scholarly journals Cardiac Toxicity of Cancer Chemotherapy

2017 ◽  
Vol 11 (1) ◽  
pp. 20
Author(s):  
Aarti Asnani ◽  
Randall T Peterson ◽  
◽  
Keyword(s):  
Antitumor Agents ◽  
Cardiac Toxicity ◽  
Survival Rates ◽  
Clinical Manifestations ◽  
Left Ventricular ◽  
Cytotoxic Agents ◽  
Cancer Therapies ◽  
Cancer Treatments ◽  
Number Of Patients ◽  
Increased Risk

With the aging of the population, the number of patients diagnosed with cancer has grown significantly over the past few decades. In parallel, survival rates have improved due to the increased efficacy and tolerability of cancer treatments. As such, the acute and long-term toxicities of cancer therapies have become increasingly prominent as contributors to morbidity and mortality in cancer survivors. Cardiac toxicity can occur with a broad range of cancer treatments, from conventional cytotoxic agents to newer targeted and immune-based therapies. Common manifestations of chemotherapy-associated cardiotoxicity include asymptomatic left ventricular dysfunction, congestive heart failure, myocardial ischemia, myocarditis, QT prolongation, and arrhythmia. In this review, we will describe antitumor agents that have commonly been associated with an increased risk of cardiac toxicity, with an emphasis on clinical manifestations, underlying mechanisms, and cardioprotective strategies that can be implemented in this setting.

Comparative analysis of polymorphic variants of IL-17A and MMP-1 genes with the risk of developing chronic periodontitis in petrochemical workers

2020 ◽  
Vol 60 (10) ◽  
pp. 687-693
Author(s):  
Iskander I. Zaidullin ◽  
Denis O. Karimov ◽  
Lilija K. Karimova ◽  
Milyausha F. Kabirova ◽  
Rasima R. Galimova ◽  
...  
Keyword(s):  
Ethylene Oxide ◽  
Chronic Periodontitis ◽  
Periodontal Diseases ◽  
Clinical Manifestations ◽  
Control Group ◽  
Periodontal Tissues ◽  
Dental Examination ◽  
Number Of Patients ◽  
Increased Risk ◽  
Harmful Substances

The susceptibility to the development and progression of inflammatory periodontal diseases, which depends on genetic and external factors (smoking, stress, oral hygiene), varies widely. In the development of these diseases, an important role is played not only by the presence of periodontal pathogenic microorganisms, but also by the presence of congenital or acquired immunodeficiency, immunoregulatory defects. The immune system plays a key role in the physiological and pathological processes of periodontal tissues. In this regard, IL17, produced by CD4+ Th cells, which has both Pro-inflammatory and protective activity, is of particular interest in the pathogenesis of periodontitis. The aim of study was to identify the relationship between polymorphic loci of the IL-17A (rs2275913) and MMP-1 (rs1799750) genes and clinical manifestations of chronic periodontitis in petrochemical workers. Dental examination was performed in 92 ethylene oxide production workers with chronic periodontitis and 74 patients with chronic periodontitis who did not come into contact with chemical factors (control group). Genotyping of polymorphisms rs2275913 of the IL17A gene and rs1799750 of the MMP1 gene was performed by allele-specific real-time polymerase chain reaction (PCR). Hygienic assessment of the degree of air pollution of the working area with harmful substances was carried out by gas chromatography according to the guidelines for the determination of harmful substances in the air № 5098-89, № 3119-84. When comparing the results of studies of both groups, there were no statistically significant differences in the frequency distributions of allelic variants and genotypes of the IL-17A and MMP-1 genes. The AA/AG genotypes of the IL-17A gene were associated with an increased risk of severe disease compared to the GG genotype in workers in the main group (OR=6.1; 95% CI 1.33-28.5; p=0.021) and in the control group (OR=7.26; 95% CI 1.34-39.25; p=0.016). Carriers of the A allele in the control group increased the risk of severe chronic periodontitis by 2.4 times compared to carriers of the G allele (OR=2.41; 95% CI 1.19-4.87; p=0.014). During the dental examination of employees of the ethylene oxide plant, the clinical course of periodontal diseases was more severe in comparison with the control group, and the number of patients with severe periodontitis was twice as high. It was found that the AA/AG genotypes of the IL-17A gene and the carrier of the A allele are associated with increased susceptibility to the development of severe chronic periodontitis. The association between the MMP-1 gene polymorphism and the risk of severe forms of chronic periodontitis has not been established. A risk factor for the development of inflammatory periodontal diseases in employees of the petrochemical complex is a complex of harmful production factors.

