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Minas Sakellakis,1 Karolina Akinosoglou,1 Anastasia Kostaki,2 Despina Spyropoulou,1 Angelos Koutras,1 1Department of Medicine, Division of Oncology, University Hospital, Patras Medical School, Patras, 2Department of Statistics, Athens University of Economics and Business, Athens, Greece Background: The primary end point of our study was to test whether the concurrent use of a statin is related to a lower risk of recurrence and increased relapse-free survival in patients with early breast cancer. Materials and methods: We reviewed 610 female patients with stage I, II, or III breast cancer who had been surgically treated and who had subsequently received at least adjuvant chemotherapy in order to prevent recurrence. Results: Among the 610 patients with breast cancer, 83 (13.6%) were receiving a statin on a chronic basis for other medical purposes. Overall, statin users displayed longer mean relapse-free survival (16.6 vs 10.2 years, P=0.028). After data had been adjusted for patient and disease characteristics, statin users maintained a lower risk of recurrence. This favorable outcome in statin users was particularly evident when we included only younger patients in the analysis (20 vs 10 years, P=0.006). Conclusion: Statins may be linked to a favorable outcome in early breast cancer patients, especially in younger age-groups. Keywords: statins, breast, cancer, adjuvant, recurrence

Minas Sakellakis,1 Thomas Makatsoris,1 Maria Gkermpesi,2 Stavros Peroukidis,1 Haralabos Kalofonos11Division of Oncology, Department of Medicine, 2Department of Pathology, University, Hospital of Patras, Patras, GreeceAbstract: The association between inflammatory bowel disease and colorectal cancer is well known. Ulcerative colitis is a risk factor for the development of colorectal cancer, and this risk increases with the activity and duration of bowel inflammation. Here we describe the case of a 52-year-old man who developed ulcerative colitis 6 years after the diagnosis and treatment of colon cancer. Although this could be a coincidence, there could be additional possibilities, like pre-existence of quiescent colitis, late effect of therapy, or maybe the existence of common pathogenetic factors contributing to the development of ulcerative colitis and colorectal cancer.Keywords: ulcerative, colitis, colorectal, cancer, inflammation

Aim: The present study aims to investigate the outcomes of Percutaneous coronary intervention (PCI) in patients with Rheumatoid arthritis (RA)., Methods: A systemic search was conducted from electronic databases (PubMed/Medline, Cochrane Library, and Google Scholar) from inception to 15th September 2023. All statistical analyses were conducted using Review Manager 5.4.1. Studies meeting inclusion criteria were selected. A random-effect model was used when heterogeneity was seen to pool the studies, and the result was reported in the odds ratio (OR) and the corresponding 95 % confidence interval (CI)., Results: Eight observational studies were selected to conduct the analysis. A statistically significant increase in major adverse cardiovascular event (MACE) was seen in RA patients after undergoing PCI as compared to the control group (OR = 1.18 (1.16, 1.21); p < 0.00001; I2 = 0 %). There was no significant difference found in the long-term revascularization outcome between the RA and non-RA patients (OR = 1.18 (0.81, 1.71); p = 0.39; I2 = 93 %). Survival rates of all-cause mortality in the long-term outcome were statistically insignificant among the two groups (OR = 1.21 (0.84, 1.74); p = 0.31; I2 = 99 %)., Conclusion: Percutaneous coronary intervention is an important intervention to reduce morbidity and mortality but special precautions and attention should be made when it comes to patients with RA. Different precautions such as close monitoring for medication interaction, and tailored post-procedural care are essential in reducing morbidity and mortality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier, a division of RELX India, Pvt. Ltd.)

Preclinical evidence suggests that voltage gradients can act as a kind of top-down master regulator during embryogenesis and orchestrate downstream molecular-genetic pathways during organ regeneration or repair. Moreover, electrical stimulation shifts response to injury toward regeneration instead of healing or scarring. Cancer and embryogenesis not only share common phenotypical features but also commonly upregulated molecular pathways. Voltage-gated ion channel activity is directly or indirectly linked to the pathogenesis of cancer hallmarks, while experimental and clinical studies suggest that their modulation, e.g., by anesthetic agents, may exert antitumor effects. A large recent clinical trial served as a proof-of-principle for the benefit of preoperative use of topical sodium channel blockade as a potential anticancer strategy against early human breast cancers. Regardless of whether ion channel aberrations are primary or secondary cancer drivers, understanding the functional consequences of these events may guide us toward the development of novel therapeutic approaches.

