Chemotherapy-Induced Peripheral Neuropathy (CIPN) as a Predictor of Decreased Quality of Life in Testicular Germ Cell Tumor Survivors.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) after curative treatment for testicular germ cell tumors (GCTs) has been previously reported. It has been shown that CIPN can contribute to impaired quality of life (QOL) in cancer survivors. Herein, we aimed to evaluate CIPN in association with QOL in GCT survivors. PATIENTS AND METHODS: European Organization for Research and Treatment of Cancer (EORTC) Quality of Life - Chemotherapy-Induced Peripheral Neuropathy questionnaire (QLQ-CIPN20) and Quality of Life Questionnaire (QLQ-C30) were prospectively completed by GCT survivors (N = 151) at National Cancer Institute in Slovakia during their annual follow-up. The median follow-up was 10 years (range 4-30). Upon obtaining the scores from each questionnaire, each score from QLQ-C30 was correlated with CIPN defined as high or low (above and below median) as obtained from CIPN20. RESULTS: GCT survivors with high overall CIPN score reported impaired QOL in QLQ-C30. The global health status was lower in survivors with high CIPN versus low CIPN (mean score ± SEM: 67.17 ± 2.00 vs. 86.18 ± 1.76, P < .00001). Survivors with high CIPN reported worse physical, role, emotional, cognitive, and social functioning compared to survivors with low CIPN (all P < .00001). CIPN high survivors perceived more fatigue, nausea, pain, dyspnea, sleeping disorders, and appetite loss compared to CIPN low survivors (all P < .004). Higher burden of CIPN was associated with more financial problems vs CIPN low (mean score ± SEM: 19.70 ± 2.64 vs. 6.67 ± 2.32, P = .00025). Spearman analysis has confirmed negative correlation of overall CIPN20 score with QLQ-C30 global health status (R = -0.53, P < .0001). CONCLUSION: CIPN is a strong predictor of impairment in QOL among GCT survivors. Molecular mechanisms of neurotoxicity should be intensively studied to find preventive and therapeutic strategies.

Prognostic role of plasma vitamin D and its association with disease characteristics in germ cell tumours.

Background: Testicular cancer is the most common malignancy among young men. Vitamin D has pluripotent effects on cancer pathogenesis and plays a role in the metastatic cascade. The aim of this study is to analyze plasma vitamin D in association with clinico-pathological findings and prognosis in patients with germ-cell tumors (GCTs). Methods: This study included 120 newly diagnosed and/or relapsed GCT patients treated from April 2013 to July 2020, for whom plasma was available in the biobank. Blood samples were drawn the 1st chemotherapy cycle as well as before the 2nd cycle. Plasma vitamin D was measured using ELISA and correlated with disease characteristics and the outcome. For survival analysis, the cohort was dichotomized into "low" and "high" based on median vitamin D. Results: There was no significant difference in vitamin D plasma levels between healthy donors and GCT patients (p = 0.71). Vitamin D level was not associated with disease characteristics except for brain metastases, where patients with brain metastases had a vitamin D level that was 32% lower compared to patients without brain metastases, p = 0.03. Vitamin D was also associated with response to chemotherapy, with an approximately 32% lower value in patients with an unfavorable response compared to a favorable response, p = 0.02. Moreover, low plasma levels of vitamin D were significantly associated with disease recurrence and inferior progression-free survival (PFS), but not with overall survival (OS) (HR = 3.02, 95% CI 1.36-6.71, p = 0.01 for PFS and HR = 2.06, 95% CI 0.84-5.06, p = 0.14 for OS, respectively). Conclusion: Our study suggests the prognostic value of pretreatment vitamin D concentrations in GCT patients. Low plasma vitamin D was associated with an unfavorable response to therapy and disease recurrence. However, it remains to be determined whether the biology of the disease confirms a causative role for low vitamin D and whether its supplementation affects the outcome.

Cognitive impairment and biomarkers of gut microbial translocation in testicular germ cell tumor survivors.

