Cytogenetic study of the action of erythropoietin on peripheral human lymphocytes in vitro and on P388 ascites tumor cells in mice in vivo

Erythropoietin (Epo) is a glycoprotein, which is produced mainly in the kidney section and secondarily in the liver. Its length is 165 aminoacetic residues and its molecular weight 30.4 kDa. Epo has multiple actions in the human organism. Its main action in the organism is the beginning of erythropoiesis, however, as it has been found, its presence in the organism has multiple beneficial results, like neuroprotection. Its action on the cells takes place via its binding with its receptor (EpoR), which, as it has been proved is inherent in many cells, among which, lymphocytes and cancer cells. In this study the action of Epo to the DNA of lymphocytes and murine P388 leukaemia cells has been analysed with one of the most sensitive cytogenetic methods, that of Sister Chromatid Exchanges (SCEs). SCEs are the genotoxicity index of the under review factor. Simultaneously with SCEs, two other indices were measured that are indicative of the promotion of cell cycle, the Proliferation Rate Index (P.R.I.), which is a cytostaticity index and the Mitotic Index (M.I.), which is a cytotoxicity index. The action of Epo on the lymphocytes has been studied both alone as well as in the presence of two chemotherapeutic factors that increase the fragility of DNA, thus augmenting the frequency of SCEs per metaphase. Those two factors are mitomycin C (MMC) and a camptothecin analogue, irinotecan (CPT-11). After cultivating cells in the presence of the studied factors, according to the related experimental protocol, and evaluating the results the following research results were reached: I. When Epo added alone to lymphocyte cultures and P388 leukemia cells, did not significantly alter any of the three cytogenetic indices. II. When Epo acted in combination with MMC, it reduced SCEs frequency and hence, the cultures where MMC and Epo were added showed lower SCEs frequency than that treated only with MMC. PRI and MI values of lymphocytes treated with the combination of the two agents are higher than that of lymphocytes treated only with MMC in the same concentration. The same findings for all the three cytogenetic indices, SCEs, PRI and MI were observed for P388 leukaemia cells in vivo. III. Epo and CPT-11 combinations decreased SCEs frequency in lymphocytes and P388 cells, in vitro and in vivo accordingly, compared to SCEs levels of cells treated only with CPT-11 in the same concentration. That proves the geno- and cytoprotective action of Epo against geno- and cytotoxic agents. Under Epo’s action and in presence of the cytostatic agent, the mitotic cycles of cells increased, compared to cells where only the cytostatic agent acted, 312 Η ΔΡΑ?Η ΣΗ? ΕΡΤΘΡΟΠΟΙΗΣΙΝΗ? ?ΣΑ ΦΡΩΜΑΣΟ?ΩΜΑΣΑ IN VITRO ΚΑΙ IN VIVO both in vitro as in vivo. PRIs and MIs of lymphocytes and murine P388 leukemia cells were higher for those treated with the combinations of the two agents than that treated only with CPT-11 in the same concentration. According to the aforementioned results and after the in vivo confirmation and clinical studies the following conclusions can be forwarded: I. Epo protects cells from the genotoxic action of both agents, MMC and CPT-11, by activating metabolic paths through its binding to EpoR, in vitro and in vivo. II. Epo’s genoprotective action may offer better survival to patients undergoing chemotherapy. Chemotherapy acts on a wide range of cells even when they are not its target. Epo’s administration to such patients may lower the genotoxic effect of chemotherapeutic drugs on those non-target cells if used in a special manner to achieve this. Administrating Epo in the forms of artificial analogues, such as rHuEpo, may offer special advantages to human body, which makes protein usage essential in a wide range of disease

Randomized Versus Real-World Evidence on the Efficacy and Toxicity of Checkpoint Inhibitors in Cancer in Patients with Advanced Non-small Cell Lung Cancer or Melanoma : A Meta-analysis

