Patients with a high defibrillation threshold: Approaches to management.

Implantable cardioverter-defibrillators (ICDs) have revolutionized the prognosis for patients at elevated risk of ventricular tachyarrhythmias. For safety, defibrillation should be effective with a minimum of 10 J below the device's maximum energy. While modern ICDs rarely deliver ineffective shocks in primary prevention, the surge in managing severe heart failure patients has led to an increased number of patients with high defibrillation thresholds (DFTs). This article elucidates the potential causes of high DFT, including clinical factors, lead and device placement, the presence of a Left Ventricular Assist Device (LVAD), prolonged ventricular arrhythmias, shock vectors, waveform tilt, medications, and manufacturer-specific options. We also detail management strategies, highlighting alternative shock coil placements, practical recommendations, and case studies from our institution. Our management algorithm suggests addressing preventable causes, re-evaluating coil positions, considering non-invasive system modifications, upgrading to a higher-capacity device, and adding extra coil(s).

Patient-reported lower limb edema after primary radiotherapy for prostate cancer.

BACKGROUND: Secondary lymphedema is a known side effect to radiotherapy (RT), but limited information regarding prevalence and risk factors for lower limb edema (LLE) after curative radiotherapy in patients with prostate cancer (PCa) is available. This study provides a descriptive analysis of patient-reported LLE with analysis of risk factors in a cohort of patients with PCa treated with curative RT. MATERIAL AND METHODS: A total of 302 patients with PCa with prospective registration of patient-reported LLE (EORTC QLQ-PR25 (Question 46)) were included. Analysis of LLE was done with the calculation of prevalence rates and Kaplan-Meier statistics. Risk factors for LLE were analyzed multivariate with Cox regression analysis. RESULTS: At a median follow-up of 15 (3-51) months, the overall crude incidence of patients reporting 'quite a bit' or 'a lot' of LLE was 49 (16.2%) and 21 (7.0%), respectively. The baseline prevalence rate of 'quite a bit' and 'a lot' of LLE was 5.0% and 0.8%, respectively. During follow-up the prevalence rate for 'quite a bit' or 'a lot' of LLE increased significantly and remained constant from 6 months where 11.5% (±1.7%) reported 'quite a bit' and 2.9% (±0.5%) reported 'very much' LLE (p < 0.001), respectively.Significant risk factors (p < 0.10) for LLE in univariate analysis included lymph node irradiation (HR:2.325), baseline Body Mass Index (BMI) (HR:1.100), Charlson Comorbidity Index (HR:1.227), Androgen Deprivation Therapy (HR:2,979), and Performance Status (HR:0.594). Only high BMI (HR:1.091) remained significant in multivariate analysis with a three-fold increase in LLE in patients with BMI ≥ 30 compared to normal weight patients. CONCLUSION: Severe patient-reported LLE after curative RT for PCa is rare. Significantly more patients with a high BMI report 'quite a bit' or 'very much' LLE compared to patients with a normal BMI. Obese PCa patients could be offered a rehabilitation program for early detection and management of LLE.

Correlation between stage of prostate cancer and tyrosine and tryptophan in urine samples measured electrochemically.

Prostate cancer (PCa) is the second most common cancer in men and one of the leading causes of cancer-related deaths. Early detection is the key to successful treatment and provides the greatest chance to cure the patient. Currently, early detection involves screening for prostate-specific antigen levels in blood, which is not a tumor-specific biomarker. There is a critical need to develop clinically useful methods for screening for more reliable biomarkers. Here, we introduce an electrochemical biosensor that measures the concentrations of the amino acids tyrosine and tryptophan, and propose it as a possible diagnostic and prognostic tool for PCa. The limits of detection of tyrosine and tryptophan using the electrochemical sensors were 1.15 and 1.13 µmol/L in 1:10 urine: PBS, respectively. This study is the first to present electrochemical measurements of tyrosine and tryptophan directly in patient urine samples. We demonstrated an inverse correlation between the measured electrochemical signals and the severity of PCa. The most notable observation was a significant difference between controls and metastatic PCa patients (P ≤ 0.001). This observation was further validated using Liquid-Chromatography-Mass Spectrometry. Our data provides the basis for further research with electrochemical measurements of tyrosine and tryptophan as potential biomarkers for PCa.

