R-ketorolac ameliorates cancer-associated cachexia and prolongs survival of tumour-bearing mice.

BACKGROUND: Cancer-associated cachexia (CAC) is a debilitating syndrome associated with poor quality of life and reduced life expectancy of cancer patients. CAC is characterized by unintended body weight reduction due to muscle and adipose tissue loss. A major hallmark of CAC is systemic inflammation. Several non-steroidal anti-inflammatory drugs (NSAIDs) have been suggested for CAC treatment, yet no single medication has proven reliable. R-ketorolac (RK) is the R-enantiomer of a commonly used NSAID. The effect of RK on CAC has not yet been evaluated. METHODS: Ten- to 11-week-old mice were inoculated with C26 or CHX207 cancer cells or vehicle control (phosphate-buffered saline [PBS]). After cachexia onset, 2 mg/kg RK or PBS was administered daily by oral gavage. Body weight, food intake and tumour size were continuously measured. At study endpoints, blood was drawn, mice were sacrificed and tissues were excised. Immune cell abundance was analysed using a Cytek® Aurora spectral flow cytometer. Cyclooxygenase (COX) activity was determined in lung homogenates using a fluorometric kit. Muscle tissues were analysed for mRNA and protein expression by quantitative real-time PCR and western blotting analysis, respectively. Muscle fibre size was determined on histological slides after haematoxylin/eosin staining. RESULTS: Ten-day survival rate of C26-bearing animals was 10% while RK treatment resulted in a 100% survival rate (P = 0.0009). Chemotherapy resulted in a 10% survival rate 14 days after treatment initiation, but all mice survived upon co-medication with RK and cyclophosphamide (P = 0.0001). Increased survival was associated with a protection from body weight loss in C26 (-0.61 ± 1.82 vs. -4.48 ± 2.0 g, P = 0.0004) and CHX207 (-0.49 ± 0.33 vs. -2.49 ± 0.93 g, P = 0.0003) tumour-bearing mice treated with RK, compared with untreated mice. RK ameliorated musculus quadriceps (-1.7 ± 7.1% vs. -27.8 ± 8.3%, P = 0.0007) and gonadal white adipose tissue (-18.8 ± 49% vs. -69 ± 15.6%, P = 0.094) loss in tumour-bearing mice, compared with untreated mice. Mechanistically, RK reduced circulating interleukin-6 (IL-6) concentrations from 334 ± 151 to 164 ± 123 pg/mL (P = 0.047) in C26 and from 93 ± 39 to 35 ± 6 pg/mL (P = 0.0053) in CHX207 tumour-bearing mice. Moreover, RK protected mice from cancer-induced T-lymphopenia (+1.8 ± 42% vs. -49.2 ± 12.1% in treated vs. untreated mice, respectively). RK was ineffective in ameliorating CAC in thymus-deficient nude mice, indicating that the beneficial effect of RK depends on T-cells. CONCLUSIONS: RK improved T-lymphopenia and decreased systemic IL-6 concentrations, resulting in alleviation of cachexia and increased survival of cachexigenic tumour-bearing mice, even under chemotherapy and independent of COX inhibition. Considering its potential, we propose that the use of RK should be investigated in patients suffering from CAC.

From lymphopenia to restoration: IL-7 immunotherapy for lymphocyte recovery in glioblastoma.

Glioblastoma, the most prevalent malignant primary brain tumor, presents substantial treatment challenges because of its inherent aggressiveness and limited therapeutic options. Lymphopenia, defined as reduced peripheral blood lymphocyte count, commonly occurs as a consequence of the disease and its treatment. Recent studies have associated lymphopenia with a poor prognosis. Factors that contribute to lymphopenia include radiotherapy, chemotherapy, and the tumor itself. Patients who are female, older, using dexamethasone, or receiving higher doses of radiation therapy are particularly vulnerable to this condition. Several preclinical studies have explored the use of interleukin-7, a crucial cytokine for lymphocyte homeostasis, to restore lymphocyte counts and potentially rebuild the immune system to combat glioblastoma cells. With the development of recombinant interleukin-7 for prolonged activity in the body, various clinical trials are underway to explore this treatment in patients with glioblastoma. Our study provides a comprehensive summary of the incidence of lymphopenia, its potential biological background, and the associated clinical risk factors. Furthermore, we reviewed several clinical trials using IL-7 cytokine therapy in glioblastoma patients. We propose IL-7 as a promising immunotherapeutic strategy for glioblastoma treatment. We are optimistic that our study will enhance understanding of the complex interplay between lymphopenia and glioblastoma and will pave the way for the development of more effective treatment modalities.