Background: Survivors of testicular germ cell tumors (GCT) may suffer from late cognitive impairment. We hypothesized that disruption of intestinal barrier during chemotherapy and/or radiotherapy may be a contributing factor of cognitive dysfunction within the gut-blood-brain axis. Methods: GCT survivors (N = 142) from National Cancer Institute of Slovakia completed the Functional Assessment of Cancer Therapy Cognitive Function questionnaires during their annual follow-up visit at 9-year median (range 4-32). Biomarkers of gut microbial translocation and dysbiosis high mobility group box-1 (HMGB-1), lipopolysaccharide, d-lactate and sCD14 were measured from peripheral blood obtained during the same visit. Each questionnaire score was correlated with biomarkers. Survivors were treated with orchiectomy only (N = 17), cisplatin-based chemotherapy (N = 108), radiotherapy to the retroperitoneum (N = 11) or both (N = 6). Results: GCT survivors with higher sCD14 (above median) had worse cognitive function perceived by others (CogOth domain) (mean ± SEM; 14.6 ± 0.25 vs 15.4 ± 0.25, p = 0.019), lower perceived cognitive abilities (CogPCA domain) (20.0 ± 0.74 vs 23.4 ± 0.73, p = 0.025) and lower overall cognitive function score (109.2 ± 0.74 vs 116.7 ± 1.90, p = 0.021). There were no significant cognitive declines associated with HMGB-1, d-lactate and lipopolysaccharide. Survivors treated with ≥ 400mg/m2 vs < 400mg/m2 of cisplatin-based chemotherapy had a higher lipopolysaccharide (567.8 µg/L ± 42.7 vs 462.9 µg/L ± 51.9, (p = 0.03). Conclusions: sCD14 is a marker of monocytic activation by lipopolysaccharide and may also serve as a promising biomarker of cognitive impairment in long-term cancer survivors. While chemotherapy and radiotherapy-induced intestinal injury may be the underlying mechanism, further research using animal models and larger patient cohorts are needed to explore the pathogenesis of cognitive impairment in GCT survivors within the gut-brain axis.

Overcoming Chemotherapy Resistance in Germ Cell Tumors.

Testicular germ cell tumors (GCTs) are highly curable malignancies. Excellent survival rates in patients with metastatic disease can be attributed to the exceptional sensitivity of GCTs to cisplatin-based chemotherapy. This hypersensitivity is probably related to alterations in the DNA repair of cisplatin-induced DNA damage, and an excessive apoptotic response. However, chemotherapy fails due to the development of cisplatin resistance in a proportion of patients. The molecular basis of this resistance appears to be multifactorial. Tracking the mechanisms of cisplatin resistance in GCTs, multiple molecules have been identified as potential therapeutic targets. A variety of therapeutic agents have been evaluated in preclinical and clinical studies. These include different chemotherapeutics, targeted therapies, such as tyrosine kinase inhibitors, mTOR inhibitors, PARP inhibitors, CDK inhibitors, and anti-CD30 therapy, as well as immune-checkpoint inhibitors, epigenetic therapy, and others. These therapeutics have been used as single agents or in combination with cisplatin. Some of them have shown promising in vitro activity in overcoming cisplatin resistance, but have not been effective in clinical trials in refractory GCT patients. This review provides a summary of current knowledge about the molecular mechanisms of cisplatin sensitivity and resistance in GCTs and outlines possible therapeutic approaches that seek to overcome this chemoresistance.

Improvement in cardiovascular risk markers by the combined effect of natural polyphenols and vitamins in patients after kidney transplantation.

OBJECTIVES: The aim of this study was to evaluate the potential of supportive therapy by natural polyphenols combined with vitamins C and E on kidney function and risk factors of cardiovascular diseases in renal transplant recipients (RTR). BACKGROUND: Transplant patients have an altered lipid profile associated with the development of cardiovascular disease, which is a major cause of graft loss and mortality in patients. METHODS: The study included 29 renal transplant recipients with mean graft function levels. The lipoprotein (atherogenic and non-atherogenic) subfractions were identified and quantified in plasma by polyacrylamide gel electrophoresis. RESULTS: After supplementation, glomerular filtration rate (GFR) was increased by 8 %, serum creatinine was decreased by 6.7 % and significant changes were found in atherogenic LDL subfractions. The effect of supplementation was observed in arylesterase and lactonase activities of paraoxonase 1 which increased by 9.3 % and 8.1 %, respectively. In addition, significantly decreased levels of neopterin (by 16 %) and asymmetric dimethylarginine (ADMA) (by 7.9 %) were found. CONCLUSION: We could summarize that supportive therapy improves the renal function (GFR, serum creatinine), and reduces the risk of cardiovascular disease by affecting important risk markers of atherosclerosis (lipid profile, paraoxonase 1 activity, neopterin and ADMA) in RTR (Tab. 4, Fig. 1, Ref. 53).

