Case report: Artificial thymic organoids facilitate clinical decisions for a patient with a TP63 variant and severe persistent T cell lymphopenia.

Pathogenic variants in the transcription factor TP63 are associated with clinically overlapping syndromes including ectrodactyly-ectodermal dysplasia clefting (EEC) and ankyloblepharon-ectodermal defects-cleft lip/palate (AEC). T cell lymphopenia has rarely been described in individuals with TP63 variants and the cause of the T cell defect is unclear. Here, we present a case of a female infant born with TP63-related syndrome and profound T cell lymphopenia, first uncovered through newborn screening. Flow cytometry analysis revealed low CD4+ naïve T cells and nearly absent CD8+ T cells with intact B and NK cell compartments. A de novo heterozygous pathogenic variant c.1040 G>A (C347Y) in exon 8 of TP63 was identified. An artificial thymic organoid system, to assess the intrinsic ability of the patient's hematopoietic cells to develop into T cells, was performed twice using separate peripheral blood samples. Ex vivo T cell differentiation was evident with the artificial organoid system, suggesting that a thymic stromal cell defect may be the cause of the T cell lymphopenia. Consistent with this, interrogation of publicly available data indicated that TP63 expression in the human thymus is restricted to thymic epithelial cells. Based on these data, congenital athymia was suspected and the patient received an allogenic cultured thymus tissue implant (CTTI). This is the first report of suspected congenital athymia and attempted treatment with CTTI associated with TP63 variant. At 9 months post-implant, peripheral lymphocyte analysis revealed measurable T cell receptor excision circles and presence of CD4+ recent thymic emigrants suggestive of early thymopoiesis. She will continue regular monitoring to ensure restoration of T cell immunity.

Case report of secondary T-cell deficiency following the AstraZeneca COVID-19 vaccine.

We present a case of secondary T-cell deficiency particularly affecting CD4 T cells, along with the emergence of chronic spontaneous urticaria in a patient following COVID-19 vaccination. The condition was partially managed with omalizumab after initial first-line therapy proved ineffective.

CYRAD: a translational study assessing immune response to radiotherapy by photons or protons in postoperative head and neck cancer patients through circulating leukocyte subpopulations and cytokine levels.

BACKGROUND: Radiotherapy has both immunostimulant and immunosuppressive effects, particularly in radiation-induced lymphopenia. Proton therapy has demonstrated potential in mitigating this lymphopenia, yet the mechanisms by which different types of radiation affect the immune system function are not fully characterized. The Circulating Immunes Cells, Cytokines and Brain Radiotherapy (CYRAD) trial aims to compare the effects of postoperative X-ray and proton radiotherapy on circulating leukocyte subpopulations and cytokine levels in patients with head and neck (CNS and ear nose throat) cancer. METHODS: CYRAD is a prospective, non-randomized, single-center non interventional study assessing changes in the circulating leukocyte subpopulations and cytokine levels in head and neck cancer patients receiving X-ray or proton radiotherapy following tumor resection. Dosimetry parameters, including dose deposited to organs-at-risk such as the blood and cervical lymph nodes, are computed. Participants undergo 29 to 35 radiotherapy sessions over 40 to 50 days, followed by a 3-month follow-up. Blood samples are collected before starting radiotherapy (baseline), before the 11th (D15) and 30th sessions (D40), and three months after completing radiotherapy. The study will be conducted with 40 patients, in 2 groups of 20 patients per modality of radiotherapy (proton therapy and photon therapy). Statistical analyses will assess the absolute and relative relationship between variations (depletion, recovery) in immune cells, biomarkers, dosimetry parameters and early outcomes. DISCUSSION: Previous research has primarily focused on radiation-induced lymphopenia, paying less attention to the specific impacts of radiation on different lymphoid and myeloid cell types. Early studies indicate that X-ray and proton irradiation may lead to divergent outcomes in leukocyte subpopulations within the bloodstream. Based on these preliminary findings, this study aims to refine our understanding of how proton therapy can better preserve immune function in postoperative (macroscopic tumor-free) head and neck cancer patients, potentially improving treatment outcomes. PROTOCOL VERSION: Version 2.1 dated from January 18, 2023. TRIAL REGISTRATION: The CYRAD trial is registered from October 19, 2021, at the US National Library of Medicine, ClinicalTrials.gov ID NCT05082961.