Platelet-to-albumin ratio and radiation-induced lymphopenia-prognostic biomarker for carcinoma esophagus.

BACKGROUND: Esophageal cancer has a poor survival outcome with 5-year OS at 16.7% despite treatment. Some inflammation-based prognostic indicators like the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been previously studied as potential biomarker for predicting outcome in esophageal cancer. Recently, platelet-to-albumin ratio (PAR) has been reported as a promising prognostic factor in gastrointestinal malignancies. METHODS: We performed a retrospective analysis of prospectively treated patients of carcinoma esophagus to evaluate the prognostic significance of inflammation-based prognostic indicators-neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and a composite inflammation-nutrition index: platelet-to-albumin ratio (PAR) in esophageal cancer. Based on previous studies, the optimal cut-off value of PAR was kept at 5.7 × 10^9, and 2.62 for NLR. RESULTS: A total of 71 patients of locally advanced esophageal cancer treated between 2019 and 2022, with either neoadjuvant or definitive chemoradiotherapy, were included. Median follow-up time was 19 months [range: 7-44 months]. Median OS and PFS in our study cohort were 11.3 months [range: 7-23 months] and 7.8 months [range: 3-17 months], respectively. In univariate analysis, lower PAR was found to be significantly correlated with shorter survival time (HR = 2.41; 1.3-4.76; p = 0.047). There was no association found between the OS and the NLR [HR = 1.09; 0.95-1.26; p = 0.222]. Univariate and multivariate linear and logistic regressions found no association between V15, V10, V5, or V2 of spleen and nadir lymphocyte count or between Dmax or Dmean and nadir lymphocyte counts. CONCLUSION: Present analysis found a trend toward an inverse association between PAR and OS. PAR, in the not-so-distant future, may evolve as a novel, convenient, and inexpensive prognostic indicator in esophageal cancer.

Lymphocyte recovery from radiation-induced lymphopenia in locally advanced esophageal squamous cell carcinoma: correlations with prognosis and lymphocyte-related organs.

BACKGROUND: Limited studies explored the relationship between lymphocyte recovery after definitive concurrent chemoradiotherapy (dCCRT) and prognosis in esophageal squamous cell carcinoma (ESCC). METHODS: ESCC patients with obtainable absolute lymphocyte counts (ALCs) at 6 months after dCCRT were screened from prospective trials. Patients were divided into groups according to the grade of ALC nadir during radiotherapy (G4 or G1-3) and lymphocyte recovery status, which was assessed by lymphocyte recovery index (LRI), calculated as the ratio of post- to pre-treatment lymphocyte counts. Cox analysis was conducted to evaluate the prognostic significance of lymphocyte recovery status. Irradiated relative volumes of the bone marrow (BM) and spleen and effective dose to immune cells (EDIC) were collected to identify their impacts on lymphocyte recovery status by logistic analysis. RESULTS: 232 patients were enrolled. In 69 patients with G4 ALC nadir (group A and B) and 163 patients with G1-3 ALC nadir (group C and D) during dCCRT, 27 (group A) and 67 (group C) patients showed an insufficient level of lymphocyte recovery (LRI < 60%), and 42 (group B) and 96 (group D) patients showed a satisfactory level of lymphocyte recovery (LRI ≥ 60%). Cox multivariable analysis revealed that inadequate lymphocyte recovery was significantly associated with worse overall survival (HR, 2.80 and 1.70) and local recurrence-free survival (HR, 2.82 and 1.60) both in group A vs group B and group C vs group D. Logistic analysis identified BM V5 (OR 4.24 and 2.29) as an independent predictor of inadequate lymphocyte recovery from G4 or G1-3 ALC nadir, respectively. CONCLUSIONS: Insufficient lymphocyte recovery might serve as a valuable prognostic factor, regardless of whether patients experienced G4 or G1-3 ALC nadir during radiotherapy. Additionally, it was observed that a larger relative volume of BM receiving ≥ 5 Gy was correlated with a higher risk of insufficient lymphocyte recovery.