scholarly journals Prognostic value of atrial fibrillation in patients with heart failure and different left ventricular ejection fraction: results of the multicenter RIF-CHF register

2021 ◽  
Vol 26 (1) ◽  
pp. 4200
Author(s):  
I. V. Zhirov ◽  
N. V. Safronova ◽  
Yu. F. Osmolovskaya ◽  
S. N. Тereschenko
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Ejection Fraction ◽  
Cardiovascular Mortality ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
Number Of Patients ◽  
Increased Risk

Heart failure (HF) and atrial fibrillation (AF) are the most common cardiovascular conditions in clinical practice and frequently coexist. The number of patients with HF and AF is increasing every year.Aim. To analyze the effect of clinical course and management of HF and AF on the outcomes.Material and methods. The data of 1,003 patients from the first Russian register of patients with HF and AF (RIF-CHF) were analyzed. The endpoints included hospitalization due to decompensated HF, cardiovascular mortality, thromboembolic events, and major bleeding. Predictors of unfavorable outcomes were analyzed separately for patients with HF with preserved ejection fraction (AF+HFpEF), mid-range ejection fraction (AF+HFmrEF), and reduced ejection fraction (AF+HFrEF).Results. Among all patients with HF, 39% had HFpEF, 15% — HFmrEF, and 46% — HFrEF. A total of 57,2% of patients were rehospitalized due to decompensated HF within one year. Hospitalization risk was the highest for HFmrEF patients (66%, p=0,017). Reduced ejection fraction was associated with the increased risk of cardiovascular mortality (15,5% vs 5,4% in other groups, p<0,001) but not ischemic stroke (2,4% vs 3%, p=0,776). Patients with HFpEF had lower risk to achieve the composite endpoint (stroke+MI+cardiovascular death) as compared to patients with HFmrEF and HFrEF (12,7% vs 22% and 25,5%, p<0,001). Regression logistic analysis revealed that factors such as demographic characteristics, disease severity, and selected therapy had different effects on the risk of unfavorable outcomes depending on ejection fraction group.Conclusion. Each group of patients with different ejection fractions is characterized by its own pattern of factors associated with unfavorable outcomes. The demographic and clinical characteristics of patients with mid-range ejection fraction demonstrate that these patients need to be studied as a separate cohort.

scholarly journals Hidden burden of arrhythmias in patients with small atrial septal defects: a nationwide study

Open Heart ◽  
2019 ◽  
Vol 6 (1) ◽  
pp. e001056
Author(s):  
Sebastian Udholm ◽  
Camilla Nyboe ◽  
Andrew Redington ◽  
Jens Erik Nielsen-Kudsk ◽  
Jens Cosedis Nielsen ◽  
...  
Keyword(s):  
Volume Overload ◽  
Left Ventricular ◽  
Adult Patients ◽  
Heart Volume ◽  
Nationwide Study ◽  
Septal Defects ◽  
Atrial Septal Defects ◽  
Background Population ◽  
Number Of Patients ◽  
Increased Risk