A Rare Case of TP63-Associated Lymphopenia Revealed by Newborn Screening Using TREC.

The expanded newborn screening (NBS) program in the Russian Federation was initiated in 2023, among which severe combined immunodeficiency (SCID) is screened using TREC/KREC assays. Here, we report a rare case of a TP63-associated disease identified through this NBS program. Dried blood spots from newborns were initially screened for TREC/KREC levels, and those with values below the cut-off underwent confirmatory testing and further genetic analysis, including whole-exome sequencing (WES). A male newborn was identified with significantly reduced TREC values, indicative of T cell lymphopenia. Genetic analysis revealed a heterozygous NM_003722.5:c.1027C>T variant in TP63, leading to the p.(Arg343Trp) substitution within the DNA binding domain. This mutation has been previously associated with Ectrodactyly-Ectodermal Dysplasia-Cleft lip/palate syndrome (EEC) syndrome and shown to reduce the transactivation activity of TP63 in a dominant-negative manner. This case represents one of the few instances of immune system involvement in a patient with a TP63 mutation, highlighting the need for further investigation into the immunological aspects of TP63-associated disorders. Our findings suggest that comprehensive immunological evaluation should be considered for patients with TP63 mutations to better understand and manage potential immune dysfunctions.

The Role of Dynamic Changes in Hematologic and Biochemical Parameters in Predicting Mortality in Covid-19 Patients.

Objectives: The role of hematologic, inflammatory and biochemical parameters as biomarkers, their role in identifying risky patients in the early stage and their role in prognosis in COVID-19 Coronavirus disease 2019 (COVID-19) were investigated. Methods: The study included patients who were hospitalized and followed up with a prediagnosis of COVID-19 in the first wave in our country at the University of Health Sciences, Sisli Hamidiye Etfal Training and Research Hospital Demographic and clinical characteristics as well as complete blood count, C reactive protein (CRP), procalcitonin (PCT), fibrinogen (FIB), ferritin, albumin (ALB), lactate dehydrogenase (LDH) levels on admission, third, seventh and 14th days were analyzed. Patients were grouped and compared according to the occurrence of death during hospital follow-up. Variables considered significant on mortality were analyzed with univariate and multivariate logistic regression models. Results: The study was conducted with 485 patients, 273 (56.3%) males and 212 (43.72%) females. The mean age of the patients was 58±16.2 years, and 71% were in the mild-moderate and 29% in the severe-critical disease group. Disease severity, the need for intensive care unit (ICU) follow-up, and the development of death were positively correlated with age, comorbidity, neutrophil (NE), leukocyte, neutrophil-lymphocyte ratio (NLR), PCT, CRP, ferritin, LDH values, and negatively correlated with lymphocyte (LE), ALB and hemoglobin (HGB) values. In multivariate analysis, elevated PCT at hospital admission (OR: 6.96 [1.63;39.65]), LDH ≥ 352U/L (OR: 4.35 [1.23;16.61]), LE<0.810 × 109/L (OR: 3.0 [1.16;7.85]) and advanced age (OR: 1.08 [1.03;1.14]) were independently associated with in-hospital death. In hemogram and acute phase reactant monitoring, PCT, CRP and LDH were the most valuable markers for predicting death, respectively (third-day AUC: 0.90;0.83;0.83 and seventh-day AUC: 0.95;0.90;0.89, respectively). Conclusion: In our study, leukocytes, lymphocytes, NLR, CRP, PCT, ferritin, albumin and LDH at admission were valuable in predicting poor prognosis. In addition, it was determined that increases in PCT, LDH and CRP during follow-up could be used to predict in-hospital death and to identify patients requiring close follow-up.

Azacitidine and cytarabine induce sustained lymphopenia with abnormal differentiation of common lymphoid progenitors and prolonged suppression of Dnmt3a and Dnmt3b expression in mice.

