Nanomedicine and epigenetics: New alliances to increase the odds in pancreatic cancer survival.

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers worldwide, primarily due to its robust desmoplastic stroma and immunosuppressive tumor microenvironment (TME), which facilitate tumor progression and metastasis. In addition, fibrous tissue leads to sparse vasculature, high interstitial fluid pressure, and hypoxia, thereby hindering effective systemic drug delivery and immune cell infiltration. Thus, remodeling the TME to enhance tumor perfusion, increase drug retention, and reverse immunosuppression has become a key therapeutic strategy. In recent years, targeting epigenetic pathways has emerged as a promising approach to overcome tumor immunosuppression and cancer progression. Moreover, the progress in nanotechnology has provided new opportunities for enhancing the efficacy of conventional and epigenetic drugs. Nano-based drug delivery systems (NDDSs) offer several advantages, including improved drug pharmacokinetics, enhanced tumor penetration, and reduced systemic toxicity. Smart NDDSs enable precise targeting of stromal components and augment the effectiveness of immunotherapy through multiple drug delivery options. This review offers an overview of the latest nano-based approaches developed to achieve superior therapeutic efficacy and overcome drug resistance. We specifically focus on the TME and epigenetic-targeted therapies in the context of PDAC, discussing the advantages and limitations of current strategies while highlighting promising new developments. By emphasizing the immense potential of NDDSs in improving therapeutic outcomes in PDAC, our review paves the way for future research in this rapidly evolving field.

Changes in CoQ10/Lipids Ratio, Oxidative Stress, and Coenzyme Q10 during First-Line Cisplatin-Based Chemotherapy in Patients with Metastatic Urothelial Carcinoma (mUC).

Oxidative stress plays an important role in cancer pathogenesis, and thiobarbituric acid-reactive substance level (TBARS)­a parameter of lipid peroxidation­has prognostic significance in chemotherapy-naive patients with metastatic urothelial carcinoma (mUC). However, the effect of cisplatin (CDDP)-based chemotherapy on oxidative stress, coenzyme Q10, and antioxidants remains unknown. The objective of this prospective study was to determine possible changes in the CoQ10 (coenzyme Q10)/lipids ratio, antioxidants (α-tocopherol, γ-tocopherol, ß-carotene, CoQ10), total antioxidant status (TAS), and TBARS in plasma at baseline and during first-line chemotherapy based on CDDP in mUC subjects. In this prospective study, 63 consecutive patients were enrolled. The median age was 66 years (range 39−84), performance status according to the Eastern Cooperative Oncology Group (ECOG) was 2 in 7 subjects (11.1%), and visceral metastases were present in 31 (49.2%) patients. Plasma antioxidants were determined by HPLC and TAS and TBARS spectrophotometrically. After two courses of chemotherapy, we recorded significant enhancements compared to baseline for total cholesterol (p < 0.0216), very low-density lipoprotein (VLDL) cholesterol (p < 0.002), triacylglycerols (p < 0.0083), α-tocopherol (p < 0.0044), and coenzyme Q10-TOTAL (p < 0.0001). Ratios of CoQ10/total cholesterol, CoQ10/HDL-cholesterol, and CoQ10/LDL-cholesterol increased during chemotherapy vs. baseline (p < 0.0048, p < 0.0101, p < 0.0032, respectively), while plasma TBARS declined (p < 0.0004). The stimulation of antioxidants could be part of the defense mechanism during CDDP treatment. The increased index of CoQ10-TOTAL/lipids could reflect the effect of CDDP protecting lipoproteins from peroxidation.

Prevention and treatment of cancer associated venous thromboembolism - interdisciplinary consensus.

The increasing volume of the data and experience with direct oral anticoagulants (DOACS) in the primary and secondary prevention of venous thromboembolism in oncologic patients (CAVTE) has recently lead to changes in several international guidelines. We reflect these changes within the conditions in Slovak republic. In the primary prevention of CAVTE we recognise oncosurgical patients and nonsurgical patients: hospitalised and out patients. Low molecular weight heparins are still dominant in the primary prevention of CAVTE. Regarding the treatment and the secondary prevention of CAVTE, we recommend always to consider the possibility to use DOACs as they proved to be non inferior to LMWH. However, LMWH should be prefered over DOACs as well as over warfarin (VKA) in all patients who are in a clinically unstable condition with the high risk of bleeding and/or interaction with the systemic treatment. Primarily in the patients with intraluminal tumours of the upper part of the gastrointestinal tract and genitourinary tumours with the high risk of bleeding. As for the lack of data, LMWH are still preferd also in patients with primary tumours and metastatic disease of the central nervous system and in hemato oncology.