BackgroundIn recent Danish nationwide register-based study, adults with small, unrepaired atrial septal defects (ASD) have increased risk of pneumonia, atrial fibrillation (AF) and stroke. Moreover, they revealed higher mortality than the background population.ObjectiveIn this nationwide study, we evaluate the hidden burden of atrial and ventricular arrhythmias in adult patients with a small, unrepaired ASD without a previous diagnosis of AF.MethodsAll Danish patients, aged 18–65, diagnosed between 1953 and 2011 with an unrepaired ASD and no documented AF were invited for 7 days Holter-recording, echocardiography and 6 min walk test. The first 48 hours Holter-recording was completely analysed, while only AF was screened for throughout all 7 days. Furthermore, the entire patient group were characterised using the unique Danish registries.ResultsA total of 151 patients (mean age 32 years) were included. Approximately 80% of the patients had spontaneous closure of their defect. Despite this, occult arrhythmias were frequent. The most common arrhythmia was supraventricular tachycardia (n=24, 16%) with non-sustained atrial arrhythmias in 21 patients and AF in two patients. A considerable number of patients had non-sustained ventricular tachycardia (n=12, 8%). Patients with ASD and tachyarrhythmias had increased right ventricular to left ventricular diastolic area in echocardiography and higher age when compared with ASD patients without arrhythmias.ConclusionAdult patients with small, unrepaired ASD have a hidden burden of both atrial and ventricular tachyarrhythmias. The mechanism likely relates to the residua of previous right-heart volume overload and incomplete reverse remodelling. Our results support guidelines recommending continued follow-up of patients with small, unrepaired ASD.

scholarly journals Implication of Current ASE/EACVI Left Ventricular Diastolic Function Classification in Predicting 2-Year MACE in Asymptomatic Patients with Diabetes and Hypertension

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
D Foo ◽  
K H Lam ◽  
M Igo ◽  
M N A Sulaiman ◽  
M Y Ku ◽  
...  
Keyword(s):  
Left Atrial Volume ◽  
Left Ventricular ◽  
Volume Index ◽  
Diabetic Patients ◽  
Prognostic Impact ◽  
Left Atrial Volume Index ◽  
Asymptomatic Patients ◽  
Number Of Patients ◽  
Increased Risk ◽  
Patients With Diabetes

Abstract Background Left ventricular diastolic dysfunction (LVDD) has been shown to be more prevalent in patients with diabetes, and once progress to overt heart failure, carry worse clinical outcomes. Substantial number of patients were classified as indeterminate DF based on the current ASE/EACVI guidelines. The implication of current DF classification in predicting MACE among diabetic patients is not well established. Purpose To assess prognostic impact of current guidelines-based DF classification, and determine predictors of 2-year MACE based on individual LVDD parameters. Methods A total of 111 patients with diabetes and hypertension who attended diabetic clinic follow-up at the primary healthcare settings were enrolled. All patients had no prior cardiovascular events, had preserved left ventricular (LV) ejection fraction on echocardiography and sinus rhythm on ECG at screening. Echocardiography was performed to obtain parameters of LV dimensions, LV volumes and LVDD. The 2016 ASE/EACVI guidelines were applied to classify DF. All patients were followed up until 2 years to assess MACE. Results There were 65 (58.6%) female patients. Mean age was 59.86 (7.45); mean duration of DM was 10.5 (5.41). 80 (72.1%) patients were classified as having normal DF (nDF); 24 (21.6%) patients were classified as indeterminate DF (iDF); 7 patients (6.3%) were classified as LVDD. Patients with LVDD had significantly higher LV mass index (LVMI) (mean 121.72±23.28g/m2 vs 116.62±24.66g/m2 in iDF vs 102.50±22.89g/m2 in nDF); higher left atrial volume index (LAVI) (mean 41.24±10.28ml/m2 vs 30.55±10.07ml/m2 in iDF vs 25.75±6.30ml/m2 in nDF); lower lateral e' velocity (mean 6.35±2.05cm/s vs 7.37±1.73cm/s in iDF vs 8.59±2.13cm/s in nDF); higher septal E/e' ratio (mean 14.89±3.29 vs 12.16±3.99 in iDF vs 9.99±2.35 in nDF); higher average septal-lateral E/e' ratio (mean 14.22±3.77 vs 11.34±3.74 in iDF vs 9.04±2.10 in nDF). Among these 111 patients, 10 patients (9%) reported MACE at 2 years. The risk of 2-year MACE is elevated in both iDF [odds ratio (OR) 3.80, 95% CI 0.87–16.54, p=0.075] and LVDD [OR 7.60, 95% CI 1.11–52.02, p=0.039]. LVMI (OR 1.027, 95% CI 1.004– 1.051, p=0.023), LAVI (OR 1.092, 95% CI 1.017–1.172), and average septal-lateral E/e' ratio (OR 1.276, 95% CI 1.047–1.557, p=0.016) significantly correlated with 2-year MACE. Conclusions LVDD is correlated with increased MACE at 2 years. LVMI, LAVI and average septal-lateral E/e' ratio were predictors of increased risk of MACE at 2 years. Further investigation with larger sample size is warranted. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Health Malaysia