Myelosuppression is a major side effect of chemotherapy. Although decreased blood cells are restored with the recovery of bone marrow cells, insufficient recovery of decreased lymphocytes was observed in mice given azacitidine (AZA), a DNA methyltransferase (DNMT) inhibitor, even following the restoration of bone marrow cells. To understand the mechanisms behind this sustained lymphopenia, we examined AZA's impact on the hematopoietic progenitor cells and the expression of Dnmts and differentiation-related genes. An antimetabolite of cytidine analog, cytarabine (Ara-C), was used as a reference compound. Decreases in almost all blood parameters and common lymphoid progenitors (CLPs) and the downregulation of Dnmts and differentiation-related genes in Lineage-Sca-1+c-kit+ (LSK) cells were observed in mice administered AZA or Ara-C for 7 d. In the posttreatment observation, all parameters, except for lymphocytes and monocytes, exhibited recovery within 3 wk after the final dosing in both treated groups. However, no recovery from the decreases in lymphocytes, especially B cells, and monocytes occurred even after 5 wk. The number of CLPs was elevated after 3 wk. There was a tendency toward recovery from the decreased expression of Dnmt1 and differentiation-related genes, but the expression levels of Dnmt3a and Dnmt3b did not fully recover even 5 wk after the final dosing. Taken together, the findings revealed that the mechanism of sustained lymphopenia observed in mice treated with AZA or Ara-C is associated, at least in part, with the abnormal differentiation of CLPs into B cells accompanied by the prolonged suppression of Dnmt3a and Dnmt3b expression on LSK cells.

Smarcd1 subunit of SWI/SNF chromatin-remodeling complexes collaborates with E2a to promote murine lymphoid specification.

Lymphocyte development from murine hematopoietic stem cells (HSCs) entails a loss of self-renewal capacity and a progressive restriction of developmental potential. Previous research from our laboratory suggests that specialized assemblies of ATP-dependent SWI/SNF chromatin-remodeling complexes play lineage-specific roles during murine hematopoiesis. Here, we demonstrate that the Smarcd1 subunit is essential for specification of lymphoid cell fate from multipotent progenitors. Acute deletion of Smarcd1 in murine adult hematopoiesis leads to lymphopenia, characterized by a near-complete absence of early lymphoid progenitors and mature B and T cells, while the myeloid and erythroid lineages remain unaffected. Mechanistically, we demonstrate that Smarcd1 is essential for the coordinated activation of a lymphoid gene signature in murine multipotent progenitors. This is achieved by interacting with the E2a transcription factor at proximal promoters and by regulating the activity of distal enhancers. Globally, these findings identify Smarcd1 as an essential chromatin remodeler that governs lymphoid cell fate.

Alterations in hematologic, coagulation, and inflammatory markers based on fever status in hospitalized COVID-19 patients: A retrospective study.

Background: Laboratory markers like lymphopenia, thrombocytopenia, elevated D-dimer, and C-reactive protein (CRP) predict worse outcomes in coronavirus disease 2019 (COVID-19). However, a comprehensive analysis of hematologic and coagulation parameter alterations based on fever status is lacking. Methods: This retrospective study analyzed 300 COVID-19 patients hospitalized from March to December 2020. Demographic, clinical, and laboratory data were extracted from electronic medical records. Patients were stratified into fever (n = 200) and no fever (n = 100) groups. Hematologic, coagulation, and inflammatory markers were compared between groups using appropriate statistical tests. Multivariate regression identified independent predictors of fever. Results: Fever was associated with leukocytosis, neutrophilia, lymphopenia, thrombocytopenia, elevated CRP, D-dimer, procalcitonin, interleukin-6, neutrophil to lymphocyte ratio (NLR), and ferritin compared to no fever (all P < 0.05). D-dimer (r = 0.42), CRP (r = 0.52), NLR (r = 0.48), and interleukin-6 (r = 0.46) demonstrated the strongest correlation with fever (P < 0.001). High D-dimer >1000 ng/mL (adjusted odds ratio 2.7), CRP >100 mg/L (3.1), lymphopenia <1.0 × 109/L (2.8), NLR >4 (2.9), and thrombocytopenia <150 × 109/L (2.7) were significant independent predictors of fever status (P < 0.005). These parameters had moderate sensitivity (40-60%) and high specificity (74-88%) for discriminating febrile patients with AUC of 0.85. Conclusions: Marked alterations in hematologic, coagulation, and inflammatory markers occur in COVID-19 based on fever. Routine laboratory parameters can facilitate diagnosis and risk stratification.

