dosimetric parameters associated with development of lymphopenia and evaluate the impact of lymphopenia on overall survival (OS) and disease-free survival (DFS). <h3>Materials/Methods</h3> We retrospectively reviewed 51 patients who underwent either preoperative, postoperative, or definitive RT for STS at our institution between April, 2010 and May, 2021. Absolute lymphocyte count (ALC) nadir was defined as lowest lymphocyte value within one year after RT, and lymphopenia grading was by CTCAE v5.0. Dosimetric parameters were evaluated for associations with ALC nadir, including PTV size as well as mean and volumetric doses (V10, V20, V30) of body, bone, heart, and lung. <h3>Results</h3> Median follow-up was 1.9 years (range 0.3-9.7 years). Stage I cancer was present in 15.7%, Stage II in 11.8%, Stage III in 68.6%, Stage IV in 3.9% (for N1). Grade 1 disease was found in 6.5%, Grade 2 in 6.5%, Grade 3 in 78.4%, and unknown in 9.8%. Chemotherapy was delivered to 35.3%. Median RT dose was 50 Gy (range 45-78 Gy) and IMRT was used for 70.6%. Time to ALC nadir was within 6 months of RT for 86% of patients. Median ALC at baseline was 1400 cells/mm³ (range 600 to 3400 cells/mm³) and at nadir was 900 cells/mm³ (range 40 to 2400 cells/mm³). Strongest correlations with ALC nadir were body V10 (r_s = 0.435, p = 0.002), mean bone (r_s = 0.632, p = 0.001), bone V10 (r_s = 0.632, p <0.001), and bone V20 (r_s = 0.562, p <0.001). Significant but weaker correlations included mean body, body V20, body V30, and bone V30. Lung and heart parameters as well as total dose did not show significant correlations. On multivariable linear regression controlling for disease grade, surgical resection, and chemotherapy use, strongest correlations with ALC nadir were body V10 (β = 0.468, p < 0.001) and bone V10 (β = 0.479, p < 0.001). Distribution of lymphopenia was: grade 1 (17.6%), grade 2 (13.7%), grade 3 (19.6%), and grade 4 (5.9%). Grade 2-4 lymphopenia was associated with inferior OS (HR 5.82, p = 0.01) and DFS (HR 3.85, p=0.002). Lower ALC nadir was also associated with worse OS (HR = 1.95, p = 0.014) and DFS (HR = 1.15, p = 0.001). On multivariate regression, only Grade 3-4 lymphopenia remained associated with worse OS and DFS. <h3>Conclusion</h3> Lower ALC nadir and development of Grade 2-4 lymphopenia were associated with worse OS and DFS in STS. Despite the heterogenous location of STS presentation, lower ALC nadir showed strong correlations with increasing body V10 and bone V10, consistent with the known radiosensitivity of lymphocyte cell lines. Our study supports efforts to reduce treatment-related hematopoietic toxicity as a move to improve oncologic outcomes. This work also raises the hypothesis that radiation effects on lymphocyte progenitors in the bone marrow dominate those of circulating lymphocytes for treatments with minimal contribution to heart and lung.

Clinical features of glioma patients who develop pneumocystis pneumonia with temozolomide chemoradiotherapy.

The treatment of glioma with temozolomide chemoradiotherapy predisposes patients to pneumocystis pneumonia (PCP). Because PCP is a rare outcome, very little is known about specific clinical risk factors for its development in patients with glioma. We performed a population-based retrospective cohort study of glioma patients undergoing temozolomide chemoradiotherapy 2005 to 2019 in Ontario, Canada. We compared clinical features of patients who did not versus did develop PCP within one year of chemoradiotherapy. We examined the overall survival of patients by PCP status. There were 5130 patients with glioma treated with temozolomide chemoradiotherapy. Ultimately, 38 patients (0.74%) were diagnosed with PCP within 1year of chemoradiotherapy. Most (71%) infections occurred between 0-90days and 29% occurred between 91-365days. Median survival was 12.3months in patients who did not develop PCP and 8.6months in those who did develop PCP (P < 0.001). Trough 90-day lymphocyte counts were lower in the PCP group. When the lymphocytes fell below 0.19 × 109/L (or 0.25 × 109/L among patients without PCP prophylaxis), the risk of PCP was > 3.5%. Pneumocystis pneumonia is rare in glioma patients who receive temozolomide chemoradiotherapy. Infection is associated with shorter survival and the development of lymphopenia. Reserving PCP prophylaxis for patients whose lymphocyte counts drop below 0.25 × 109/L may be a reasonable strategy.