scholarly journals NMN does not protect the ovarian reserve from cancer treatments

Reproduction ◽  
2020 ◽  
Vol 159 (2) ◽  
pp. 105-113 ◽  
Author(s):  
Jessica Stringer ◽  
Ella Groenewegen ◽  
Seng H Liew ◽  
Karla Hutt
Keyword(s):  
Ovarian Reserve ◽  
Cancer Survival ◽  
Survival Rates ◽  
Primordial Follicle ◽  
Cancer Therapies ◽  
Γ Irradiation ◽  
Cancer Treatments ◽  
Primordial Follicles ◽  
Nicotinamide Mononucleotide ◽  
Cyclophosphamide Treatment

Primordial follicle oocytes are extremely vulnerable to DNA damage caused by exogenous agents, such as those commonly used to treat cancer. Consequently, female cancer patients often have diminished ovarian reserve, which if severe enough, can cause premature ovarian failure and early menopause. Advances in cancer therapies have resulted in significantly improved cancer survival rates; therefore, it is becoming increasingly important to devise strategies to protect the ovarian reserve from cancer treatments, to avoid loss of fertility and endocrine dysfunction. In this study, we aimed to determine whether supplementation with nicotinamide mononucleotide (NMN) could preserve the ovarian reserve following exposure to DNA-damaging cancer treatments. Adult female mice (n = 5–6/group) received saline or NMN (500 mg/kg/day) for 8 days. Mice were left untreated or exposed to γ-irradiation (0.1 Gy) or cyclophosphamide (150 mg/kg) on day 7 and ovaries and serum collected for analysis on day 12. We report that γ-irradiation treatment significantly reduced the number of primordial follicles, but supplementation with NMN did not prevent the observed follicle loss. Similarly, cyclophosphamide treatment significantly reduced primordial follicle numbers, but these losses were not prevented by NMN supplementation. In conclusion, depletion of the ovarian reserve following γ-irradiation or cyclophosphamide was not protected by NMN supplementation under the conditions employed in this study.

Moderate Reduction in LVEF Is Associated with an Increased Risk of Post-HSCT Symptomatic Cardiomyopathy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2023-2023
Author(s):  
Kinjal Parikh ◽  
Lekha Mikkilineni ◽  
Fern Martin ◽  
Dolores Grosso ◽  
Benjamin Leiby ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiac Function ◽  
Cardiac Toxicity ◽  
Continuous Variable ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Categorical Variables ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Increased Risk