Less Irradiation to Lymphocyte-Related Organs Reduced the Risk of G4 Lymphopenia in Esophageal Cancer: Re-Analysis of Prospective Trials.

BACKGROUND: This study aimed to explore the relationship between irradiation of lymphocyte-related organs at risk (LOARs) and lymphopenia during definitive concurrent chemoradiotherapy (dCCRT) for esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: Cases of ESCC patients who received dCCRT from 2 prospective clinical trials were identified. To find its correlation with survival outcomes, grades of absolute lymphocyte counts (ALCs) nadir during radiotherapy were recorded following COX analysis. Associations of lymphocytes at nadir and dosimetric parameters including relative volumes of spleen and bone marrow receiving 0.5, 1, 2, 3, 5, 10, 20, 30, and 50Gy (V0.5, V1, V2, V3, V5, V10, V20, V30, and V50), and effective dose to circulating immune cells (EDIC) were examined by logistic risk regression analysis. The cutoffs of dosimetric parameters were determined by the receiver operating characteristic curve (ROC). RESULTS: A total of 556 patients were included. The incidences of grades 0, 1, 2, 3, and 4 (G4) lymphopenia during dCCRT were 0.2%, 0.5%, 9.7%, 59.7%, and 29.8%, respectively. Their median overall survival (OS) and progression-free survival (PFS) time were 50.2 and 24.3 months, respectively; the incidence of local recurrence and distant metastasis were 36.6% and 31.8%, respectively. Patients once suffering from G4 nadir during radiotherapy had unfavorable OS (HR, 1.28; P = .044) and a higher incidence of distant metastasis (HR, 1.52; P = .013). Furthermore, patients with EDIC ≤8.3Gy plus spleen V0.5 ≤11.1% and bone marrow V10 ≤33.2% were strongly associated with lower risk of G4 nadir (OR, 0.41; P = .004), better OS (HR, 0.71; P = .011) and lower risk of distant metastasis (HR, 0.56; P = .002). CONCLUSIONS: Smaller relative volumes of spleen V0.5 and bone marrow V10 plus lower EDIC were jointly prone to reduce the incidence of G4 nadir during definitive concurrent chemoradiotherapy. This modified therapeutic strategy could be a significant prognostic factor for survival outcomes in ESCC.

Lymphopenia predicts reduced survival in canine hepatocellular carcinoma.

Platelet to lymphocyte ratio (PLR) is a prognostic marker in human hepatocellular carcinoma (HCC) however, its utility in canine HCC has not been explored. The aim of the study was to determine if PLR could predict survival outcomes in 42 dogs with HCC. PLR was not a significant predictive factor (p = 0.15) but lymphopenia alone was significantly correlated with a reduced probability of survival (p = 0.024). Further studies are needed to evaluate if peripheral lymphocyte count mirrors that of the tumor microenvironment in canine HCC.

Low muscle mass measured at T12 is a prognostic biomarker in unresectable oesophageal cancers receiving chemoradiotherapy.