Development of Lymphopenia during Therapy with Immune Checkpoint Inhibitors Is Associated with Poor Outcome in Metastatic Cutaneous Melanoma.

Simple SummaryPredictive markers are necessary for immune checkpoint inhibitor (ICI) therapy. The aim of our retrospective study was to investigate the relationship between the occurrence of lymphopenia under ICI and disease outcome. A total of 116 patients with metastatic melanoma who received ICI therapy with normal lymphocyte counts at baseline were analyzed. Lymphopenia occurred in 42.2% of patients with a mean onset after 17 weeks (range 1–180 weeks). The occurrence of lymphopenia during immunotherapy was significantly associated with a shorter PFS and OS. Patients who developed lymphopenia (n = 49) had a mean PFS of 13.3 months (range 1–67 months) compared to 16.9 months (range 1–73 months) for patients who did not develop lymphopenia (n = 67; p = 0.025). Similarly, patients with lymphopenia had a significantly shorter OS of 28.1 months (range 2–70 months) compared with 36.8 months (range 4–106 months) in patients who did not develop lymphopenia (p = 0.01). Predictive markers for immune checkpoint inhibitor (ICI) therapy are needed. Thus, baseline blood counts have been investigated as biomarkers, showing that lymphopenia at the start of therapy with (ICI) is associated with a worse outcome in metastatic melanoma. We investigated the relationship between the occurrence of lymphopenia under ICI and disease outcome. Patients with metastatic melanoma who had undergone therapy with ICI were identified in our database. Only patients with a normal lymphocyte count at baseline were included in this retrospective study. Progression-free survival (PFS) and overall survival (OS) were compared between patients in which lymphopenia occurred during ICI therapy and those who did not develop lymphopenia. In total, 116 patients were analyzed. Lymphopenia occurred in 42.2% of patients, with a mean onset after 17 weeks (range 1–180 weeks). The occurrence of lymphopenia during immunotherapy was significantly associated with a shorter PFS and OS. Patients who developed lymphopenia (n = 49) had a mean PFS of 13.3 months (range 1–67 months) compared to 16.9 months (range 1–73 months) for patients who did not develop lymphopenia (n = 67; p = 0.025). Similarly, patients with lymphopenia had a significantly shorter OS of 28.1 months (range 2–70 months) compared with 36.8 months (range 4–106 months) in patients who did not develop lymphopenia (p = 0.01). Patients with metastatic melanoma who develop lymphopenia during ICI therapy have a worse prognosis with significantly shorter PFS and OS compared with patients who do not develop lymphopenia.

Vertebral body and splenic irradiation are associated with lymphopenia in localized pancreatic cancer treated with stereotactic body radiation therapy