Pericardial malignant infiltration as the cause of sudden death of a patient with metastatic urothelial carcinoma treated with atezolizumab.

BACKGROUND: Muscle-infiltrating urothelial carcinoma of the bladder is the most common genitourinary cancer. Immunotherapeutic agents targeting protein-1 programmed death or protein-1 programmed death ligand are currently considered the standard treatment in patients with either inoperable locally advanced or metastatic urothelial carcinoma (MUC) after platinum-based chemotherapy failure. CASE PRESENTATION: Here we report the case of a Caucasian male patient with metastatic urothelial carcinoma treated with second-line atezolizumab within a trial who achieved complete response by computed tomography (CT), but suddenly died due to cardiac tamponade resulting from malignant pericardial infiltration. Histopathology confirmed this as the only site of disease progression. CONCLUSIONS: Cardiovascular toxicity of atezolizumab was considered within differential diagnoses, however histopathological examination revealed progression of malignancy in the pericardium as the cause of the sudden death. This is the first published case report of a patient treated with second-line atezolizumab in whom the rare disease progression of pericardial infiltration was confirmed. Despite its rarity, the clinicians should always consider the possibility of pericardial metastases.

Effectiveness, Adverse Events, and Immune Response Following Double Vaccination with BNT162b2 in Staff at the National Comprehensive Cancer Center (NCCC).

Vaccination remains the leading strategy against COVID-19 worldwide. BNT162b2 is among the first licensed vaccines with high effectiveness. However, the role of antibody and cell immunity response monitoring after vaccination remains unclear. We conducted a 6-month prospective study involving the employees of NCCC in Slovakia, who were tested for IgG antibody and cell immune responses after double vaccination with BNT162b2. IgG antibodies were detected at 3, 7, and 26 weeks, respectively. At 6 months, blood samples were tested by two different interferon-γ release assays to determine responses to spike protein antigen and nucleocapsid protein antigen of the novel coronavirus. Results were stratified by gender and body mass index (BMI). Statistical significance was set at p = 0.05. The medical records of 94 respondents (71 females) were analyzed. The mean age was 40.2 years and the mean BMI was 26.4 kg/m2. At 6 months after double vaccination, effectiveness was 97.9%. The side effects of the BNT162b2 vaccine were similar after both doses, with no serious adverse events or new safety signals recorded. The IgG index declined rapidly (p < 0.0001), and 42.6% of subjects had positive and 57.4% borderline or negative immune cell response at 6 months (p < 0.0001). Both T cell activation and IgG counts were lower in morbidly obese patients when compared to some other BMI categories. This study confirmed an acceptable toxicity profile and the high efficacy of BNT162b2 despite a rapid decline of IgG level and negative cell-mediated immunity response in most subjects. An individualized approach to vaccination could be considered in morbidly obese individuals.

A case report of a patient with inoperable primary diffuse leptomeningeal melanomatosis treated with whole-brain radiotherapy and pembrolizumab.

RATIONALE: Primary diffuse leptomeningeal melanomatosis (PDLM) is a rare disease that affects melanocytes in the leptomeninges. There is very limited data on the efficacy of immunotherapy in this setting. PATIENT CONCERNS: A patient (23 years old) was diagnosed with PDLM. Histologically, atypical melanocytic cells were also observed. DIAGNOSIS: Immunohistochemistry showed positivity for S100 protein, NKiC3, and vimentin, and negativity for Melan-A and HMB-45, with a proliferation index of 30%. Extracranial disease was excluded using dermatological and other examinations, including positron emission tomography/computed tomography with 18F-fluorodeoxyglucose. INTERVENTIONS: The patient was treated with whole-brain radiotherapy (10 fractions to a total dose of 30 Gy) concomitantly with pembrolizumab and then continued with immunotherapy until disease progression with a maximum effect of partial remission on magnetic resonance imaging scans. OUTCOMES: Progression-free survival was 6.0 months and overall survival 6.5 months. LESSONS: This is one of the few case reports of an adult patient with this rare malignancy being treated with a programmed death-1 inhibitor with partial response. Immunotherapy in metastatic PDLM may be a reasonable therapeutic option.