Abstract Background: Evaluation of comorbidities prior to allogeneic hematopoietic stem cell transplantation (HSCT) is important in predicting patient outcomes and has contributed to the increasing proportion of long-term HSCT survivors. In comparison to the general population, there is a greater burden of cardiovascular disease in HSCT survivors primarily in those who have undergone allogeneic HSCT. It has been hypothesized that these effects are secondary to chronic inflammation and its effect on the vascular endothelium. Prior studies have shown the presence of cardiovascular risk factors, including obesity, dyslipidemia, and hypertension, as well as exposure to chest radiation and anthracyclines, to be associated with an increased risk for the development of post HSCT cardiomyopathy (CM). The evaluation of left ventricular ejection fraction (LVEF) is routine pre-HSCT, however, studies have shown variable results in its utility in predicting cardiac toxicity post-HSCT. In addition, other morbidity outcomes in the setting of pre-existing cardiac dysfunction have yet to be fully explored, including the development of severe acute kidney injury (AKI) requiring renal dialysis. This study examines the role of pre-HSCT cardiac risk factors and LVEF as prognostic tools for post-HSCT development of symptomatic CM, severe AKI requiring dialysis, and early mortality. Methods: We undertook a retrospective analysis of 384 patients who underwent allogeneic HSCT between 2004 and 2014 at Thomas Jefferson University Hospital. LVEF values were collected from transthoracic echocardiograms or multigated acquisition (MUGA) scans. Documentation of symptomatic CM post-HSCT was established based on clinical signs and symptoms (decreased LVEF associated with new need for medical therapy for heart failure including beta blocker, ACE-inhibitor and/or diuretic), within 100 days after HSCT. Assessment of development of severe AKI was determined by the need for dialysis within the 100 days after HSCT. Univariate association of categorical variables with outcomes and potential confounding variables was assessed using exact Chi-square tests. Logistic regression was used to calculate estimates of association between LVEF as a continuous variable and outcomes. Results: The final sample included 364 patients with a median age of 54 (range, 19 to 78); 42% of subjects were female. 20 patients were excluded due to inadequate data available regarding cardiac function and/or disease course. 30-day mortality was 6.3%, 100-day mortality was 15.9%, severe AKI requiring dialysis was 13.7%, and the development of symptomatic CM was 9.9%. Patients with a pre-HSCT LVEF <50% (5.2% of the sample size) were more likely than those with an LVEF ≥ 50% to develop symptomatic CM (21.1% compared to 9.3%), need for dialysis (26.3% compared to 13%), and 100 day mortality (26.3% compared to 15.4%). However, given the small number of patients with LVEF <50%, these trends were not statistically significant. However, as a continuous variable, LVEF was associated with the development of symptomatic CM (OR=0.95; p=0.029); every one-unit increase in LVEF above 45% was associated with a 5% decrease in the likelihood of developing symptomatic CM. This association remained statistically significant after adjustment for age. Discussion: When addressing 'fitness' for transplant, a thorough investigation of risk factors and exposures may assist in predicting risk of cardiovascular morbidity as well as overall mortality. Cardiac toxicity may account for nearly 5 to 10% of non-relapse mortality during the first 100 days post-HSCT. Evaluation of cardiac function, using LVEF as a marker, has been standard; however, studies have shown mixed results on its predictive utility. Our study showed a nearly linear relationship between baseline LVEF and the development of CM. It remains difficult to define a precise LVEF value that should be required prior to HSCT. Further study, particularly in patients with low baseline LVEF (i.e. 40-50%), may help our understanding of risk factors relating to post-HSCT development of symptomatic cardiac and renal morbidity as suggested in this study, and better define a reasonable cutoff to use to determine to whom we can safely offer allogenic HSCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Potential Markers of Arterial and/or Venous Thromboses and their Complications in Primary Antiphospholipid Syndrome

2007 ◽  
Vol 26 (4) ◽  
pp. 259-268
Author(s):  
Mirjana Bećarević ◽  
Nada Majkić-Singh
Keyword(s):  
Risk Factors ◽  
Antiphospholipid Syndrome ◽  
Clinical Manifestations ◽  
Primary Antiphospholipid Syndrome ◽  
Number Of Patients ◽  
Increased Risk ◽  
Significant Difference ◽  
Recurrent Abortions ◽  
Venous Thromboses