ObjectivesThe purpose of this study was to determine if vertebral body and splenic dosimetry was associated with the development of lymphopenia in patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) treated with stereotactic body radiation therapy (SBRT).MethodsPatients with BRPC/LAPC who were treated with SBRT and who had lymphocyte counts and radiation treatment plans available for review were included in the study. Vertebral body levels T11-L3 and the spleen were retrospectively contoured for each patient. Univariate (UVA) and multivariable analyses (MVA) were performed to identify associations between vertebral body and splenic dosimetric parameters with absolute lymphocyte count (ALC) and grade ≥ 2 lymphopenia. Receiver operator characteristic curves were generated to identify dose-volume thresholds in predicting grade ≥ 2 lymphopenia.ResultsA total of 132 patients were included in the study. On UVA and MVA, vertebral V15 (regression coefficient [β]: − 0.026, 95% CI − 0.044 to − 0.009, p = 0.003), vertebral V2.5 (β: − 0.011, 95% CI − 0.020 to − 0.002, p = 0.015), and log10PTV (β: − 0.15, 95% CI − 0.30 to − 0.005, p = 0.042) were associated with post-SBRT ALC. On UVA and MVA, vertebral V15 (odds ratio [OR]: 3.98, 95% CI 1.09–14.51, p = 0.027), vertebral V2.5 (OR: 1.04, 95% CI 1.00–1.09, p = 0.032), and spleen V10 (OR: 1.05, 95% CI 1.09–1.95, p = 0.004) were associated with development of grade ≥ 2 lymphopenia. Development of grade ≥ 2 lymphopenia was more likely in patients with vertebral V15 ≥ 5.84% (65.5% vs 34.0%, p = 0.002), vertebral V2.5 ≥ 48.36% (48.9% vs 23.8%, p = 0.005), and spleen V10 ≥ 4.17% (56.2% vs 26.9%, p < 0.001).ConclusionsIncreasing radiation dose to vertebral bodies and spleen were associated with the development of lymphopenia in BRPC/LAPC treated with SBRT. Optimization of vertebral body and splenic dosimetry may reduce the risk of developing lymphopenia and improve clinical outcomes in this population.

Association of severe lymphopenia and disease progression in unresectable locally advanced non-small cell lung cancer treated with definitive chemoradiation and immunotherapy

BackgroundDefinitive chemoradiation with consolidative immunotherapy offers the best chance for cure in patients with unresectable, locally advanced non-small cell lung cancer (NSCLC). However, treatment-related lymphopenia (TRL) may negatively impact outcomes. MethodsPatients definitively treated with chemoradiation and immunotherapy from 2015 to 2019 at a single tertiary academic center were identified. Severe lymphopenia was defined as <0.5 × 109 cells/L. Progression-free survival (PFS) was calculated by Kaplan Meier methodology. Univariate and multivariate Cox Proportional Hazard modeling was used to correlate clinical variables with disease outcome. Immune-related adverse events (irAEs) were assessed according to CTCAE version 5.0 criteria. ResultsSeventy-eight patients were included in the final cohort. The median age was 66 years (IQR: 58−73), 55 % were males, and 88 % had a KPS of >70. At baseline, 90 % (n = 70/78) of patients had a normal ALC and one patient had severe lymphopenia. After chemoradiation, the median ALC decreased from 1.52 × 109cells/L (IQR: 1.23–1.98) to 0.72 × 109cells/L (IQR: 0.52−0.94) (p < 0.001), 22 % (n = 17/78) of patients had a normal ALC, and 23 % (n = 18/78) of patients developed severe lymphopenia. Patients who initiated consolidative immunotherapy with severe lymphopenia had worse PFS than those who did not (median 217 days [IQR: 120–434] vs. 570 days [IQR: 401-NR], p < 0.001). On multivariate modeling, severe lymphopenia at the time of immunotherapy initiation remained an independent predictor of worse PFS (HR 4.90, p < 0.001). ConclusionsThis is the first report to associate severe TRL with disease progression in patients with locally advanced NSCLC receiving consolidative immunotherapy. Factors associated with development of lymphopenia and strategies to mitigate lymphopenic effects should be considered.

Risk factors for severe and critically ill COVID-19 patients: A review.

The pandemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused an unprecedented global social and economic impact, and high numbers of deaths. Many risk factors have been identified in the progression of COVID-19 into a severe and critical stage, including old age, male gender, underlying comorbidities such as hypertension, diabetes, obesity, chronic lung diseases, heart, liver and kidney diseases, tumors, clinically apparent immunodeficiencies, local immunodeficiencies, such as early type I interferon secretion capacity, and pregnancy. Possible complications include acute kidney injury, coagulation disorders, thoromboembolism. The development of lymphopenia and eosinopenia are laboratory indicators of COVID-19. Laboratory parameters to monitor disease progression include lactate dehydrogenase, procalcitonin, high-sensitivity C-reactive protein, proinflammatory cytokines such as interleukin (IL)-6, IL-1β, Krebs von den Lungen-6 (KL-6), and ferritin. The development of a cytokine storm and extensive chest computed tomography imaging patterns are indicators of a severe disease. In addition, socioeconomic status, diet, lifestyle, geographical differences, ethnicity, exposed viral load, day of initiation of treatment, and quality of health care have been reported to influence individual outcomes. In this review, we highlight the scientific evidence on the risk factors of severity of COVID-19.