BACKGROUND AND PURPOSE: Low muscle mass is an imaging biomarker of patient frailty that has been associated with increased toxicity and decreased survival in a number of cancers. Patients with unresectable oesophageal cancer receive chemoradiotherapy as standard of care. Muscle mass is not yet an established prognostic marker in this population. Muscle mass is usually assessed by segmenting skeletal muscle at the L3 vertebral level. But radiotherapy planning scans for oesophageal cancers do not always image this level, which has limited previous studies of body composition. Skeletal muscle is known to regulate immune function, but the association of muscle mass with lymphopenia in cancer patients has not been shown. MATERIALS AND METHODS: We retrospectively analyse 135 oesophageal cancer patients who received chemoradiotherapy and investigate the prognostic value of skeletal muscle area assessed at T12. We also examine the association between muscle mass and radiation-induced lymphopenia. RESULTS: We find that low muscle mass is associated with poorer overall survival (hazard ratio [95% confidence interval]: 0.72 [0.53-0.97]). However, this effect interacts with body mass index (BMI) such that the prognostic value of low muscle mass is removed by high BMI. In our study, patients with low muscle mass were more prone to radiation-induced lymphopenia (75% vs. 50% in patients with high muscle mass). A significant decrease in circulating lymphocytes was associated with poorer overall survival (hazard ratio [95% confidence interval]: 0.68 [0.47-0.99]). CONCLUSION: Our study shows that assessing muscle mass at T12 is feasible and provides prognostic information. Low muscle mass at T12 is associated with poorer overall survival and increased risk of radiation-induced lymphopenia. Muscle mass provides additional information over performance status and BMI. Low BMI patients are most affected by low muscle mass, highlighting the importance of close nutritional support in this population.

Association Between Lymphopenia and Survival Outcomes in Esophageal Carcinoma Patients Receiving Combined Immunotherapy and Chemoradiotherapy.

BACKGROUND: To investigate the association between absolute lymphocyte count (ALC) nadir and survival outcomes in esophageal squamous cell carcinoma (ESCC) patients who received definitive chemoradiotherapy (CRT) combined with anti-PD-1 immunotherapy, as well as to explore clinical characteristics and dosimetric parameters that affect ALC nadir during CRT. PATIENTS AND METHODS: Patients with ESCC (n = 602) who underwent definitive CRT were analyzed, of whom 166 received combined anti-PD-1 immunotherapy and CRT. Changes in ALC and survival were compared between patients with and without immunotherapy. Propensity score matching (PSM) was performed to minimize the effects of confounding factors. Low ALC was defined as nadir of <0.33 × 103 cells/µL during CRT (top tertile). Univariate and multivariate logistic regression were used to identify predictors of low ALC nadir. RESULTS: Patients with immunotherapy had significantly higher ALC in the first 3 weeks during CRT and higher ALC nadir than those without. Overall survival was more favorable in patients with immunotherapy both before and after PSM. After a median follow-up of 12.1 months, patients with low ALC during CRT had a worse progression-free survival (PFS) (P = .026). In multivariate analysis, low ALC remained a significant prognostic factor for PFS. Planning target volume (PTV) and heart V5 were revealed to be independent predictors of low ALC. CONCLUSIONS: The addition of anti-PD-1 immunotherapy to definitive CRT could mitigate the decline of ALC during radiotherapy and might prolong survival. Low ALC nadir was correlated to worse PFS, larger PTV, and higher heart V5 in patients receiving combined immunotherapy and CRT.

Immunological signature of patients with thymic epithelial tumors and Good syndrome.

Background: Thymic epithelial tumors (TETs) are frequently accompanied by Good Syndrome (GS), a rare immunodeficiency, characterized by hypogammaglobulinemia and peripheral B cell lymphopenia. TETs can be also associated to other immunological disorders, both immunodeficiency and autoimmunity. Methods: In this study, we enrolled TET patients with GS to address differences between patients with or without associated autoimmune diseases (AD). We analyzed the immunophenotype from peripheral blood of these patients focusing on selected immune cell subsets (CD4+T cells, CD8+T cells, T regulatory cells, NK cells, B-cells, monocytes, eosinophils, basophils, neutrophils) and serum levels of cytokines, chemokines and growth factors. Results: We observed higher number of leucocytes, in particular lymphocytes, B lymphopenia and lower number of T regulatory cells in TET patients with associated AD compared to TET patients without AD. In the group of TET patients with AD, we also observed increased serum levels of IL-15, VEGF, IP-10, GM-CSF, IL-6, and MIP-1α. Thus, we identified considerable differences in the lymphocyte profiles of TET patients with and without ADs, in particular a reduction in the numbers of B lymphocytes and T-regulatory cells in the former, as well as differences in the serum levels of various immune modulators. Conclusions: Although the pathogenic mechanisms are still unclear, our results add new knowledge to better understand the disease, suggesting the need of surveilling the immunophenotype of TET patients to ameliorate their clinical management.