Potential Markers of Arterial and/or Venous Thromboses and their Complications in Primary Antiphospholipid SyndromeAntiphospholipid syndrome is characterized by venous or arterial thromboses and/or recurrent abortions accompanied by antiphospholipid antibodies and it can be primary (PAPS) or secondary (SAPS) to another disease. Arterial thromboses are less common than venous and most frequently they manifest as ischemia or infarction. Venous thromboses are usually multiple and bilateral and the most common complication of venous thromboses are pulmonary emboli. Considering that laboratory diagnosis of PAPS is currently based on persistently positive aCL, aβ2gpl and/or LA tests, and that neither one of those tests can discriminate between PAPS patients with arterial or venous thromboses or their complications, the aim of this study was to investigate the diagnostical significance of the determination of apo(a), oxLDL, anti-oxLDL antibodies, antianxA5 antibodies, hsCRP, C3 and C4 complement components and HPT for discrimination between PAPS patients with diverse clinical manifestations. Considering that elevated oxLDL and anti-oxLDL antibodies concentrations were found in PAPS patients, and also in subgroups of PAPS patients with MI or PE, it can be concluded that those parameters represent additional risk factors which together with other factors may lead to thromboses and their complications in PAPS. Regarding the fact that C3 and C4 concentrations were decreased in PAPS patients and that a positive correlation was found between hsCRP and C3 concentrations, this finding could indicate potential roles of these parameters as markers of atherosclerosis, which represents the leading cause of morbidity and mortality. HPT and apo(a) concentrations are not independent risk factors for MI in PAPS because lower levels were found in those patients in comparison to MI survivors without PAPS. No significant correlation of anti-anxA5 antibodies and the presence of arterial or venous thromboses or their complications was found, but increased concentrations of the IgG isotype of those antibodies could be a marker for recurrent abortions in PAPS, although this finding should be further investigated on a larger number of patients with this clinical finding. Determination of hsCRP in PAPS patients could not be an adequate parameter which would provide discrimination between patients with increased risk for development and/or recurrence of venous and/or arterial thromboses, nor for their complications, because no statistically significant difference in concentrations of this parameter was found among PAPS, IM, PE and SLE patients who were included in this study.

scholarly journals Purine Analogues Increase the Risk of Lethal and/or Prolonged COVID19 While Obinutuzumab Increases the Risk of Prolonged but Not Lethal Infection in Patients Treated for Lymphoid Malignancies -a Study of Krohem, the Croatian Group for Hematologic Diseases

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3553-3553
Author(s):  
Igor Aurer ◽  
Ozren Jaksic ◽  
Sandra Bašić-Kinda ◽  
Stefan Mrdenovic ◽  
Slobodanka Ostojic Kolonic ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Standard Dose ◽  
Cytotoxic Agents ◽  
Purine Analogues ◽  
Lymphoid Malignancies ◽  
Risk Of Death ◽  
Number Of Patients ◽  
Increased Risk ◽  
Anti Cd20 ◽  
Lymphoma Therapy