Investigation of hematological parameters related to the severity of COVID-19 disease in Mashhad, Iran

Introduction:Human coronavirus disease 2019 (COVID-19) is an emerging respiratory disease that has become pandemic worldwide. The patients have a range of mild to severe symptoms, such as pneumonia, acute respiratory distress syndrome, arrhythmia, shock, and other organs involvement. Clinical and hematological evidence can serve as a prognostic factor to detect severe cases of COVID-19. Objectives: The present study aimed to evaluate hematological parameters related to the severity of the disease in COVID-19 patients in Mashhad, Eastern Iran. Patients and Methods: All the individuals with positive real-time reverse transcription-polymerase chain reaction test results and the patients with clinical symptoms whose computed tomography scan results were matched with the diagnosis of viral pneumonia were included in the study. The hematological examinations and complete blood count of the patients were performed by the healthcare personnel through collecting blood samples at the time of admission and discharge from the hospital. Results: In total, 189 COVID-19 patients were included in the study, 47.6% and 58.73% of whom were over 60 years old and male, respectively. Investigation of the hematological parameters revealed that the number of white blood cells, mean value of corpuscular volume, number of platelets, and lymph count had significantly increased at the time of discharge (P&lt;0.01). On the other hand, red blood cells, hemoglobin, hematocrit, mean corpuscular hemoglobin, mean corpuscular hemoglobin, and red cell distribution width values were significantly higher at the time of admission in comparison to discharge (P&lt;0.01). Furthermore, it was found that male gender had a significant relationship with the development of lymphopenia in the patients (P=0.021). Conclusion: It can be concluded that hematological parameters and inflammatory biomarkers in COVID-19 patients could potentially act as the independent factors and affect the prognosis of the disease.

Hematological Alterations Related to Treatment with Teriflunomide and Dimethyl Fumarate in Multiple Sclerosis

The exact mechanism of action of different modifying treatments in the evolutionary course of multiple sclerosis (MS) remains unknown, but it is assumed that they act upon the cells involved in acquired immunity. One effect of these treatments is the development of lymphopenia, which carries inherent safety risks. This study was conducted to understand the alterations that teriflunomide (TERI) and dimethyl fumarate (DMF) exert upon white blood cells in a series of patients with MS. This study included a total of 99 patients; 44 treated with DMF and 55 patients treated with TERI. Blood counts were evaluated at baseline and every 6 months in order to track the absolute leukocyte, lymphocyte, and neutrophil counts. Twelve months after starting treatment, we observed a significant decrease in leukocytes (21.1%), lymphocytes (39.1%), and neutrophils (10%) in the DMF group. In the TERI group, leukocytes decreased by 11.1%, lymphocytes by 8.1%, and neutrophils by 15.7%. Both TERI and DMF produced a significant decrease in leukocytes during the first year of treatment and this was mainly related with a decrease in neutrophils in the TERI group and a decrease in lymphocytes in the DMF group.

FTY720 (Fingolimod) Ameliorates Brain Injury through Multiple Mechanisms and is a Strong Candidate for Stroke Treatment.