Long-Term Cognitive Dysfunction in Cancer Survivors.

Cancer-related cognitive impairment (CRCI) is a frequent side effect experienced by an increasing number of cancer survivors with a significant impact on their quality of life. Different definitions and means of evaluation have been used in available literature; hence the exact incidence of CRCI remains unknown. CRCI can be described as cognitive symptoms reported by cancer patients in self-reported questionnaires or as cognitive changes evaluated by formal neuropsychological tests. Nevertheless, association between cognitive symptoms and objectively assessed cognitive changes is relatively weak or absent. Studies have focused especially on breast cancer patients, but CRCI has been reported in multiple types of cancer, including colorectal, lung, ovarian, prostate, testicular cancer and hematological malignancies. While CRCI has been associated with various treatment modalities, including radiotherapy, chemotherapy, hormone therapy and novel systemic therapies, it has been also detected prior to cancer treatment. Therefore, the effects of cancer itself with or without the psychological distress may be involved in the pathogenesis of CRCI as a result of altered coping mechanisms after cancer diagnosis. The development of CRCI is probably multifactorial and the exact mechanisms are currently not completely understood. Possible risk factors include administered treatment, genetic predisposition, age and psychological factors such as anxiety, depression or fatigue. Multiple mechanisms are suggested to be responsible for CRCI, including direct neurotoxic injury of systemic treatment and radiation while other indirect contributing mechanisms are hypothesized. Chronic neuroinflammation mediated by active innate immune system, DNA-damage or endothelial dysfunction is hypothesized to be a central mechanism of CRCI pathogenesis. There is increasing evidence of potential plasma (e.g., damage associated molecular patterns, inflammatory components, circulating microRNAs, exosomes, short-chain fatty acids, and others), cerebrospinal fluid and radiological biomarkers of cognitive dysfunction in cancer patients. Discovery of biomarkers of cognitive impairment is crucial for early identification of cancer patients at increased risk for the development of CRCI or development of treatment strategies to lower the burden of CRCI on long-term quality of life. This review summarizes current literature on CRCI with a focus on long-term effects of different cancer treatments, possible risk factors, mechanisms and promising biomarkers.

Covalent and noncovalent interactions of coordination compounds with DNA: An overview.

Deoxyribonucleic acid plays a central role in crucial cellular processes, and many drugs exert their effects through binding to DNA. Since the discovery of cisplatin and its derivatives considerable attention of researchers has been focused on the development of novel anticancer metal-based drugs. Transition metal complexes, due to their great diversity in size and structure, have a big potential to modify DNA through diverse types of interactions, making them the prominent class of compounds for DNA targeted therapy. In this review we describe various binding modes of metal complexes to duplex DNA based on covalent and noncovalent interactions or combination of both. Specific examples of each binding mode as well as possible cytotoxic effects of metal complexes in tumor cells are presented.

Challenges and solutions in management of cardiotoxicity induced by checkpoint inhibitors.