J waves, or Osborn waves, are a notable EKG finding in hypothermia, often appearing as prominent deflections but sometimes manifesting subtly. We report a 78-year-old female with moderate hypothermia (87.9°F) presenting with sinus bradycardia and subtle J waves on her EKG. After rewarming, these J waves resolved. Hypothermia management should prioritize gentle handling to avoid arrhythmias and ensure rapid rewarming during cardiopulmonary resuscitation. Continuous monitoring is crucial, as J waves can indicate a higher risk of ventricular fibrillation and cardiac arrest., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Batikyan et al.)

Introduction: Intraoperative hemodynamic and metabolic optimization of both the high-risk surgical patients and critically ill patients remains challenging. Reductions in oxygen delivery or increases in oxygen consumption can initiate complex cellular processes precipitating oxygen debt (OXD)., Methods: This study tested the hypothesis that intraoperative changes in sublingual microcirculatory flow reflect clinically relevant transitions from aerobic to anaerobic metabolism (TRANAM). We included patients undergoing elective major and emergency non-cardiac surgery. Macro- and microcirculatory variables, oxygen extraction, and transitions of metabolism were assessed in both cohorts., Results: In the elective group, OXD was progressively increased over time, with an estimated 2.24 unit increase every 30 min (adjusted p < 0.001). Also, OXD was negatively correlated with central venous pressure (ρ = -0.247, adjusted p = 0.006) and positively correlated with stroke volume variation (ρ = 0.185, adjusted p = 0.041). However, it was not significantly correlated with sublingual microcirculation variables. In the emergency surgery group, OXD increased during the first two intraoperative hours and then gradually decreased until the end of surgery. In that cohort, OXD was positively correlated with diastolic arterial pressure (ρ = 0.338, adjpatients and the critically ill patients remains challengingsted p = 0.015). Also, OXD was negatively correlated with cardiac index (ρ = -0.352, adjusted p = 0.003), Consensus Proportion of Perfused Vessels (PPV) (ρ = -0.438, adjusted p < 0.001), and Consensus PPV (small) (ρ = -0.434, adjusted p < 0.001)., Conclusions: TRANAM were evident in both the elective major and emergency non-cardiac surgery cohorts independent of underlying alterations in the sublingual microcirculation.

Elevated resting heart rate is frequently observed in cancer patients, and is associated with increased mortality. Although specific chemotherapeutic agents can induce cardiotoxicity, the presence of sinus tachycardia in chemotherapy-naive patients suggests other factors likely contribute to this clinical presentation. Despite its prevalence, cancer-associated resting sinus tachycardia has not been fully recognized and comprehensively described as a separate clinical entity. Secondary effects of cancer, especially structural cardiac changes, secretory factors (inflammatory cytokines), and thromboembolic disease can cause resting tachycardia. Alternatively, rapid heart rate may reflect compensatory mechanisms responding to increased metabolic demands, raised cardiac output states, and even pain. Hence, cancer-associated tachycardia presents a clinical dilemma; acute life-threatening conditions (such as sepsis, pulmonary embolism, etc.) must be ruled out, but cancer itself can explain resting sinus tachycardia and more conservative management can avoid unnecessary testing, cost and patient stress. Furthermore, identification and management of cardiac conditions associated with cancer may improve survival and the quality of life of cancer patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Sakellakis, Reet, Kladas, Hoge, Chalkias and Radulovic.)