Abstract Patients with lymphoid malignancies are at increased risk of death due to COVID19. Currently, it is not completely clear whether this is mainly due to disease biology or to anti-lymphoma treatment and whether the prognosis of infection differs in patients treated with different therapies. Anti-CD20 monoclonal antibodies increase the risk of prolonged infection. It is not known whether this risk is affected by the choice of the antibody. To study these questions, KroHem collected data on patients with lymphoid malignancies diagnosed with COVID19 between October 2020 and April 2021. Death during infection was considered as due to COVID19. Patients were considered to have prolonged disease if they were continuously or repetitively positive by PCR for more than 6 weeks. Percentage of patients with prolonged disease was calculated based on the number of patients with available data who were alive 6 weeks after beginning of infection. Treatment regimens were divided into those containing purine analogues (PA), mainly bendamustine and fludarabine, standard-dose chemotherapy without PA (e.g. CHOP, CVP, chlorambucil, etc.), high-dose chemotherapy without PA (e.g. DHAP, ICE, etc.), B-cell receptor inhibitors (iBCR) and venetoclax. We identified 314 patients, 20-88 years old (median 66), 180 male and 134 female; 75 were untreated, 61 off treatment and 178 on treatment (Table). Eleven (15%) untreated patients died; 10% had prolonged infection none of whom died. Ten (16%) off-treatment patients died; 9% had prolonged infection none of whom died. In the on-treatment group 6 (3%) are still prolonged positive, 110 (62%) recovered and 62 (35%) died; 42% had prolonged infection of whom 47% recovered and 42% died. The single allografted patient died as did both patients treated with CAR-T cells after prolonged infection. We analyzed prognostic factors for lethal and prolonged infection in the 175 conventionally treated patients. Disease type, use of anti-CD20 monoclonal antibodies, prior autologous stem-cell transplantation (ASCT) and line of treatment did not significantly affect mortality. Mortality was higher in older (p=0.0078) and those treated with PA in comparison to standard-dose chemotherapy without PA and iBCR (47% vs. 26%, p=0.012). The effect of anti-lymphoma therapy on mortality was similar in all age groups. All of the 7 patients who received neither cytotoxic agents nor iBCR (4 were on rituximab monotherapy, 2 on cyclosporine and 1 on vemurafenib) recovered, none had prolonged infection. Prolonged COVID19 was significantly more frequent in patients treated with anti-CD20 monoclonal antibodies (p=0.012), especially obinutuzumab (67% in comparison to 42% in those treated with rituximab and 21% in those treated without anti-CD20 antibodies). Treatment with PA also increased the risk of prolonged disease (69% vs. 25-45% in other groups, p=0.012). The effect of PA on prolonged infection was similar in patients treated with rituximab and obinutuzumab. Age, prior ASCT and treatment line did not significantly affect risk of prolonged infection. Our data suggest that the type of anti-lymphoma therapy is, besides age, a main determinant of prognosis of COVID19 in patients with lymphoid malignancies. Use of purine analogues, such as bendamustine and fludarabine, is related to increased risk of lethal and/or prolonged COVID19. These drugs should probably be avoided in patients with indolent NHL and CLL, diseases for whom other effective treatments are available, during the current pandemia. Anti-CD20 monoclonal antibodies seem to have a smaller effect on mortality, with obinutuzumab increasing the risk of prolonged disease, but not of death, in comparison to rituximab. Figure 1 Figure 1. Disclosures Aurer: takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Swixx/BMS: Honoraria; Teva/Pilva: Honoraria; Abbvie: Consultancy, Honoraria; sanofi genzyme: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Eusapharma: Consultancy, Honoraria. Jaksic: Roche, Oktal-Pharma/Celtrion, Sandoz: Consultancy, Honoraria. Mrdenovic: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria. Ostojic Kolonic: Roche, Oktal-Pharma/Celtrion, Sandoz: Consultancy, Honoraria. Lozic: Roche, Oktal-Pharma/Celtrion, Sandoz: Consultancy, Honoraria. Holik: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria. Novakovic Coha: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria. Bernes: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria. Krecak: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria. Moric Peric: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria. Mitrovic: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria.