FTY720 (Fingolimod) is a known sphingosine-1-phosphate (S1P) receptor agonist that exerts strong anti-inflammatory effects and was approved as the first oral drug for the treatment of multiple sclerosis by the US Food and Drug Administration (FDA) in 2010. FTY720 is mainly associated with unique functional “antagonist” and “agonist” mechanisms. The functional antagonistic mechanism is mediated by the transient down-regulation and degradation of S1P receptors on lymphocytes, which prevents lymphocytes from entering the blood stream from the lymph node. This subsequently results in the development of lymphopenia and reduces lymphocytic inflammation. Functional agonistic mechanisms are executed through S1P receptors expressed on the surface of various cells including neurons, astrocytes, microglia, and blood vessel endothelial cells. These functions might play important roles in regulating anti-apoptotic systems, modulating brain immune and phagocytic activities, preserving the Blood-Brain-Barrier (BBB), and the proliferation of neural precursor cells. Recently, FTY720 have shown receptor-independent effects, including intracellular target bindings and epigenetic modulations. Many researchers have recognized the positive effects of FTY720 and launched basic and clinical experiments to test the use of this agent against stroke. Although the mechanism of FTY720 has not been fully elucidated, its efficacy against cerebral stroke is becoming clear, not only in animal models, but also in ischemic stroke patients through clinical trials. In this article, we review the data obtained from laboratory findings and preliminary clinical trials using FTY720 for stroke treatment.

Lymphopenia during radiotherapy in patients with oropharyngeal cancer

Purpose/ObjectiveRadiation-induced lymphopenia has been associated with poor survival outcomes in certain solid tumors such as esophageal, lung, cervical and pancreatic cancers. We aim to determine the effect of treatment-related lymphopenia during radiotherapy on outcomes of patients with oropharyngeal cancer. Materials/MethodsA retrospective analysis of all patients who completed definitive radiotherapy for oropharyngeal cancer at The University of Texas MD Anderson Cancer Center and had blood counts taken during radiotherapy from 2002 to 2013 were included. Patient, tumor and treatment characteristics, clinical outcomes and lymphocyte counts during radiotherapy were recorded. Lymphopenia was graded according to the CTCAE v4.0. Survival rates were estimated using the Kaplan-Meier method and compared with log-rank tests. Results850 patients were evaluated. The median age was 57 years. The majority of the cohort had p16/HPV-positive disease (71%), 8% had HPV-negative disease and 21% were unknown. The median radiation total dose was 70 Gy. 45% of patients had induction chemotherapy, and 87% had concurrent chemotherapy. 703 (83%) patients developed ≥grade 3 (G3) lymphopenia and 209 (25%) had grade 4 (G4) lymphopenia during radiotherapy. The median follow-up was 59 months; the 5-year overall survival rate was 81%. There were no significant differences in overall survival rates nor in disease control rates, in those who developed G3/G4 lymphopenia compared with those who did not. No significant effect of lymphopenia on survival was observed when analyzed according to p16/HPV status. ConclusionIn this large cohort of patients with oropharyngeal cancer, the development of lymphopenia during radiotherapy did not impact outcomes.

Effects of cardiopulmonary bypass on the development of lymphopenia and sepsis after cardiac surgery in children with congenital cardiopathy.

The objective of the present study was to investigate whether lymphopenia occurring after heart surgery with cardiopulmonary bypass (CPB) is related to apoptosis and or sepsis in children. The design was a prospective cohort study in a third level care hospital in Mexico City. In total, 68 children (31 girls and 37 boys) with congenital cardiopathy who needed corrective cardiac surgery with or without CPB were included. The samples were obtained from central blood before, immediately after and 24 h after surgery. Complete blood counts and lymphocyte apoptosis were analyzed. Systemic inflammatory response syndrome (SIRS), sepsis and the type of microorganism were recorded. A total of 53 patients received CPB and 15 did not. Lymphocyte count decreased after surgery in both groups (P<0.001). However, neutrophil count increased markedly in both groups. Apoptosis of B (CD19+) lymphocytes was higher in the non-CPB group (14, 2 and 21% before, immediately after and 24 h after surgery, respectively) than the CPB group (0, 2 and 3%, respectively), but apoptosis of cytotoxic T lymphocytes (CD8+) was higher in the CPB group (5, 4 and 3% before, immediately after and 24 h after surgery, respectively) than in the non-CPB group (2, 3 and 2%, respectively). However, the extent of apoptosis of T and B lymphocytes after surgery did not differ between groups. The CPB group had more complications than the non-CPB group [38 (71.7%) vs. 9 (60.0%)]. In conclusion, the decrease in lymphocyte count may be related to apoptosis of cytotoxic T lymphocytes in children receiving cardiac surgery with CPB and to apoptosis of B lymphocytes in those not receiving CPB. The decreased lymphocyte counts in both groups suggested that CPB is not the main cause of this decrease. Children who received CPB during surgery had more complications, such as sepsis and cardiogenic shock than did those who did not receive CPB.