BACKGROUND: The use of immune checkpoint inhibitors has dramatically improved the prognosis of many cancer patients. However, their increasing use has also revealed several unexpected side effects - including cardiovascular complications. Increased attention was paid to them in recent years only, especially due to their potentially fatal character. Checkpoint inhibitors cardiotoxicity includes myocarditis, rhythm disorders (atrioventricular blocks, atrial and ventricular arrhythmias), pericarditis, myocardial infarction, left ventricular dysfunction/heart failure, dilated cardiomyopathy, cardiogenic shock and sudden cardiac death. The risk of ICI-associated cardiotoxicity is increased in patients treated with dual immune therapy, in combination with other cardiotoxic drugs, with preexisting cardiac damage, diabetes mellitus, underlying autoimmune disease and some other factors. Currently, there are no guidelines for prediction and management of ICI-associated cardiotoxicity. PURPOSE: Herein, we briefly summarize the findings regarding checkpoint inhibitor-induced cardiotoxicity and provide a new definition of anti-tumor-induced myocarditis together with a suitable design for immune- induced myocarditis management prepared by experts from the field of cardiooncology.

An Effect of Oak-Wood Extract (Robuvit®) on Energy State of Healthy Adults-A Pilot Study.

The purpose of our study was to examine the psychological benefits of the treatment with Robuvit® (Horphag Research Ltd.) - polyphenolic extract obtained from the wood of oak Quercus robur - on the healthy elderly individuals using energy subscale scores of the Activation - Deactivation Adjective Check List. Analysis was focused on the comparison of pre-post treatment effect of Robuvit on symptoms of fatigue. In the total group of volunteers, significant increase of average question scores was found in three of four subscales of feelings (energy, tiredness, and tension) after 4 weeks of Robuvit administration. Effects of extract were observed mainly after stratification of total group of volunteers according to the level of feeling at the pre-treatment questionnaire. Our results demonstrate positive effect of Robuvit on mental and energy level in healthy human without any unwanted side effects.

Influence of oak wood polyphenols on cysteine, homocysteine and glutathione total levels and PON1 activities in human adult volunteers - a pilot study.

Oxidative stress reflects an imbalance between antioxidants and pro-oxidants. Many diseases like atherosclerosis or heart failure are involved in oxidative stress. Increased oxidative stress is one of the potential contributing factors to aging. The aim of this study was to monitor the total thiol levels as markers of oxidative stress in 20 healthy volunteers after polyphenols intake (extract from the French oak wood Quercus robur - Robuvit® (300 mg/day)). Polyphenols are known as biomodulators with antioxidant activities. Homocysteine, cysteine and glutathione total levels were determined by using HPLC with electrochemical detection. The activity of the antioxidant enzyme paraoxonase-1 toward two substrates was determined by spectrophotometry. The level of thiol compounds and paraoxonase-1 activities were controlled after run-in (week 0), intervention (week 4) and washout (week 6) period. After the intervention period the results showed that Robuvit® had no significant influence on glutathione level (p = 0.382) and paraoxonase activities towards both, arylester and lactone substrates. On the other hand, homocysteine and cysteine levels decreased significantly (p = 0.029; p < 0.001, respectively). The negative correlation between paraoxonase lactonase activity and homocysteine level was noticed. This confirms that paraoxonase might play an important role in homocysteine-thiolactone metabolism.

Effect of the French oak wood extract Robuvit on markers of oxidative stress and activity of antioxidant enzymes in healthy volunteers: a pilot study.

We examined in vitro antioxidant capacity of polyphenolic extract obtained from the wood of oak Quercus robur (QR), Robuvit, using TEAC (Trolox equivalent antioxidant capacity) method and the effect of its intake on markers of oxidative stress, activity of antioxidant enzymes, and total antioxidant capacity in plasma of 20 healthy volunteers. Markers of oxidative damage to proteins, DNA, and lipids and activities of Cu/Zn-superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were determined in the erythrocytes. We have found an in vitro antioxidant capacity of Robuvit of 6.37 micromole Trolox equivalent/mg of Robuvit. One month intake of Robuvit in daily dose of 300 mg has significantly decreased the serum level of advanced oxidation protein products (AOPP) and lipid peroxides (LP). Significantly increased activities of SOD and CAT as well as total antioxidant capacity of plasma after one month intake of Robuvit have been shown. In conclusion, we have demonstrated for the first time that the intake of Robuvit is associated with decrease of markers of oxidative stress and increase of activity of antioxidant enzymes and total antioxidant capacity of plasma in vivo.

The effect of natural polyphenols on the oxidative stress markers in patients with diabetic nephropathy.