Peripheral Lymphocyte Counts and Lymphocyte-Related Inflammation Indicators During Radiotherapy for Pelvic Malignancies: Temporal Characterization and Dosimetric Predictors.

Purpose: To identify the dosimetric predictors of lymphocytopenia and retrospectively analyze the changing trend of peripheral lymphocyte counts and lymphocyte-related inflammatory indicators in patients with simple pelvic radiotherapy. Methods and Materials: We retrospectively reviewed the clinical data of 188 patients with pelvic malignancies undergoing pelvic radiotherapy. The absolute count of neutrophils, lymphocytes, monocytes, and platelets at each time point was collected, and lymphocyte-related inflammation indicators were obtained, including neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and the systemic immune-inflammation index (SII). The total pelvic bone (TPB) and the body within the 5 Gy coverage were retrospectively delineated for each patient. Dose-volume histograms corresponding to the delivered volumetric arc therapy plan were used to assess the dose volumes received by the TPB and body. A paired-samples t-test or Wilcoxon signed-rank test for matched pairs was applied for pairwise comparisons. We also established a stepwise multiple linear regression model for the peripheral lymphocyte count (PLC) value at the end of radiotherapy. Results: The PLC and lymphocyte-related inflammatory indicators changed significantly after the start of radiotherapy and persisted for 3-6 months after radiotherapy. The nadirs of PLC occurred at RT-End, and the PLC was still significantly lower than the baseline value at RT-3 months and RT-6 months. NLR, PLR, and SII at RT-End are about 3.5 times the value at RT-Baseline, while LMR is one-fourth of the basal value. In a further multiple stepwise linear regression analysis, the basal PLC (ß = 0.156, p ≤ .001), gender (ß = 0.096, p = .005), and TPB-V5 (ß = -0.016, p ≤ .001) turned out to be the predictor of the absolute value of lymphocytes at the end of radiotherapy. Conclusions: The impact of pelvic radiotherapy on PLC and lymphocyte-related inflammatory indicators is considerable and long-lasting. Minimizing pelvic bone radiation exposure dose (5 Gy) may help to avoid severe cases of lymphocytopenia.

Radiation-induced lymphopenia does not impact treatment efficacy in a mouse tumor model.

Radiation-induced lymphopenia is a common occurrence in radiation oncology and an established negative prognostic factor, however the mechanisms underlying the relationship between lymphopenia and inferior survival remain elusive. The relevance of lymphocyte co-irradiation as critical normal tissue component at risk is an emerging topic of high clinical relevance, even more so in the context of potentially synergistic radiotherapy-immunotherapy combinations. The impact of the radiotherapy treatment volume on the lymphocytes of healthy and tumor-bearing mice was investigated in a novel mouse model of radiation-induced lymphopenia. Using an image-guided small-animal radiotherapy treatment platform, translationally relevant tumor-oriented volumes of irradiation with an anatomically defined increasing amount of normal tissue were irradiated, with a focus on the circulating blood and lymph nodes. In healthy mice, the influence of irradiation with increasing radiotherapy treatment volumes was quantified on the level of circulating blood cells and in the spleen. A significant decrease in the lymphocytes was observed in response to irradiation, including the minimally irradiated putative tumor area. The extent of lymphopenia correlated with the increasing volumes of irradiation. In tumor-bearing mice, differential radiotherapy treatment volumes did not influence the overall therapeutic response to radiotherapy alone. Intriguingly, an improved treatment efficacy in mice treated with draining-lymph node co-irradiation was observed in combination with an immune checkpoint inhibitor. Taken together, our study reveals compelling data on the importance of radiotherapy treatment volume in the context of lymphocytes as critical components of normal tissue co-irradiation and highlights emerging challenges at the interface of radiotherapy and immunotherapy.

Early onset of severe lymphopenia during definitive radiotherapy correlates with mean body dose and predicts poor survival in cervical cancer.