Innate-Like Lymphocytes Are Immediate Participants in the Hyper-Acute Immune Response to Trauma and Hemorrhagic Shock.

Adverse outcomes following severe traumatic injury are frequently attributed to a state of immunological dysfunction acquired during treatment and recovery. Recent genomic evidence however, suggests that the trajectory toward development of multiple organ dysfunction syndrome (MODS) is already in play at admission (<2 h following injury). Improved understanding of the molecular events during the hyper-acute immunological response to trauma, <2 h following injury, may reveal opportunities to ameliorate organ injury and expedite recovery. Lymphocytes have not previously been considered key participants in this early response; however, two observations in human trauma patients namely, raised populations of circulating NKT and NK cells during the hyper-acute phase and persistent lymphopenia beyond 48 h show association with the development of MODS during recovery. These highlight the need for greater understanding of lymphocyte function in the hyper-acute phase of inflammation. An exploratory study was therefore conducted in a well-established murine model of trauma and hemorrhagic shock (T&HS) to investigate (1) the development of lymphopenia in the murine model and (2) the phenotypic and functional changes of three innate-like lymphocyte subsets, NK1.1+ CD3–, NK1.1+ CD3+, γδTCR+ CD3+ cells, focusing on the first 6 h following injury. Rapid changes in phenotype and function were demonstrated in these cells within blood and spleen, but responses in lung tissue lagged behind. This study describes the immediacy of the innate-like lymphocyte response to trauma in different body compartments and considers new lines for further investigation to develop our understanding of MODS pathogenesis.

Dosimetry of the brain and hypothalamus predicting acute lymphopenia and the survival of glioma patients with postoperative radiotherapy

BackgroundThe aim of this study was to investigate dosimetric factors for predicting acute lymphopenia and the survival of glioma patients with postoperative intensity‐modulated radiotherapy (IMRT).MethodsA total of 148 glioma patients were reviewed. Acute lymphopenia was defined as a peripheral lymphocyte count (PLC) lower than 1.0 × 109/L during radiotherapy with a normal level at pretreatment. PLCs with the corresponding dates and dose volume histogram parameters were collected. Univariate and multivariate Cox regression analyses were constructed to assess the significance of risk factors associated with lymphopenia and overall survival (OS).ResultsSixty‐nine (46.6%) patients developed lymphopenia during radiotherapy. Multivariate analyses revealed that the risk increased with the maximal dose of the hypothalamus (HT Dmax) ≥56 Gy (58.9% vs 28.5%, P = 0.002), minimal dose of the whole brain (WB Dmin) ≥2 Gy (54.3% vs 33.9%, P = 0.006), or mean dose of the WB (WB Dmean) ≥34 Gy (56.0% vs 37.0%, P = 0.022). Patients with older age, high‐grade glioma, development of lymphopenia, high HT Dmax, WB Dmin, and WB Dmean had significantly inferior OS in the multivariate analyses.ConclusionsHT Dmax, WB Dmin, and WB Dmean are promising indicators of lymphopenia and the survival of glioma patients undergoing postoperative IMRT. The necessity and feasibility of dosimetric constraints for HT and WB is warranted with further investigation.

Lymphopenia During Radiation Therapy In Patients with Oropharyngeal Cancer: Does It Affect Survival Outcomes?