Clinical Translation of a Deep Learning Model of Radiation-Induced Lymphopenia for Esophageal Cancer.

Purpose: Radiation-induced lymphopenia is a common immune toxicity that adversely impacts treatment outcomes. We report here our approach to translate a deep-learning (DL) model developed to predict severe lymphopenia risk among esophageal cancer into a strategy for incorporating the immune system as an organ-at-risk (iOAR) to mitigate the risk. Materials and Methods: We conducted "virtual clinical trials" utilizing retrospective data for 10 intensity-modulated radiation therapy (IMRT) and 10 passively-scattered proton therapy (PSPT) esophageal cancer patients. For each patient, additional treatment plans of the modality other than the original were created employing standard-of-care (SOC) dose constraints. Predicted values of absolute lymphocyte count (ALC) nadir for all plans were estimated using a previously-developed DL model. The model also yielded the relative magnitudes of contributions of iOARs dosimetric factors to ALC nadir, which were used to compute iOARs dose-volume constraints, which were incorporated into optimization criteria to produce "IMRT-enhanced" and "intensity-modulated proton therapy (IMPT)-enhanced" plans. Results: Model-predicted ALC nadir for the original IMRT (IMRT-SOC) and PSPT plans agreed well with actual values. IMPT-SOC showed greater immune sparing vs IMRT and PSPT. The average mean body doses were 13.10 Gy vs 7.62 Gy for IMRT-SOC vs IMPT-SOC for patients treated with IMRT-SOC; and 8.08 Gy vs 6.68 Gy for PSPT vs IMPT-SOC for patients treated with PSPT. For IMRT patients, the average predicted ALC nadir of IMRT-SOC, IMRT-enhanced, IMPT-SOC, and IMPT-enhanced was 281, 327, 351, and 392 cells/µL, respectively. For PSPT patients, the average predicted ALC nadir of PSPT, IMPT-SOC, and IMPT-enhanced was 258, 316, and 350 cells/µL, respectively. Enhanced plans achieved higher predicted ALC nadir, with an average improvement of 40.8 cells/µL (20.6%). Conclusion: The proposed DL model-guided strategy to incorporate the immune system as iOAR in IMRT and IMPT optimization has the potential for radiation-induced lymphopenia mitigation. A prospective clinical trial is planned.

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.

Characterization of lymphopenia and correlating the risk of cytopenias with dose and BM volume irradiated in aggressive B-cell lymphoma patients bridged with radiation therapy for CAR-T cell therapy.

INTRODUCTION: The impact of bridging radiation therapy (bRT) for CAR T-cell therapy on absolute lymphocyte count (ALC) kinetics and treatment outcome is unknown. METHODS: We retrospectively reviewed adults with relapsed/refractory aggressive large B-cell lymphoma (LBCL) who received bRT prior to CD-19 CAR-T between 11/2017-4/2023. The change in ALC (ALC Δ RT) was computed by subtracting ALC pre- and post-bRT. Percent bone marrow (%BM) irradiated was calculated by estimating skeletal BM distribution. PFS, DSS, and OS were modeled via Kaplan-Meier. RESULTS: Fifty-one patients received bRT, of which 13 (25.5%) had bulky disease (≥7.5cm). The median bRT dose was 30Gy (range: 4-48Gy); 26 patients (51%) received ≥30Gy. Thirty-one patients (61%) received bRT comprehensively to all disease sites. The median cumulative %BM irradiated was 5.05% (range: 0-50%). At a median follow-up of 10.3 months (95% CI: 7.7-16.4), the 1-year OS, PFS, and DSS rates were 80% (95% CI: 66-99), 78% (64-87), and 82% (68-90), respectively. The incidence of ≥Grade 3 lymphopenia was 33% pre-RT and 68% post-RT, but recovered to 43% at the conditioning chemotherapy (CC) timepoint. There was no correlation between post-RT Grade ≥3 lymphopenia and the receipt of comprehensive bRT, combined modality bridging, ≥30Gy bRT, or bRT to ≥15% of BM (all p>0.2). Among patients with Grade 0-2 lymphopenia pre-RT, increased conversion to Grade ≥3 lymphopenia post-RT correlated with comprehensive or ≥30Gy bRT, but these factors did not impair ALC recovery at CC. There was no association between ALC Δ RT or post-RT ALC with 30 or 90 day response (p>0.25), DSS, PFS, or OS (p>0.3). CONCLUSIONS: Lymphocyte change during bRT is not associated with CAR-T outcomes. Persistent cytopenia risk following bRT is not associated with bRT to ≥30Gy, ≥15% of BM, or comprehensive coverage. While bRT can be delivered safely, we urge careful treatment planning when incorporating into pre-CAR-T regimens.