Background Both randomized controlled trials (RCTs) and real-world evidence (RWE) studies provide results regarding the efficacy and toxicity of checkpoint inhibitors in cancer patients. The results from these two sources are considered complementary but whether they are comparable remains unknown. Objective The aim of this study was to compare the efficacy and toxicity of checkpoint inhibitors between RCTs and RWE studies in patients with advanced non-small cell lung cancer (NSCLC) or melanoma. Patients and Methods Two electronic databases were searched to identify eligible studies, either RCTs or RWE studies, investigating the efficacy or toxicity of checkpoint inhibitors given for indications that were approved by the European Medicines Agency (EMA) at the date of the last search. A meta-analysis was performed and the pooled estimates of objective response rates (ORR), progression-free survival (PFS), overall survival (OS), and toxicity and treatment discontinuation between RCTs and RWE studies were compared. Results In total, 43 RWE studies and 15 RCTs were eligible, with adequate data for pooled estimates for immunotherapy indications regarding NSCLC and melanoma. No statistically significant or clinically meaningful differences in terms of pooled PFS, OS, or rates of treatment discontinuation due to toxicity between RCTs and RWE studies were observed. In some indications, a higher rate of response rates and lower rate of toxicity in favor of RWE was observed. Conclusion In patients with melanoma or NSCLC, the clinical value of checkpoint inhibitors is evident in both RCTs and real-world settings. Some differences in response or toxicity rates in favor of RWE mainly reflects the inherent difficulties in evaluating these outcomes in RWE studies

The role of dacarbazine and temozolomide therapy after treatment with immune checkpoint inhibitors in malignant melanoma patients : A case series and meta-analysis

Dacarbazine (DTIC) and its oral counterpart temozolomide (TMZ) have been the most used agents in advanced malignant melanoma (MM) patients and they are still used routinely. The preferred first line treatment, immune checkpoint inhibitors (CPIs) might shape the tumor and the tumor microenvironment, possibly affecting the response to subsequent therapies. The aim of this study was to investigate the treatment effect of DTIC/TMZ in MM patients after CPI therapy in a consecutive patient cohort and through systematic literature review and meta-analysis. Thirty-five patients with advanced MM treated with DTIC/TMZ after previous CPI therapy in three Swedish regions between 2017 and 2021 were recognized and seven case series studies were identified through systematic database review. Pooled data from all 345 patients showed a median real-world progression-free survival (rwPFS) of 1.9 months and overall survival (OS) of 6.0 months. Three of these studies were included in a meta-analysis comparing DTIC/TMZ after CPI treatment, versus no previous immunotherapy, showing no statistically significant differences in rwPFS or OS but higher real-world response rate to chemotherapy for the prior-CPI treated group (Odds Ratio: 2.24; 95% Confidence Interval: 1.04-4.86). The current study supports consideration of DTIC/TMZ in later line of treatment in the immunotherapy era. We found that the effectiveness of dacarbazine and temozolomide treatment is similar when given after immunotherapy compared to the pre-immunotherapy era. Our results support consideration of dacarbazine and temozolomide in later line of treatment.imag

Improved survival without increased toxicity with influenza vaccination in cancer patients treated with checkpoint inhibitors

In international guidelines, influenza vaccination is recommended to cancer patients receiving antitumor treatment. Whether this recommendation should include patients treated with the recently introduced and now widely used checkpoint inhibitors (CPIs) is unclear. The immune hyperactivation after vaccination in a patient on CPI treatment may strengthen the antitumor immunity and improve patients ' prognosis. On the other hand, the hyperactivation might increase the risk for immune-related adverse events (IRAEs). Furthermore, there is a risk for decreased antitumor effect by the phenomenon of antigenic competition. Only results from few studies addressing survival have been reported and the results from studies on IRAEs are contradictory. We performed a multi-center retrospective cohort study at three Swedish centers in patients with metastatic cancer. All patients previously not treated with CPIs and who received monotherapy with a PD-1 or PD-L1 blocker between January 1st, 2016 until May 31st, 2019 were included. The most common type of malignancy was melanoma (47.8%) followed by non-small cell lung cancer (31.0%). Statistically significant longer PFS and OS were observed in multivariate analyses at 6-month landmark time in the vaccinated compared to the non-vaccinated group after adjustment for age, gender, comorbidity, performance status, CNS metastasis and line of treatment (p = .041 and 0.028, respectively). Furthermore, the incidence of any IRAE grade was comparable between vaccinated and non-vaccinated group (p = .85). In conclusion, the current study indicates that survival improves with influenza vaccination while not increasing the risk for side effects in cancer patients treated with checkpoint inhibitors. Hence, our results strongly support influenza vaccination in cancer patients receiving checkpoint inhibitors

Influenza vaccination in breast cancer patients during subcutaneous trastuzumab in adjuvant setting