Perioperative stroke is a devastating complication that occurs during surgery or within 30 days following the surgical procedure. Its prevalence ranges from 0.08 to 10% although it is most likely an underestimation, as sedatives and narcotics can substantially mask symptomatology and clinical presentation. Understanding the underlying pathophysiology and identifying potential therapeutic targets are of paramount importance. Protease-activated receptors (PARs), a unique family of G-protein-coupled receptors, are widely expressed throughout the human body and play essential roles in various physiological and pathological processes. This review elucidates the biology and significance of PARs, outlining their diverse functions in health and disease, and their intricate involvement in cerebrovascular (patho)physiology and neuroprotection. PARs exhibit a dual role in cerebral ischemia, which underscores their potential as therapeutic targets to mitigate the devastating effects of stroke in surgical patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The clinical impact of vasopressin in hemorrhagic shock remains largely unknown., Objective: This systematic review and meta-analysis was designed to investigate the effects of vasopressin receptor agonists during the resuscitation of hemorrhagic shock., Methods: A systematic search of PubMed (MEDLINE), Scopus, and PubMed Central was conducted for relevant articles. Experimental (animal) and clinical studies were included. The primary objective was to investigate the correlation of vasopressin receptor agonist use with mortality and various hemodynamic parameters., Results: Data extraction was possible in thirteen animal studies and two clinical studies. Differences in risk of mortality between patients who received a vasopressin receptor agonist were not statistically significant when compared to those who were not treated with such agents [RR (95% CI): 1.17 (0.67, 2.08); p = 0.562; I 2 = 50%]. The available data were insufficient to conduct a meta-analysis assessing the effect of vasopressin receptor agonists on hemodynamics. Drawing safe conclusions from animal studies was challenging, due to significant heterogeneity in terms of species and dosage of vasopressin receptor agonists among studies., Conclusions: Differences in risk of mortality between patients who received a vasopressin receptor agonist were not statistically significant when compared to those who were not treated with such agents after hemorrhagic shock. More data are needed to deduce certain conclusions.

Background: The calculated plasma volume status (cPVS) was validated as a surrogate of intravascular filling. The aim of this study is to assess the cPVS in relation to sublingual perfusion and organ injury., Methods: Pre- and postoperative cPVS were obtained by determining the actual and ideal plasma volume levels in surgical patients. The sublingual microcirculation was assessed using SDF imaging, and we determined the De Backer score, the Consensus Proportion of Perfused Vessels (Consensus PPV), and the Consensus PPV (small). Our primary outcome was the assessment of the distribution of cPVS and its association with intraoperative sublingual microcirculation and postoperative complications., Results: The median pre- and postoperative cPVS were -7.25% (IQR -14.29--1.88) and -0.4% (IQR -5.43-6.06), respectively ( p < 0.001). The mean intraoperative administered fluid volume was 2.5 ± 2.5 L (1.14 L h -1 ). No statistically significant correlation was observed between the pre- or postoperative cPVS and sublingual microcirculation variables. Higher preoperative (OR = 1.04, p = 0.098) and postoperative cPVS (OR = 1.057, p = 0.029) were associated with postoperative organ injury and complications (sepsis (30%), anemia (24%), respiratory failure (13%), acute kidney injury (6%), hypotension (6%), stroke (3%))., Conclusions: The calculated PVS was associated with an increased risk of organ injury and complications in this cohort.

Prostate cancer is the second most diagnosed form of cancer in men worldwide and accounted for roughly 1.3 million cases and 359,000 deaths globally in 2018, despite all the available treatment strategies including surgery, radiotherapy, and chemotherapy. Finding novel approaches to prevent and treat prostate and other urogenital cancers effectively is of major importance. Chemicals derived from plants, such as docetaxel and paclitaxel, have been used in cancer treatment, and in recent years, research interest has focused on finding other plant-derived chemicals that can be used in the fight against cancer. Ursolic acid, found in high concentrations in cranberries, is a pentacyclic triterpenoid compound demonstrated to have anti-inflammatory, antioxidant, and anticancer properties. In the present review, we summarize the research studies examining the effects of ursolic acid and its derivatives against prostate and other urogenital cancers. Collectively, the existing data indicate that ursolic acid inhibits human prostate, renal, bladder, and testicular cancer cell proliferation and induces apoptosis. A limited number of studies have shown significant reduction in tumor volume in animals xenografted with human prostate cancer cells and treated with ursolic acid. More animal studies and human clinical studies are required to examine the potential of ursolic acid to inhibit prostate and other urogenital cancers in vivo.