BACKGROUND: Nephropathy remains a significant cause of morbidity and mortality in the diabetic population and is the leading cause of end-stage renal failure, hence kidney transplantations. As a result of the diabetic milieu, increased generation of reactive oxygen species is thought to play a key role in the progression of diabetic nephropathy. Aim of this study was to evaluate the effect of Pycnogenol (Pyc), the extract from Pinus pinaster, on the level of glucose, advanced glycation end products (AGE) and oxidative stress markers in patients with Diabetic nephropathy (DN). SUBJECT AND METHODS: To double blind randomised placebo controlled exploratory study were enrolled 20 men with DN received daily Pyc (120mg) or a placebo. Patients were investigated before, one and three months after Pyc administration and after termination of drugs supplementation. RESULTS: The level of glucose, AGEs, malondialdehyde (MDA), 8-isoprostanes (8-Iso), as well as protein carbonyls (PC) were increased in comparison to control group. We have found lower level of glucose, AGEs, MDA and 8-Iso after 3 months of Pyc administration in comparison to the beginning state and to placebo group, but these results did not reach significance. CP and TAS were not affected. CONCLUSION: Our data allow us to conclude that Pycnogenoladministration reduces oxidative damage to lipids rather through the decreased glucose level than through the influence of antioxidant capacity of plasma. This study was supported by grant Ministry of Health 2012/8-ukba-8.

Effects of N1-methylnicotinamide on oxidative and glycooxidative stress markers in rats with streptozotocin-induced diabetes mellitus.

OBJECTIVES: This study was focused on the monitoring how the anti-inflammatory substance, N(1)-methylnicotinamide (MNA), could influence oxidation and glycooxidation stress markers in rats under conditions of streptozotocin (STZ)-induced diabetes mellitus. METHODS: Diabetes mellitus was induced in 60 male Wistar rats by intraperitoneal injection of STZ and after 7 days diabetic animals were allocated to five groups according to the dose of MNA administered for 7 weeks. The degree of DNA damage in lymphocytes, as well as advanced glycation endproducts (AGEs), protein carbonyls, lipid peroxides, and total antioxidant capacity (TEAC) in plasma were measured. RESULTS: Glycation damage to proteins (represented by AGEs level) was significantly increased in all diabetic groups compared to untreated non-diabetic animals. MNA did not affect TEAC of plasma in any group of diabetic rats. Supplementation of diabetic rats with MNA at the dose of 200 mg/kg resulted in decreased protein carbonyls (from 0.0818±0.0091 to 0.0558±0.0044 nmol/mg proteins; P<0.05, n=15) and DNA oxidation, reflected by the levels of 8-oxoG (0.6302±0.085 vs. 0.9213±0.108 8-oxoG/10(6) G; P<0.05, n=15), compared to untreated diabetic animals. DISCUSSION: Our results demonstrated that MNA at suitable concentrations could influence oxidative modifications of proteins and DNA.

Influence of pyridoxylidene aminoguanidine on biomarkers of the oxidative stress and selected metabolic parameters of rats with diabetes mellitus.

Oxidative damage is considered to play an important role in the pathogenesis of several diseases, such as diabetes mellitus (DM), atherosclerosis, cardiovascular complications and chronic renal failure. DM is associated with the oxidative stress and formation of advanced glycation end products (AGEs). Different drugs inhibit oxidative stress and formation of advanced glycation end products. Aminoguanidine (AG) has been proposed as a drug of potential benefit in prophylaxis of the complications of DM. Recent reports show a pro-oxidant activity of AG. Therefore we examined the effect of structural analogue of AG, its Schiff base with pyridoxal-pyridoxylidene aminoguanidine (PAG) on the level of selected markers of oxidative stress. We found that PAG decreased total damage to DNA in controls as well as in diabetic group of rats. However, we also found that PAG supplementation increases susceptibility of lipoproteins to oxidation and formation of conjugated dienes in both, diabetic as well as control animals. Its administration to diabetic rats decreases antioxidant capacity of plasma. Therefore, it is necessary to search for other structural modifications of AG that would combine its higher anti-diabetic activity with less toxicity.