Background Despite the current recommendation for influenza vaccination in cancer patients with active oncological therapy, limited data are available on the efficacy of vaccination in cancer patients receiving targeted therapies. We aimed to investigate the immunogenicity and tolerability of influenza vaccination in breast cancer patients treated with trastuzumab in adjuvant setting. Methods A prospective open-label multicenter study was performed including patients with breast cancer during trastuzumab treatment in adjuvant setting and healthy controls. Blood samples were taken before, 4 weeks after, and 12 weeks after a single dose of trivalent influenza vaccine containing inactivated A/California/7/2009 (H1N1) pdm09, A/Hongkong4801/2014 (H3N2), and B/Brisbane/60/2008. Levels of serum antibody titers to hemagglutinin for H1N1 and influenza B strains were measured. Results Twenty breast cancer patients and 37 controls were included in the study. No difference in seroprotection rate between trastuzumab-treated patients and controls was observed for either H1N1 (100% in both groups) or B strain (78.9% vs. 89.2%,pvalue = 0.423). A statistically significant increase in geometric mean titers from baseline was seen in both groups and was evident both 4 weeks and 12 weeks after vaccination. Adverse events in the trastuzumab-treated group were uncommon and mild with only one serious adverse event not related to vaccination. Conclusion Breast cancer patients treated with trastuzumab in adjuvant setting seem to benefit from influenza vaccination in terms of immunogenicity without increasing the risk for adverse events. The current data support the recommendation to offer influenza vaccination in breast cancer patients treated with this type of targeted therapy

Predicting immune‐related adverse events using a simplified frailty score in cancer patients treated with checkpoint inhibitors: A retrospective cohort study

Abstract Objective Checkpoint inhibitors (CPIs) are in widespread clinical use. Little is known about which patients are at risk for developing toxicity. It is essential being able to identify patients with higher risk of experiencing immune‐related adverse events (IRAEs) before initiation of CPI treatment to optimize treatment decisions and follow‐up strategy. The aim of this study was to investigate whether a simplified frailty score based on performance status (PS), age, and comorbidity expressed as Charlson comorbidity index (CCI) could predict development of IRAEs. Methods We performed a retrospective cohort study at three Swedish centers. All patients (n = 596) treated with PD‐L1 or PD‐1 inhibitor for advanced cancer between January 2017 and December 2021 were included. Results In total, 361 patients (60.6%) were classified as nonfrail and 235 (39.4%) as frail. The most common cancer type was non‐small cell lung cancer (n = 203; 34.1%) followed by malignant melanoma (n = 195; 32.7%). Any grade of IRAE occurred in 138 (58.7%) frail and in 155 (42.9%) non‐frail patients (OR: 1.58; 95% CI: 1.09–2.28). Age, CCI, and PS did not independently predict the occurrence of IRAEs. Multiple IRAEs occurred in 53 (22.6%) frail and in 45 (12.5%) nonfrail patients (OR: 1.62; 95% CI: 1.00–2.64). Discussion In conclusion, the simplified frailty score predicted all grade IRAEs and multiple IRAEs in multivariate analyses whereas age, CCI, or PS did not separately predict development of IRAEs suggesting that this easy‐to‐use score may be of value in clinical decision making but a large prospective study is needed to assess its true value

Real‐world data on treatment concepts in classical Hodgkin lymphoma in Sweden 2000–2014, focusing on patients aged >60 years

Abstract Treatment for patients > 60 years with classical Hodgkin lymphoma (cHL) is problematic; there is no gold standard, and outcome is poor. Using the Swedish Lymphoma Registry, we analysed all Swedish patients diagnosed with cHL between 2000 and 2014 (N = 2345; median age 42 years; 691 patients were >60 years). The median follow‐up time was 6.7 years. Treatment for elderly patients consisted mainly of ABVD or CHOP, and the younger patients were treated with ABVD or BEACOPP (with no survival difference). In multivariable analysis of patients > 60 years, ABVD correlated with better survival than CHOP (p = 0.027), and ABVD became more common over time among patients aged 61–70 years (p = 0.0206). Coinciding with the implementation of FDG‐PET/CT, the fraction of advanced‐stage disease increased in later calendar periods, also in the older patient group. Survival has improved in cHL patients > 60 years (p = 0.027), for whom ABVD seems superior to CHOP