Circulating miRNAs in localized/locally advanced prostate cancer patients after radical prostatectomy and radiotherapy.

BACKGROUND: Overtreatment is a well-known clinical challenge in local prostate cancer (PCa). Although risk assessment models have contributed to a better stratification of patients with local PCa, a tailored management is still in its infancy. Over the last few decades, microRNAs (miRNAs) have shown promising results as biomarkers in PCa. The aim of this study was to investigate circulating miRNAs after management of local PCa. METHODS: The relative expression of four miRNAs (miRNA-21, -93, -125b, and miRNA-221) was assessed in plasma from 149 newly diagnosed patients with local or locally advanced PCa. Real-time polymerase chain reaction was used for analysis. A baseline sample at time of diagnosis and a follow-up sample after 6 months were assessed. The patients were grouped in an interventional cohort (radical prostatectomy, curative intent radiotherapy, or androgen-deprivation therapy alone) and an observational cohort (watchful waiting or active surveillance). RESULTS: In the interventional cohort, levels of both miRNA-93 and miRNA-221 were significantly lower in the follow-up samples compared to baseline z = -2.738, P = 0.006, and z = -4.498, P < 0.001, respectively. The same observation was recorded for miRNA-125b in the observational cohort (z = -2.656, P = 0.008). Both miRNA-125b and miRNA-221 were correlated with risk assessment r = 0.23, P = 0.015, and r = 0.203, P = 0.016 respectively, while miRNA-93 showed tendency to significant correlation with the prostatectomy Gleason score (r = 0.276, P = 0.0576). CONCLUSIONS: The current results indicate a possible role of miRNA-93 and miRNA-221 in disease monitoring in localized and locally advanced PCa. Larger studies are warranted to assess the clinical impact of these biomarkers.

microRNA expression in tumour tissue and plasma in patients with newly diagnosed metastatic prostate cancer.

Prostate cancer is the most common cancer among men in the western world. Clinical practice is continuously challenged by the pitfalls of the available diagnostic tools. microRNAs may represent promising biomarkers in many types of human cancers, including prostate cancer. The aim of this study was to investigate microRNA expression in tumour tissue and matched plasma in a cohort of patients with primary metastatic prostate cancer. The relative expression of 12 microRNAs was assessed in diagnostic needle biopsies from the prostate and matched plasma samples in two prospective cohorts (screening cohorts) comprising 21 patients with metastatic prostate cancer and 25 control patients. An independent validation cohort of plasma samples was collected prospectively from 149 newly diagnosed patients with local/locally advanced prostate cancer. Analyses were performed using real-time polymerase chain reaction. miRNA-93 showed a significant negative correlation between expression in tumour tissue and plasma in patients with metastatic prostate cancer. Furthermore, the plasma level of miRNA-93 significantly decreased after treatment in patients with local/locally advanced prostate cancer compared to baseline plasma level. The expression of six microRNAs (let-7b, miRNA-34a, -125b, -143, -145 and -221) was downregulated, and three microRNAs (miRNA-21, -25 and miRNA-93) were upregulated in tumour tissue compared to benign prostate tissue. In plasma, six microRNAs were upregulated (miRNA-21, -125b, -126, -141, -143 and -375), while let-7b was downregulated in patients with metastatic prostate cancer compared to the control cohort. In the metastatic prostate cancer cohort, the expression of four microRNAs (miRNA-125b, -126, -143 and -221), and miRNA-141 in tissue was associated with Gleason score and prostate-specific antigen, respectively. The expression of miRNA-93 in tumour tissue was correlated with matched plasma levels and showed a significant decrease in plasma level after intervention in local prostate cancer. Differential expression between tumour and benign prostate was detected for several microRNAs in both tissue and plasma.