The introduction of tyrosine kinase inhibitors (TKIs) against vascular endothelial growth factor receptors (VEGFRs) has transformed the therapeutic landscape for patients with advanced renal cell carcinoma (RCC). However, dose reductions and interruptions are frequently needed due to limited toxicity, mostly from off-target effects. Tivozanib is a potent, selective VEGFR TKI with weak off-target effects. TIVO-1 and TIVO-3 were randomized controlled phase 3 trials that investigated the efficacy and safety of tivozanib versus sorafenib as initial targeted therapy and after failing two previous lines (including targeted therapy), respectively. Tivozanib did not confer any survival advantage, but it significantly increased progression-free survival, response rates, and the duration of responses with a superior safety profile. Although results from subgroup analysis need to be interpreted cautiously, tivozanib demonstrated superiority after two previous lines of VEGFR TKIs or after axitinib, another selective VEGFR inhibitor. Tivozanib also demonstrated durable activity after therapy with an immune-checkpoint inhibitor, while an ongoing study investigating the combination of tivozanib/nivolumab has shown promising preliminary results regarding efficacy and safety. In conclusion, tivozanib was recently added to our therapeutic armamentarium against advanced RCC. Ongoing rational therapeutic combinations of tivozanib will determine the optimal setting in which the maximum benefit can be derived., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Sakellakis et al.)

Ion channels have major regulatory functions in living cells. Apart from their role in ion transport, they are responsible for cellular electrogenesis and excitability, and may also regulate tissue homeostasis. Although cancer is not officially classified as a channelopathy, it has been increasingly recognized that ion channel aberrations play an important role in virtually all cancer types. Ion channels can exert pro-tumorigenic activities due to genetic or epigenetic alterations, or as a response to molecular signals, such as growth factors, hormones, etc. Increasing evidence suggests that ion channels and pumps play a critical role in the regulation of prostate cancer cell proliferation, apoptosis evasion, migration, epithelial-to-mesenchymal transition, and angiogenesis. There is also evidence suggesting that ion channels might play a role in treatment failure in patients with prostate cancer. Hence, they represent promising targets for diagnosis, staging, and treatment, and their effects may be of particular significance for specific patient populations, including those undergoing anesthesia and surgery. In this article, the role of major types of ion channels involved in the development and progression of prostate cancer are reviewed. Identifying the underlying molecular mechanisms of the pro-tumorigenic effects of ion channels may potentially inform the development of novel therapeutic strategies to counter this malignancy., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Recently approved agents for post-vascular endothelial growth factor/post-vascular endothelial growth factor receptor (VEGF/VEGFR) inhibitors treatment of metastatic renal-cell carcinomas (mRCC), such as axitinib, nivolumab, and cabozantinib were shown to improve prognosis and substituted everolimus in this setting. We studied practice patterns, efficacy, and tolerability of these agents in a real-world series of Greek patients. We included patients with mRCC who received everolimus, axitinib, or nivolumab after progression on first-line anti-VEGF/VEGFRs therapy. Patients were stratified into three groups. Group A received nivolumab with or without cabozantinib at some point in their disease. Group B received axitinib but without nivolumab or cabozantinib. Group C received only everolimus among the four approved agents. Overall, 131 patients were included in the analysis. Everolimus and nivolumab were mainly used in the second line, while axitinib and cabozantinib were mostly used in the third and fourth lines. Median overall survival (OS) from first-line initiation was 8.7 [95% confidence interval (CI), 4-not reached], 3.6 (95% CI, 2-6), and 2.1 years (95% CI, 1.4-2.6) for Group A, B, and C, respectively ( P  < 0.001). Median OS from the initiation of second-line therapy was 3.5, 2.7, and 1.3 years, respectively ( P  < 0.001). There was no impact of first-line agent or treatment timing on survival. International Metastatic Renal Cell Carcinoma Database Consortium risk stratification was associated with OS. Toxicities observed were within expected frequencies. Grade ≥3 events were rare. Adoption of modern standards in everyday treatment of mRCC results in prolongation of survival. Real-world datasets are the new landmarks of survival for future research., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Preclinical studies have suggested that metformin exerts antitumor effects on various types of cancers. However, the results of human clinical trials have been inconsistent., Summary: Metformin is widely considered to be a prime example of a clinically relevant compound that inhibits oxidative phosphorylation (OXPHOS). However, the efficacy of metformin in inhibiting OXPHOS in cancer patients remains uncertain. The available evidence suggests that the plasma concentration of metformin remains within the micromolar range when administered at therapeutic doses. While millimolar concentrations are necessary to inhibit complex I activity in isolated mitochondria, there is no evidence supporting the idea that metformin accumulates within the mitochondria. Metformin exerts a modest effect on the adenosine diphosphate to adenosine triphosphate (ATP) ratio, resulting in AMP-activated protein kinase activation, which promotes ATP-generating catabolic pathways and restores cellular energy balance., Key Messages: The value of metformin as an OXPHOS inhibitor for cancer treatment is debatable, and caution should be exercised while using metformin for this purpose., (© 2023 S. Karger AG, Basel.)