Understanding the impact of radiation-induced lymphopenia: Preclinical and clinical research perspectives.

Immunotherapy has revolutionized the field of cancer treatment, changing the standard of care to the use of immune checkpoint inhibitors. Radiotherapy can boost anti-tumour immune responses by changing the tumour microenvironment, but it also can cause radiotherapy-induced lymphopenia (RIL), a decrease in circulating lymphocyte counts. RIL has been associated with lower survival in patients undergoing radiotherapy, and new studies have suggested that it can also affect immunotherapy outcome. To study RIL's effects and to explore mitigation treatment strategies, preclinical models closely mimicking the clinical situation are needed. State-of-the-art image-guided small animal irradiators now offer the possibility to target specific organs in small animals to induce RIL, aiding research on its molecular mechanisms and prevention. This review covers the relationship between radiotherapy and RIL, its impact on patient survival, and future directions to generate models to investigate and prevent RIL.

Lymphopenia in sepsis: a narrative review.

This narrative review provides an overview of the evolving significance of lymphopenia in sepsis, emphasizing its critical function in this complex and heterogeneous disease. We describe the causal relationship of lymphopenia with clinical outcomes, sustained immunosuppression, and its correlation with sepsis prediction markers and therapeutic targets. The primary mechanisms of septic lymphopenia are highlighted. In addition, the paper summarizes various attempts to treat lymphopenia and highlights the practical significance of promoting lymphocyte proliferation as the next research direction.

Investigating the relationship between lymphocyte cells apoptosis and DNA damage and oxidative stress and therapeutic and clinical outcomes of COVID-19 elderly patients.

BACKGROUND: While COVID-19 has been controlled and deaths have decreased, the long-term consequences of COVID-19 remain a challenge we face today. This study was conducted to determine the relationship between the apoptosis of lymphocyte cells with DNA damage and oxidative stress and the therapeutic and clinical outcomes of elderly patients with COVID-19. METHODS: This study was conducted from April 2020 to May 2021 (the period of severe attacks of the epidemic peak of COVID-19) and September 2022 (the post-COVID-19 period). The study groups included elderly patients with COVID-19 hospitalized in the ICU and normal wards of the hospital as well as elderly patients with influenza. A polymerase chain reaction was used to check the validity of the studied diseases. The Annexin V/Propidium Iodide method was used to evaluate the level of apoptosis. Genotoxic effects and DNA damage were assessed by the comet assay method. Total antioxidant status (TAS), total oxidant status (TOS), and myeloperoxidase activity (MPO) were measured by photometric methods. RESULTS: The highest level of apoptosis in peripheral blood lymphocytes and the highest level of DNA damage were observed at both times in the intubated-ICU and non-intubated-ICU groups. In all groups, there was a significant increase in peripheral blood lymphocyte apoptosis levels and DNA damage levels compared to the healthy control group (p < 0.01). The level of apoptosis and DNA damage decreased significantly in the post-COVID-19 period (p < 0.01). In the investigation of oxidative stress biomarkers, the oxidative stress index, including TOS and MPO levels, increased in patients (p < 0.01), and the TAS level decreased (p < 0.01). CONCLUSION: It shows that the apoptosis of lymphocyte cells, DNA damage, and oxidative stress can be effective in prognostic decisions and is a suitable predictor for diagnosing the condition of patients with viral infections such as COVID-19 and influenza.

Persistent inflammation and lymphopenia and weaning outcomes of patients with prolonged mechanical ventilation.