Radiation-induced lymphopenia have been associated with poor survival outcomes in certain solid tumors such as breast, colorectal, lung, cervical and pancreatic cancers. We aim to determine the effect of treatment-related lymphopenia during radiotherapy on outcomes of patients with oropharyngeal cancer. A retrospective analysis of patients who completed definitive radiotherapy for oropharyngeal cancer and had blood counts taken during radiotherapy from 2002 to 2013 were included. Patient, tumor and treatment characteristics, clinical outcomes and lymphocyte counts during radiotherapy were recorded. Lymphopenia was graded according to the CTCAE v4.0. Survival rates were estimated using the Kaplan-Meier method and compared with log-rank tests. A total of 850 patients were evaluated. The median age was 57 years. The most common primary sites were base of tongue (55%) and tonsil (43%). The majority of the cohort had p16/HPV-positive disease (71%), 8% had HPV-negative disease and 21% were unknown. The median radiation total dose was 70 Gy. A total of 45% of patients had induction chemotherapy, and 87% had concurrent chemotherapy. A total of 703 (83%) patients developed ≥grade 3 (G3) lymphopenia and 209 (25%) had grade 4 (G4) lymphopenia during radiotherapy. The median follow-up was 59 months; the 5-year overall survival rate was 81%. There were no significant differences in overall survival rates nor in disease control rates, in those who developed G3/G4 lymphopenia compared with those who did not. No significant effect of lymphopenia on survival was observed when analyzed according to p16/HPV status. In this large cohort of patients with oropharyngeal cancer, the development of lymphopenia during radiotherapy did not impact outcomes.

196: Interleukin-7-mediated NFAT activation sets the threshold for T cell development

Interleukin-7 (IL-7), a member of the common cytokine gamma-chain family, plays critical role in T cell biology. Studies using gene knock out mice for IL-7 or the components of IL-7 signaling have unequivocally established that IL-7-Jak3-STAT5 signaling is an absolute necessity for development of a normal T cell repertoire. However, subtle differences in the phenotype of STAT5 deficient mice to that of IL-7 or IL-7R deficient mice implicate that transcription factors other than STAT5 might be activated upon IL-7 signaling. Transcription factors of NFAT family play prominant role in T cell development and function. However, the role of NFAT family proteins in the early cytokine-dependent stages of thymocyte development is unclear. Additionally, whether the activity of individual NFAT family members during thymocyte development are complementary, antagonistic or redundant is unknown. Differentiation of DN thymocytes from the early thymic progenitor (ETP) cells is critically dependent on IL-7 signaling. We have elucidated a novel aspect of IL-7 signaling, whereby IL-7 signals activate NFATc1 in the DN1-DN3 thymocytes by Jak3-mediated tyrosine phosphorylation, which occurs parallel to that of STAT5 activation. Conventionally, in T cells NFAT proteins are activated via calcineurin-mediated multiple serine/threonine dephosphorylation in its regulatory domain upon TCR signaling. However the alternative NFAT activation pathway we have elucidated is distinct from that of the calcineurin-mediated NFAT activation pathway. First, instead of ser/thr dephosphorylation, IL-7 activates NFAT via tyrosine (tyr) phosphorylation. Second, JAK3 activated downstream to IL-7 signals is the kinase responsible for NFAT activation. Third, IL-7 induced NFAT activation is insensitive to cyclosporin A treatment and finally, this alternative NFAT activation pathway is vital for the survival of the early DN thymocytes which have not yet acquired the cell surface pre-TCR. We show that NFATc1 is the pre-dominant NFAT protein over NFATc2 or NFATc3 in regulating early thymocyte development and synergistically with STAT5, it controls the gene expression programs associated with early T cell survival. Accordingly, ablation of NFATc1, and not NFATc2 or NFATc3, severely impaired the T cell development resulting in T-cell lymphopenia similar to that observed in mice deficient for STAT5 or IL-7 signaling. Thus by elucidating a previously unknown aspect of IL-7 signaling, we demonstrate that in addition to STAT5, NFATc1 activation by IL-7/JAK3 sets the threshold between development of lymphopenia or that of a normal functional T cell repertoire during the cytokine-dependent phases of thymocyte development.