Identification of early stage and metastatic prostate cancer using electrochemical detection of beta-2-microglobulin in urine samples from patients.

To improve prostate cancer (PCa) diagnosis, it is imperative to identify novel biomarkers and establish effective screening techniques. Here, we introduce electrochemical biosensing of ß-2-Microglobulin (ß2M) in urine as a potential diagnostic tool for PCa. The immunosensor is composed of a screen-printed graphene electrode coated with anti ß2M antibodies. The sensor is capable of detecting the protein directly in urine without any sample pretreatment within 45 min including sample incubation and a lower limit of detection of 204 µg/L. The sensor demonstrated a significant difference in the ß2M-creatinine ratio in urine between control and both local- and metastatic PCa (mPCa) (P = 0.0302 and P = 0.0078 respectively), and between local- and mPCa (P = 0.0302). This first example of electrochemical sensing of ß2M for the diagnosis of PCa may set the stage for an affordable, on-site screening technique for PCa.

Correlation Between Natural Killer Cell Activity and Treatment Effect in Patients with Disseminated Cancer.

INTRODUCTION: The aim of the present study was to analyze the possible correlation between Natural Killer (NK) cell activity as measured by the NK Vue assay and treatment efficacy in patients with disseminated cancer. MATERIALS AND METHODS: The study included four trials encompassing palliative treatment, i.e. one trial on prostate- and ovarian cancer, respectively, and two trials on colorectal cancer. The current results are based on 93 patients with mature data on treatment effect. Blood samples were collected at baseline and prior to each treatment cycle into NK Vue. Following 24 hours of stimulation the level of interferon-gamma (IFNγ) in the plasma was measured as a surrogate for NK cell activity. RESULTS: The relationship between NK cell activity and treatment response was similar across tumor types and treatment. The IFNγ either remained at or dropped to an abnormal level (<200 pg/mL) during treatment in group 1 (n = 35). In group 2 (n = 30) the level remained within a normal range (>200 pg/mL), while in group 3 (n = 28) it increased from an abnormal to a normal level. The response rate was 14%, 47%, and 82%, respectively, P < .001. The median progression free survival was 2.6 months (95% confidence interval (CI) 2.1-3.9), 10.0 months (95% CI 6.5-11.1), and 8.3 months (95% CI 6.5-8.7), respectively, P < .001 (log-rank). CONCLUSION: Patients lacking the ability to mount an immune response during the first 2 months of treatment have a poor prognosis, and their clinical benefit of the treatment is questionable.

Heterogeneity of miRNA expression in localized prostate cancer with clinicopathological correlations.

INTRODUCTION: In the last decade microRNAs (miRNAs) have been widely investigated in prostate cancer (PCa) and have shown to be promising biomarkers in diagnostic, prognostic and predictive settings. However, tumor heterogeneity may influence miRNA expression. The aims of this study were to assess the impact of tumor heterogeneity, as demonstrated by a panel of selected miRNAs in PCa, and to correlate miRNA expression with risk profile and patient outcome. MATERIAL AND METHODS: Prostatectomy specimens and matched, preoperative needle biopsies from a retrospective cohort of 49 patients, who underwent curatively intended surgery for localized PCa, were investigated with a panel of 6 miRNAs (miRNA-21, miRNA-34a, miRNA-125b, miRNA-126, miRNA-143, and miRNA-145) using tissue micro-array (TMA) and in situ hybridization (ISH). Inter- and intra-patient variation was assessed using intra-class correlation (ICC). RESULTS: Four miRNAs (miRNA-21, miRNA-34a, miRNA-125, and miRNA-126) were significantly upregulated in PCa compared to benign prostatic hyperplasia (BPH), and except for miRNA-21 these miRNAs documented a positive correlation between the expression level in PCa cores and their matched BPH cores, (r > 0.72). The ICC varied from 0.451 to 0.764, with miRNA-34a showing an intra-tumoral heterogeneity accounting for less than 50% of the total variation. Regarding clinicopathological outcomes, only miRNA-143 showed potential as a prognostic marker with a higher expression correlating with longer relapse-free survival (p = 0.016). CONCLUSION: The present study documents significant upregulation of the expression of miRNA-21, miRNA-34a, miRNA-125, and miRNA-126 in PCa compared to BPH and suggests a possible prognostic value associated with the expression of miRNA-143. The results, however, document intra-tumoral heterogeneity in the expression of various miRNAs calling for caution when using these tumor tissue biomarkers in prognostic and predictive settings.