BACKGROUND: Weaning outcomes of patients receiving mechanical ventilation (MV) are affected by multiple factors. A clinical feature of critically ill patients is the presence of lymphopenia, however the clinical significance of lymphopenia in patients receiving prolonged MV remains unclear. METHODS: We enrolled patients who received at least 21 consecutive days of MV in a medical center in Taiwan between 2007 and 2016. Patients with and without lymphopenia (mean count <1000/µL) were compared after propensity score matching. RESULTS: Of the 3460 patients included in the analysis, 1625 (47.0%) were liberated from MV within 100 days. Lymphopenia and severe lymphopenia (mean count <500/µL) during the first 21 days of MV were common (52.9% and 14.5%, respectively), and restricted cubic spline analysis showed a significant reduction in weaning success when the lymphocyte count dropped below 1000/µL. After propensity score matching, the patients with lymphopenia during the third week had a lower rate of weaning success within 100 days (p = 0.005) and a higher in-hospital mortality rate (p = 0.001) than those without lymphopenia. The lymphopenia group also had significantly reduced platelet (p < 0.001) and albumin (p < 0.001) levels. CONCLUSIONS: Our findings suggest that lymphopenia during the first 3 weeks may be a marker of poor weaning outcomes in patients with prolonged MV.

Improved Clinical Outcomes Associated With Hungry Bone Syndrome Following Parathyroidectomy in Dialysis Patients.

OBJECTIVE: Hungry bone syndrome (HBS) is a common complication after parathyroidectomy in dialysis patients with severe secondary hyperparathyroidism. The rapid decline in parathyroid hormone (PTH) levels diminishes bone resorption and accelerates bone formation. This causes a significant influx of calcium and phosphate into the bone, resulting in severe and prolonged hypocalcemia. While previous studies have established risk factors for HBS, the outcomes beyond the reduced recurrence rate of hyperparathyroidism have been largely unexplored. METHODS: This single-center retrospective study analyzed 322 cases in 314 dialysis patients who underwent parathyroidectomy between 2012 and 2022. The study examined baseline factors associated with HBS, adverse events, and clinical outcomes, including changes in blood pressure and hematologic and nutritional parameters over 3-12 months of follow-up, stratified by HBS status. RESULTS: Total parathyroidectomy was performed in 28 cases (8.7%), total parathyroidectomy with implantation in 98 cases (30.4%), and subtotal parathyroidectomy in 196 cases (60.9%). HBS occurred in 207 cases (64%). Independent predictors of HBS included male sex, lower serum calcium levels, higher PTH levels, and lack of active vitamin D treatment at baseline. Patients with HBS had longer hospital stays but did not experience an increase in other adverse events. Following parathyroidectomy, the HBS group showed a greater reduction in blood pressure and more significant increases in hemoglobin, total lymphocyte count, and serum creatinine. This group also saw a more substantial decrease in the proportions of patients with hemoglobin <11 g/dL and serum creatinine/body surface area <380 µmol/L/m2. Although the HBS group showed a more significant decline in PTH levels from baseline, similar proportions achieved the target PTH level by the end of the study. Serum calcium levels remained substantially lower in the HBS group throughout the follow-up, while serum phosphate and PTH levels were comparable. CONCLUSION: HBS was associated with more pronounced improvements in blood pressure, anemia, and nutritional parameters. The presence of HBS could indicate greater achievement in controlling hyperparathyroidism following parathyroidectomy.

Radiation-Induced Lymphopenia and Its Impact on Survival in Patients with Brain Metastasis.