Human Immunodeficiency Virus Type 1 gp120 Reprogramming of CD4+T-Cell Migration Provides a Mechanism for Lymphadenopathy

Infection by human immunodeficiency virus type 1 (HIV-1) is associated with decreases in peripheral CD4(+) T cells and development of lymphadenopathy. The precise mechanisms by which HIV-1 induces these changes have not been elucidated. T-cell trafficking through lymphoid tissues is facilitated by CCL21-mediated entry and sphingosine-1-phosphate (S1P)-mediated egress. Having previously determined that HIV-1 envelop glycoprotein, gp120, directly alters T-cell migration, we investigated whether gp120 without HIV-1 infection could influence the responses of CD4(+) T cells to the signals involved in T-cell trafficking through lymph tissue. Incubation of normal human T cells with gp120 for 1 h resulted in reprogramming of CD4 T-cell migratory responses by increasing sensitivity to CCL20 and CCL21 and complete inhibition of migration to S1P. Incubation of human T cells with gp120 prior to injection into NOD.CB17-Prkdc(scid)/J mice resulted in increases in lymph node accumulation of CD4(+) T cells, with reciprocal decreases in blood and spleen compared to T cells not exposed to gp120. The effects of gp120 required CD4 signaling mediated through p56(lck). These findings suggest that gp120 alone can alter CD4(+) influx and efflux from lymph nodes in a fashion consistent with the development of lymphopenia and lymphadenopathy.

Hematological Effects of Inhaled Plutonium Dioxide in Beagles

A life-span study indicated that plutonium activity in the thoracic lymph nodes is a contributor to development of lymphopenia in beagles exposed to 239PuO2. Significant lymphopenia was found in 67 (58%) beagles given a single nose-only exposure to 239PuO2 to result in mean initial lung depositions ranging from 0.69 to 213.3 kBq. Lymphoid atrophy and sclerosis of the thoracic lymph nodes and lymphopenia were observed in exposure-level groups with initial lung depositions > or = 2.5 kBq. Those dogs with final plutonium concentrations in the thoracic lymph nodes > or = 0.4 kBq/g and dose rates > or = 0.01 Gy/day developed lymphopenia. Marked differences existed between chronically lymphopenic dogs and intermittently lymphopenic dogs with regard to initial lung deposition, time to lymphopenic events and absolute lymphocyte concentrations. Linear regression analysis revealed moderate correlation between reduction in lymphocyte values and initial lung deposition, in both magnitude and time of appearance after exposure. Cumulative dose and dose rate appeared to act together to produce initial effects on lymphocyte populations, while dose rate alone appeared to be responsible for the maintenance and subsequent cycles of lymphopenia seen over the life span. No primary tumors were associated with the thoracic lymph nodes in this study, although 70% of the lymphopenic dogs developed lung tumors.

EXTRACORPOREAL IRRADIATION OF THE BLOOD

Abstract. The development and duration of lymphopenia in 71 uremic patients undergoing extracorporeal irradiation of the blood (ECIB) have been investigated. The median duration of each ECIB session was 9 1/2 hours, administered at intervals ranging from 1 to 4 days. The median total duration of one series of ECIB was 100 hours. The changes in the lymphocyte concentration during ECIB were analysed by means of the least squares method and could be expressed by the equation Y = B(1)e(‐ B(2) X) + B(3), in which Y is the lymphocyte count in % of pre‐ECIB level and X the number of blood volumes radiated. The development of lymphopenia was then defined by the slope — B(2) and the degree by the intercept B(3). In all patients a rapid reduction of the lymphocyte concentration in peripheral blood to 25–30% of pre‐ECIB level was observed. Continuation of ECIB treatment did not result in a further significant reduction of the lymphocyte concentration. A direct relationship was found between the transit dose and the development and degree of lymphopenia for transit doses between 100 and 500 rads. Variation neither in blood flow rate nor in spacing of the ECIB sessions had any detectable influence on the development and degree of the lymphopenia produced. After cessation of ECIB the lymphocyte concentration was followed in 19 patients within a period of 18 months. An increase in the lymphocyte counts to 35–40% of pre‐ECIB level was observed within the first 5 months after cessation of ECIB, but from the 5th to the 18th month no further increase could be demonstrated.