Cardiac vasoplegia syndrome: pathophysiology, risk factors and treatment.

Vasoplegia syndrome is a well known complication after cardiac surgery and has a significant morbidity and mortality. It is characterized by profound vasodilation and loss of systemic vascular resistance leading to hypotension. The pathogenesis of vasoplegia involves the activation of contact, coagulation and complement systems and the activation of leukocytes, platelets and endothelial cells resulting in an imbalance in the regulation of the vascular tone leading to postcardiac surgery vasoplegia. Multiple risk factors have been identified that help predict vasoplegia. Treatment requires mainly vasopressors, but hypotension can be refractory to vasopressors. Some studies suggest that methylene blue can reverse refractory hypotension in these patients and may prevent the development of the syndrome, but more studies are needed with this drug. In this review, we will discuss the pathophysiology of the vasoplegia syndrome and associated risk factors for this complication and briefly outline current therapeutic strategies.

Chemotherapy-induced polyneuropathy: major agents and assessment by questionnaires.

Chemotherapy-induced polyneuropathy (CIPN) is a common, but underestimated, clinical challenge. Incidence varies depending on many factors that are equally as important as the type of chemotherapeutic agent itself. Moreover, the assessment of CIPN is still uncertain, as several of the most frequently used scales do not rely on a formal neurological evaluation and depend on patients' reports and examiners' interpretations. Therefore, the aim of this MiniReview was to introduce the most common chemotherapies that cause neuropathy, and in addition to this, highlight the most significant differences between the neuropathic pain scales, which are most commonly used for assessing CIPN.

Drug-induced peripheral neuropathy.

Peripheral neuropathy can be caused by medication, and various descriptions have been applied for this condition. In this MiniReview, the term 'drug-induced peripheral neuropathy' (DIPN) is used with the suggested definition: Damage to nerves of the peripheral nervous system caused by a chemical substance used in the treatment, cure, prevention or diagnosis of a disease. Optic neuropathy is included in this definition. A distinction between DIPN and other aetiologies of peripheral neuropathy is often quite difficult and thus, the aim of this MiniReview is to discuss the major agents associated with DIPN.

Oxaliplatin-induced neuropathy in colorectal cancer: many questions with few answers.

Oxaliplatin is a chemotherapeutic agent effective against advanced colorectal cancer. Unlike with other platinum-based agents, the main side effect of oxaliplatin is polyneuropathy. Oxaliplatin-induced polyneuropathy (OIPN) has a unique profile, which can be divided into acute and chronic neurotoxicity. Early identification of the neurotoxicity and alterations in dose or schedule for the medication could prevent the development of chronic symptoms, which, once established, may take many months or years to resolve or even persist throughout life with a substantial effect on quality of life. There is no doubt that the use of pharmacogenomic methods to identify genetic bases of interindividual differences in drug response has led to what is called tailoring treatment. Yet there are some challenges regarding the application of these differences. Many efforts have been made to prevent or treat OIPN. Better understanding of the mechanisms underlying the acute and chronic forms of OIPN will be a key component of future advances in the prevention and treatment of OIPN. The aim of this review is to highlight the clinical presentation, assessment, and management of OIPN, as well as the underlying pathophysiologic and pharmacogenomic background.