BACKGROUND: Differences in radiation-induced lymphopenia and prognosis between methods of radiotherapy (RT) for brain metastases remain unclear. METHODS: In this retrospective analysis of patients who underwent whole-brain radiotherapy (WBRT) or stereotactic radiosurgery/radiotherapy (SRS/SRT) for brain metastases, baseline total lymphocyte count (TLC) data were obtained within 2 weeks before RT initiation. Follow-up TLC data were evaluated at 0-2, 2-4, and 4-8 weeks after RT completion. Persistent lymphopenia was defined as <800/µL at any time point. RESULTS: Overall, 138 RT courses in 128 patients were eligible (94 WBRT; 44 SRS/SRT). In the WBRT courses, the median baseline TLC was 1325/µL (IQR: 923-1799). Follow-up TLC decreased significantly to 946/µL (626-1316), 992/µL (675-1291), and 1075/µL (762-1435) (p < 0.001). SRS/SRT courses showed no significant TLC decrease. Multivariate analysis revealed female sex, prior RT, baseline TLC < 800/µL, and WBRT use were significantly associated with persistent lymphopenia. In the WBRT group, overall survival was significantly different between those with and without persistent lymphopenia (median, 2.6 and 6.1 months; p < 0.001). However, there was no significant difference in survival in the SRS/SRT group (p = 0.60). CONCLUSION: This study suggests SRS/SRT might be preferable for lymphocyte preservation in brain metastasis patients.

Profound T Lymphocyte and DNA Repair Defect Characterizes Schimke Immuno-Osseous Dysplasia.

Schimke immuno-osseous dysplasia is a rare multisystemic disorder caused by biallelic loss of function of the SMARCAL1 gene that plays a pivotal role in replication fork stabilization and thus DNA repair. Individuals affected from this disease suffer from disproportionate growth failure, steroid resistant nephrotic syndrome leading to renal failure and primary immunodeficiency mediated by T cell lymphopenia. With infectious complications being the leading cause of death in this disease, researching the nature of the immunodeficiency is crucial, particularly as the state is exacerbated by loss of antibodies due to nephrotic syndrome or immunosuppressive treatment. Building on previous findings that identified the loss of IL-7 receptor expression as a possible cause of the immunodeficiency and increased sensitivity to radiation-induced damage, we have employed spectral cytometry and multiplex RNA-sequencing to assess the phenotype and function of T cells ex-vivo and to study changes induced by in-vitro UV irradiation and reaction of cells to the presence of IL-7. Our findings highlight the mature phenotype of T cells with proinflammatory Th1 skew and signs of exhaustion and lack of response to IL-7. UV light irradiation caused a severe increase in the apoptosis of T cells, however the expression of the genes related to immune response and regulation remained surprisingly similar to healthy cells. Due to the disease's rarity, more studies will be necessary for complete understanding of this unique immunodeficiency.

Early lymphocyte levels and low doses radiation exposure of lung predict lymphopenia in radiotherapy for lung cancer.

Introduction: Radiation induced lymphopenia (RIL) deteriorate survival and diminishes the benefit of immune checkpoint inhibitors in combined treatment of lung cancer. Given the inconsistent data across various studies on the predictors of RIL, we aim to methodically elucidate these predictors and formulate a practical guide for clinicians. Methods: We conducted observational cohort study in four tertiary cancer centers. Patients with non-small cell lung cancer and small cell lung cancer, without lymphopenia grade >1, who underwent standalone radiotherapy (RT) in minimum 15 fractions were eligible. Dose-volume parameters of structures and clinical factors were comprehensively analyzed using various predictors selection methods and statistical models (Linear Regressors, Elastic Net, Bayesian Regressors, Huber Regression, regression based on k-nearest neighbors, Gaussian Process Regressor, Decision Tree Regressor, Random Forest Regressor, eXtreme Gradient Boosting, Automated Machine Learning) and were ranked to predict lymphocytes count nadir (alc_nadir). Results: Two hundred thirty eight patients (stage I-3.4%, II-17.6%, III-75.2%, IV-3.8%) who underwent RT to median dose of 60 Gy were analyzed. Median alc_nadir was 0.68K/mm3. The 60 feature sets were evaluated in 600 models (RMSE 0.27-0.41K/mm³). The most important features were baseline lymphocyte count (alc_1), mean lung_dose, lung v05, lung v10, heart v05 and effective dose to immune cells (edic). In patients with alc_1 ≤ 2.005K/mm3, median alc_nadir predictions were 0.54K/mm3 for lung_v05p > 51.8% and 0.76K/mm3 for lung_v05p ≤ 51.8%. Lymphopenia was rare in patients with alc_1 > 2.005K/mm3. Discussion: RIL was most severe in patients with low early lymphocyte counts, primarily triggered by low RT doses in the heart and lungs.