Survival Prediction by Baseline Systemic Immune-inflammation Index (SII) and its Changes During First-line Platinum-based Treatment in a Caucasian Population of Patients With Metastatic Urothelial Carcinoma (MUC).

BACKGROUND/AIM: Systemic immune-inflammation index (SII) predicts survival of patients with various malignancies. This study explored the prognostic value of SII in metastatic urothelial carcinoma (MUC) subjects. PATIENTS AND METHODS: We evaluated 181 consecutive MUC patients treated with first-line platinum-based therapy. Karnofsky performance status <80% and visceral metastasis were present in 18.2% and 46.4% of patients, respectively. SII was based on platelet × neutrophil/lymphocyte counts. Study population was dichotomized by median into high and low SII groups before the initiation of chemotherapy and at week 6. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared with the log-rank test. RESULTS: At median follow-up of 9.6 months, 174 patients experienced disease progression and 173 died. Patients with low SII at baseline and at week 6 had significantly better PFS (HR=0.58; p=0.0002 and HR=0.55; p<0.0001) and OS (HR=0.54; p<0.0001 and HR=0.54; p<0.0001) compared to patients with high SII. Independent prognostic value of SII was confirmed in a multivariate analysis. CONCLUSION: High SII before chemotherapy that persists at week 6 negatively affects survival. SII at baseline can be used in the stratification of patients within clinical trials and in clinical practice.

COVID-19 and oncological disease.

BACKGROUND: Coronavirus disease 2019 (COVID-19), a respiratory tract infection caused by the severe acute respiratory syndrome coronavirus named SARS-CoV-2, initially emerged in China in late 2019. The rapid global spread of this novel virus led the World Health Organization declare a pandemic with > 30,000,000 confirmed cases, 946,000 deaths and > 21,000,000 recoveries reported as of 18 September 2020, according to the Johns Hopkins Coronavirus Resource Center. Initial reports from Asia suggested that elderly patients with multiple comorbidities, specifically diabetes, hypertension, and obesity were at an increased risk of developing severe COVID-19 following a SARS-CoV-2 infection. As data on these risks have evolved, evidence has increasingly shown that patients with cancer are indeed a particularly vulnerable group. However, the effects of various confounding factors, including an older than average patient population who often have underlying comorbidities including a suppressed immune system and/ or a hypercoagulable state, have been difficult to separate from the effects of having cancer. Common presenting symptoms of SARS-CoV-2 including dyspnoea, cough, fever, fatigue, dysgeusia and, less commonly, diarrhoea and/ or a hyperinflammatory syndrome are equally confusing to clinicians as they all are common symptoms of both cancer and toxicity from anti-cancer therapy. Furthermore, the radiographic dilemma of distinguishing between immune-checkpoint inhibitor-induced pneumonitis from that caused by SARS-CoV-2 infection and conflicting data on the effects of certain therapies on patient outcomes has left clinicians with considerable angst on how to help patients with acute or worsening symptoms in an optimal way. Predicted increase in mortality follows not only from the delay in discovery and progress resulting from temporary closing of research laboratories at cancer centers but also from diversion of resources to patient care and temporary suspension of clinical trial enrolment both by companies and local institutions. The possibilities of travelling to specialized medical centers whose activities are essential for the delivery and improvement of patient care were reduced, too. Viral mutations might also occur during transmission and spread; this leads to a statement that SARS-CoV-2 will forever remain a looming threat to the oncological community. What is crucial to remember is that cancer itself is a pandemic with > 18,000,000 people dia-gnosed worldwide every year. Many societies, including the European Society for Medical Oncology and the American Society of Clinical Oncology, are providing clinical recommendations for the management of patients with cancer during this challenging time, recognizing that continuation in the precise treatment of our patients is critical for our role of physicians. PURPOSE: The aim of the presentation is to point out the contact or overlapping areas of both mentioned disease entities for the purpose of possible simplification of dia-gnostic and therapeutic management of a cancer patient with suspected or already proven  COVID-19 disease.

Platelet Mitochondrial Bioenergetics Reprogramming in Patients with Urothelial Carcinoma.