BACKGROUND: Lymphopenia during definitive radiotherapy (RT) has been shown to reduce survival in patients with cervical cancer. However, there are few studies on the significance of onset time of lymphopenia during RT in patients with cervical cancer. OBJECTIVE: This study aimed to exam the prognostic significance of early onset of severe lymphopenia (EOSL) during definitive RT in patients with cervical cancer. METHODS: Newly diagnosed cervical cancer patients treated with definitive RT from January 2015 to December 2019 were eligible for this retrospective study. EOSL was defined as first onset of grade 3-4 lymphopenia ⩽ 3 weeks from the start of RT. Mean body dose (MBD) was the mean radiation dose absorbed by the body during the whole course of external beam RT (EBRT) and was directly obtained from the dose volume histogram (DVH) of the EBRT planning. Logistic regression analysis and restricted cubic spline (RCS) models were applied to assess relationships between clinicopathological factors and EOSL. Survival analysis was performed using Kaplan-Meier curves and log-rank test. A COX regression model was developed to predict overall survival (OS). RESULTS: A total of 104 patients were included and 59.6% had EOSL. MBD (P= 0.04), concurrent cisplatin (P= 0.011), and pre-RT absolute lymphocyte count (ALC) (P= 0.001) were associated with EOSL. A linear relationship (P for non-linearity = 0.803) between MBD and risk of EOSL was found. Patients with EOSL had decreased OS (2-yr 75.1% vs 91.1%, P= 0.021) and progression-free survival (PFS) (2-yr 71.2% vs 83.7%, P= 0.071). An OS prediction COX model was developed with C-index of 0.835 and AUC of 0.872. CONCLUSIONS: EOSL during definitive RT correlates with MBD and predicts poor survival in patients with cervical cancer.

COVID-19 Lung Pathogenesis in SARS-CoV-2 Autopsy Cases.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health issue. COVID-19 is considered an airway/multi-systemic disease, and demise has been associated with an uncontrolled immune response and a cytokine storm in response to the virus. However, the lung pathology, immune response, and tissue damage associated with COVID-19 demise are poorly described and understood due to safety concerns. Using post-mortem lung tissues from uninfected and COVID-19 deadly cases as well as an unbiased combined analysis of histology, multi-viral and host markers staining, correlative microscopy, confocal, and image analysis, we identified three distinct phenotypes of COVID-19-induced lung damage. First, a COVID-19-induced hemorrhage characterized by minimal immune infiltration and large thrombus; Second, a COVID-19-induced immune infiltration with excessive immune cell infiltration but no hemorrhagic events. The third phenotype correspond to the combination of the two previous ones. We observed the loss of alveolar wall integrity, detachment of lung tissue pieces, fibroblast proliferation, and extensive fibrosis in all three phenotypes. Although lung tissues studied were from lethal COVID-19, a strong immune response was observed in all cases analyzed with significant B cell and poor T cell infiltrations, suggesting an exhausted or compromised immune cellular response in these patients. Overall, our data show that SARS-CoV-2-induced lung damage is highly heterogeneous. These individual differences need to be considered to understand the acute and long-term COVID-19 consequences.

Bone marrow dosimetric analysis of lymphopenia in patients with esophageal squamous cell carcinoma treated with chemoradiotherapy.

BACKGROUND: We analyzed the relationship among peripheral blood lymphocytes, exposed sternum and vertebra body bone marrow (BM), and overall survival (OS) to find BM dosimetric parameters of lymphopenia during chemoradiotherapy (CRT) for patients with esophageal squamous cell carcinoma (ESCC). METHODS: We examined 476 ESCC patients from January 2012 to January 2015, all of whom received concurrent or sequential CRT. Absolute lymphocyte counts (ALC) during radiotherapy (RT) of each patient were collected from the routine workup at the following RT times: pretreatment ALC (ALC0), at 1-5, 6-10, 11-15, 16-20, and 21-25, and more than 26 sessions (called ALC1-6, respectively). The sternum and vertebral body BM were delineated in accordance with uniform standards, and the irradiated volumes were calculated by dose-volume histograms (DVH). The Kaplan-Meier method and Cox proportional hazards regression were used to analyze the survival of the patients. Comparisons of DVH were performed using the Mann-Whitney U test or two-sample t-test where appropriate. RESULTS: A relative volume of sternum BM irradiated by more than 20 Gy could clearly affect the peripheral blood lymphocytes. The V20 of sternum BM and V50 of vertebra body BM were related to the OS of the patients, and the level of ALC2 (at 6-10 times of RT) could predict the outcomes of patients. The Cox regression analyses showed that the 218 patients with ALC2 ≥ 0.8 × 109 /L had a significantly higher OS (47.0 months vs. 30.9 months, p < 0.0001) than the 258 patients with ALC2 < 0.8×109 /L. CONCLUSION: In patients with ESCC, the relative volume of sternum BM irradiated by more than 20 Gy was associated with lymphocytes. Patients with ALC2 ≥ 0.8 × 109 /L had a significantly higher OS. The V20 of the sternum BM, the V50 of the vertebra body BM, and the level of ALC2 were significant prognostic factors in patients with ESCC.