A recent phase Ib study investigating the use of reformulated niclosamide in combination with abiraterone and prednisone in patients with castration-resistant prostate cancer (CRPC) demonstrated encouraging preliminary efficacy with low toxicity. Preclinical studies have reported that niclosamide at clinically relevant concentrations inhibits androgen receptor splice variant 7 (AR-V7), a known tumor driver in CRPC. However, the magnitude of anti-tumor effects of niclosamide either used alone or in combination with abiraterone in these experimental models, far exceeded what could have been explained as a simple AR-V7 inhibition. Niclosamide at clinically relevant concentrations also acts as an oxidative phosphorylation (OxPhos) uncoupler in mitochondria. This raises the question whether the observed effects of niclosamide were partly mediated by OxPhos inhibition. Most OxPhos inhibitors did not demonstrate selectivity towards cancer cells and failed to enter clinical practice due to unacceptable toxicity. However, some mitochondrial uncouplers have greater cytotoxicity against cancerous cells compared to non-cancerous. Hyperpolarization of cancer cell mitochondria, or the more alkaline mitochondrial matrix of cancer cells could be potential reasons for this. Niclosamide can also alter Wnt/β-catenin, mTOR, Notch, NF-kB and STAT3 signaling pathways. Hence, the mechanism of action of reformulated niclosamide in CRPC patients requires further investigation. This will potentially lead to new opportunities to develop and investigate even more selective and effective treatments against prostate cancer., Competing Interests: Declaration of Competing Interest The author reports no financial or non-financial conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Mitochondria are more than just the cellular powerhouse. They also play key roles in vital functions such as apoptosis, metabolism regulation, and other intracellular interactions. The mitochondrial DNA (mtDNA) encodes for 12 subunits of the oxidative phosphorylation (OXPHOS) system. Depletion of mtDNA in androgen-dependent prostate cancer (PCa) cell lines renders them androgen-independent and more aggressive. Paradoxically, pharmaceutical inhibition of OXPHOS is lethal for subsets of PCa cells, whereas others become dependent on androgen receptor (AR) signaling for survival. Given that the AR-mitochondria interaction is critical for early PCa, it is crucial to understand the details of this interaction. Technical hurdles have made mitochondria traditionally difficult to study, with many techniques used for isolation masking the properties of given individual mitochondria. Although the isolation of mitochondria enables us to study OXPHOS, we miss the context in which mitochondria interact with the rest of the cell. Both AR signaling and mtDNA affect apoptosis, metabolism regulation, cellular calcium storage and homeostasis, intracellular calcium signaling, and redox homeostasis. In this review, we will attempt to understand how the crosstalk between AR-mtDNA-OXPHOS is responsible for "life or death" decisions inside the cells. Our aim is to point toward potential vulnerabilities that can lead to the discovery of novel therapeutic targets., Competing Interests: No conflict of interest has been declared by the authors., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc.)

Arterial thromboembolism has been associated with cancer or its treatment. Unlike venous thromboembolism, the incidence and risk factors have not been extensively studied. Here, we investigated the incidence of arterial thromboembolic events (ATEs) in an institutional series of advanced urinary tract cancer (aUTC) treated with cytotoxic chemotherapy. The ATE definition included peripheral arterial embolism/thrombosis, ischemic stroke and coronary events. A total of 354 aUTC patients were analyzed. Most patients (95.2%) received platinum-based chemotherapy. A total of 12 patients (3.4%) suffered an ATE within a median time of 3.6 months from the start of chemotherapy. The most frequent ATE was ischemic stroke (n = 7). Two ATEs were fatal. The 6-month and 24-month incidence were 2.1% (95% confidence interval [CI]: 0.9-4.1) and 3.6% (95% CI: 1.9-6.2), respectively. Perioperative chemotherapy increased the risk for ATE by 5.55-fold. Tumors other than UTC and pure non-transitional cell carcinoma histology were also independent risk factors. No association with the type of chemotherapy was found. Overall, ATEs occur in 4.6% of aUTC patients treated with chemotherapy and represent a clinically relevant manifestation. Perioperative chemotherapy significantly increases the risk for ATE. The role of prophylaxis in high-risk groups should be prospectively studied.