The Potential Impacts of Tylophora Alkaloids and their Derivatives in Modulating Inflammation, Viral Infections, and Cancer

2019 ◽  
Vol 26 (25) ◽  
pp. 4709-4725 ◽  
Author(s):  
Duc-Hiep Bach ◽  
Sang Kook Lee
Keyword(s):  
Immune Modulation ◽  
Antitumor Agents ◽  
Viral Infections ◽  
Treatment Options ◽  
Current Treatment ◽  
Cytotoxic Agents ◽  
Targeted Agents ◽  
Cancer Treatments ◽  
New Era ◽  
Cancer Pathogenesis

Cancer chemotherapies or antitumor agents mainly remain the backbone of current treatment based on killing the rapidly dividing cancer cell such as tylophora alkaloids and their analogues which have also demonstrated anticancer potential through diverse biological pathways including regulation of the immune system. The introduction of durable clinically effective monoclonal antibodies, however, unmasked a new era of cancer immunotherapies. Therefore, the understanding of cancer pathogenesis will provide new possible treatment options, including cancer immunotherapy and targeted agents. Combining cytotoxic agents and immunotherapies may offer several unique advantages that are complementary to and potentially synergistic with biologic modalities. Herein, we highlight the dynamic mechanism of action of immune modulation in cancer and the immunological aspects of the orally active antitumor agents tylophora alkaloids and their analogues. We also suggest that future cancer treatments will rely on the development of combining tumor-targeted agents and biologic immunotherapies.

Novel heterozygous PIK3CD mutation presenting with only laboratory markers of combined immunodeficiency

2020 ◽  
Vol 7 (2) ◽  
pp. 49-55
Author(s):  
Amarilla B. Mandola ◽  
Harjit Dadi ◽  
Brenda Reid ◽  
Chaim M. Roifman
Keyword(s):  
Newborn Screening ◽  
Catalytic Domain ◽  
Clinical Course ◽  
Phenotypic Variability ◽  
Severe Combined Immunodeficiency ◽  
Clinical Manifestations ◽  
Combined Immunodeficiency ◽  
Laboratory Findings ◽  
Number Of Patients ◽  
Increased Risk

Introduction: Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Delta (PIK3CD) is one part of a heterodimer forming the enzyme phosphoinositide 3-kinase (PI3K), found primarily in leukocytes. PIK3CD generates phosphatidyl-inositol 3,4,5-trisphosphate (PIP3), and is involved in cell growth, survival, proliferation, motility, and morphology. An increasing number of patients have been described with heterozygous PIK3CD gain-of-function (GOF) mutations, leading to combined immunodeficiency with both B- and T-cell dysfunction. Patients suffer recurrent respiratory infections, often associated with bronchiectasis and ear and sinus damage, as well as severe recurrent or persistent infections by herpesviruses, including EBV-induced lymphoproliferation. Aim: To present the clinical phenotypic variability of a novel PI3KCD mutation within a family. Methods: Patient information was collected prospectively and retrospectively from medical records. Comprehensive immune work up, genetic, and signaling evaluation was performed. Results: We describe here 2 patients, daughter and mother, with heterozygous PIK3CD mutation identified by whole exome sequencing and Sanger confirmation. The child was screen-positive by newborn screening for severe combined immunodeficiency (SCID). Cellular assays revealed an increase in the baseline phosphorylation of T cells in the patient. Furthermore, both patients had hyper-activation of the catalytic domain, resulting in increased phosphorylation of AKT upon activation. Discussion: GOF mutations affecting the PIK3CD gene are associated with an increased risk for lymphoproliferation leading to Activated PIK3-delta syndrome (APDS). The clinical course of APDS is highly variable, ranging from combined immunodeficiency with recurrent infections, autoimmune complications, and requiring stem cell transplantation, through isolated antibody deficiency, to asymptomatic adults. Our patient is the first to be identified by newborn screening for SCID. Surprisingly, the clinical course has so far been unremarkable, as well, the mother appears to be completely asymptomatic. Nevertheless, the persistent lymphopenia indicates PIK3CD dysfunction. Because of the wide gap between laboratory findings and clinical manifestations, this kindred poses both a diagnostic as well treatment challenge. Statement of novelty: We report here a novel PIK3CD mutation diagnosed due to abnormal newborn screen for SCID.

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