Distinct Mitochondria-Mediated T-Cell Apoptosis Responses in Children and Adults With Coronavirus Disease 2019.

BACKGROUND: Lymphopenia is a key feature for adult patients with coronavirus disease 2019 (COVID-19), although it is rarely observed in children. The underlying mechanism remains unclear. METHODS: Immunohistochemical and flow cytometric analyses were used to compare the apoptotic rate of T cells from COVID-19 adults and children and apoptotic responses of adult and child T cells to COVID-19 pooled plasma. Biological properties of caspases and reactive oxygen species were assessed in T cells treated by COVID-19 pooled plasma. RESULTS: Mitochondria apoptosis of peripheral T cells were identified in COVID-19 adult patient samples but not in the children. Furthermore, increased tumor necrosis factor-α and interleukin-6 in COVID-19 plasma induced mitochondria apoptosis and caused deoxyribonucleic acid damage by elevating reactive oxygen species levels of the adult T cells. However, the child T cells showed tolerance to mitochondrial apoptosis due to mitochondria autophagy. Activation of autophagy could decrease apoptotic sensitivity of the adult T cells to plasma from COVID-19 patients. CONCLUSIONS: Our results indicated that the mitochondrial apoptosis pathway was activated in T cells of COVID-19 adult patients specifically, which may shed light on the pathophysiological difference between adults and children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 ).

The journey of SARS-CoV-2 in human hosts: a review of immune responses, immunosuppression, and their consequences.

Coronavirus disease 2019 (COVID-19) is a highly infectious viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Laboratory findings from a significant number of patients with COVID-19 indicate the occurrence of leukocytopenia, specifically lymphocytopenia. Moreover, infected patients can experience contrasting outcomes depending on lymphocytopenia status. Patients with resolved lymphocytopenia are more likely to recover, whereas critically ill patients with signs of unresolved lymphocytopenia develop severe complications, sometimes culminating in death. Why immunodepression manifests in patients with COVID-19 remains unclear. Therefore, the evaluation of clinical symptoms and laboratory findings from infected patients is critical for understanding the disease course and its consequences. In this review, we take a logical approach to unravel the reasons for immunodepression in patients with COVID-19. Following the footprints of the virus within host tissues, from entry to exit, we extrapolate the mechanisms underlying the phenomenon of immunodepression.

Characterizing the differences between multisystem inflammatory syndrome in children and Kawasaki disease.

To characterize the new SARS-Co-V-2 related multisystem inflammatory syndrome in children (MIS-C) among Israeli children and to compare it with Kawasaki disease (KD). We compared, in two medical centers, the clinical and laboratory characteristics of MIS-C, KD and an intermediate group, which met the case definitions of both conditions. MIS-C patients were older, were more likely to be hypotensive, to have significant gastrointestinal symptoms, lymphopenia and thrombocytopenia and to have non-coronary abnormal findings in their echocardiogram. Lymphopenia was an independent predictor of MIS-C. Most of our MIS-C patients responded promptly to corticosteroid therapy. KD incidence in both centers was similar in 2019 and 2020. Although there is clinical overlap between KD and MIS-C, these are separate entities. Lymphopenia clearly differentiates between these entities. MIS-C patients may benefit from corticosteroids as first-line therapy.