Mitochondrial bioenergetics reprogramming is an essential response of cells to stress. Platelets, an accessible source of mitochondria, have a crucial role in cancer development; however, the platelet mitochondrial function has not been studied in urothelial carcinoma (UC) patients. A total of 15 patients with UC and 15 healthy controls were included in the study. Parameters of platelet mitochondrial respiration were evaluated using the high-resolution respirometry method, and the selected antioxidant levels were determined by HPLC. In addition, oxidative stress was evaluated by the thiobarbituric acid reactive substances (TBARS) concentration in plasma. We demonstrated deficient platelet mitochondrial respiratory chain functions, oxidative phosphorylation (OXPHOS), and electron transfer (ET) capacity with complex I (CI)-linked substrates, and reduced the endogenous platelet coenzyme Q10 (CoQ10) concentration in UC patients. The activity of citrate synthase was decreased in UC patients vs. controls (p = 0.0191). γ-tocopherol, α-tocopherol in platelets, and ß-carotene in plasma were significantly lower in UC patients (p = 0.0019; p = 0.02; p = 0.0387, respectively), whereas the plasma concentration of TBARS was increased (p = 0.0022) vs. controls. The changes in platelet mitochondrial bioenergetics are consistent with cell metabolism reprogramming in UC patients. We suppose that increased oxidative stress, decreased OXPHOS, and a reduced platelet endogenous CoQ10 level can contribute to the reprogramming of platelet mitochondrial OXPHOS toward the activation of glycolysis. The impaired mitochondrial function can contribute to increased oxidative stress by triggering the reverse electron transport from the CoQ10 cycle (Q-junction) to CI.

Plasma thiobarbituric acid reactive substances predicts survival in chemotherapy naïve patients with metastatic urothelial carcinoma.

Oxidative stress plays a significant role in development and progression of cancer, including urothelial carcinomas. TBARS (Thiobarbituric acid reactive substances) represents a marker of oxidative stress increased in various diseases. In this prospective study, we tested the hypothesis of plasma TBARS concentration and correlation with survival in chemotherapy naïve MUC (metastatic urothelial carcinoma) patients. Most of subjects (N = 65) were treated with gemcitabine and cisplatin (GC) chemotherapy. Performance status ECOG ≥2 had 11 patients, visceral metastases were present in 43. Based upon the mean of plasma TBARS, subjects were dichotomized into low and high groups. Progression-free survival (PFS), overall survival (OS) and their 95% CI were estimated by Kaplan-Meier method and compared by log-rank test. At median follow-up of 9.6 months, 65 patients experienced progression and 64 died. Subjects with low TBARS had significantly better PFS (HR 0.51) and OS (HR 0.44) opposed to high TBARS. Patients with low TBARS had significantly higher rate of neutropenia G4 and less liver involvement. High TBARS correlated with BMI above 30 kg/m2. Performance status and plasma TBARS were proven to be independent predictors of PFS and OS. In this study, high TBARS in MUC patients were associated with poor survival, likely due to more aggressive disease activity as reflected in increased liver involvement. Therefore, this biomarker could be used in clinical practice for early identification of patients with worse prognosis, better patient stratification, and treatment decision making.

The first cancer patient with COVID-19 in Slovakia.

BACKGROUND: In December 2019 a new strain of coronavirus SARS-CoV-2 has emerged and affected health care worldwide. Patients with cancer and other comorbidities are at increased risk for adverse outcomes in this infection. CASE: In this case report we present a 75-year-old patient with a localized gastric adenocarcinoma, currently treated by perioperative chemotherapy regimen, who had an rT-PCR proven novel coronavirus SARS-CoV-2 infection. Laboratory and radiologic assessments were performed in order to assess disease severity; however, the findings were not altered in accordance with the findings associated with COVID-19 disease. RESULTS: On the first hospital day the patient had a low grade fever with chills. Subsequently a pharmacological therapy with hydroxychloroquine and azithromycin was started. After pharmacologic and symptomatic treatment, the patient was reassessed for SARS-CoV-2, with negative results. At discharge, the patient was ordered a 14-day mandatory quarantine. After 57 days of follow-up, the patient underwent a new rapid antibody test by Acro Biotech inc., which gave negative results for IgM and IgG. CONCLUSION: An infection with SARS-CoV-2 is associated with a more severe disease in patients with comorbidities and cancer; however, this case patient had a mild course of COVID-19 disease. The aim of this case report is to share the information on the clinical course and outcomes of a patient with malignancy. Rapid spreading of information is crucial in the management of COVID-19.