The outcomes of patients with genitourinary (GU) cancers have been steadily improving in recent years. Novel therapies have entered our armamentarium, while several other regimens are currently being studied in clinical trials. This recent explosion of new agents has improved patient survival and the quality of life for patients, but has also significantly increased the frequency of several side effects. The current review will focus on the potential ocular adverse reactions of GU neoplastic treatments. The broad spectrum of manifestations of ocular toxicity underscores the uniqueness and complexity of the anatomic, physiologic, and metabolic features of the human eye. Most side effects are mild in severity and transient, but some can be severe, disabling, and irreversible. Clinicians should be aware of complications that might be vision threatening and impact the patient's quality of life. In this review, we focused on the ocular toxicity of the antineoplastic regimens that are currently used for the treatment of GU, including prostate cancer, bladder cancer, renal cell carcinoma, testicular cancer, pheochromocytoma, adrenocortical carcinoma, and penile cancer., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Sakellakis et al.)

Glucocorticoids act through the glucocorticoid receptor (GR) and exert pleiotropic effects in different cancer types. In prostate cancer cells, GR and androgen receptor (AR) share overlapping transcriptomes and cistromes. Under enzalutamide treatment, GR signaling can bypass AR activation and promote castration resistance via the expression of a subset of AR-target genes. However, GR-dependent growth under enhanced antiandrogen inhibition occurs only in a subset of primed cells. On the other hand, glucocorticoids have been used successfully in the treatment of prostate cancer for many years. In the context of AR signaling, GR competes with AR for DNA-binding and has the potential to halt the proliferation rate of prostate cancer cells. Their target genes overlap by <50% and they execute unique functions in vivo. In addition, even when AR and GR upregulate the same transcriptional target gene, the effect might not be identical in magnitude. Besides being able to drive tumor proliferation, GR is also a key player in prostate cancer cell survival. Stimulation of GR activity can undermine the effects of enhanced antiandrogen treatment, chemotherapy and radiotherapy. GR activation in prostate cancer can increase prosurvival gene expression. Identifying the full spectrum of GR activity will inform the optimal use of glucocorticosteroids in prostate cancer. It will also determine the best strategies to target the protumorigenic effects of GR., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The identification of new cellular receptors has been increasing rapidly. A receptor is called "orphan" if an endogenous ligand has not been identified yet., Methods: Here we review receptors that contribute to prostate cancer and are considered orphan or partially orphan. This means that the full spectrum of their endogenous ligands remains unknown., Results: The orphan receptors are divided into two major families. The first group includes G protein-coupled receptors. Most are orphan olfactory receptors. OR51E1 inhibits cell proliferation and induces senescence in prostate cancer. OR51E2 inhibits prostate cancer growth, but promotes invasiveness and metastasis. GPR158, GPR110, and GPCR-X play significant roles in prostate cancer development and progression. However, GPR160 induces cell cycle arrest and apoptosis. The other major subset of orphan receptors are nuclear receptors. Receptor-related orphan receptor α (RORα) inhibits tumor growth, but RORγ stimulates androgen receptor signaling. PXR contributes to metabolic deactivation of androgens and inhibits cell proliferation. TLX has protumorigenic effects in prostate cancer, while its knockdown triggers cellular senescence and growth arrest. Estrogen-related receptor ERRγ can inhibit tumor growth but ERRα is protumorigenic. Dax1 and short heterodimeric partner are also inhibitory in prostate cancer., Conclusion: There is a "zoo" of relatively underappreciated orphan receptors that play key roles in prostate cancer., (© 2022 Wiley Periodicals LLC.)

Although prostate cancer is a major cause of cancer-related mortality worldwide, most patients will have a relatively indolent clinical course. Contrary to most other types of cancer, even the diagnosis of locally advanced or metastatic disease is not always lethal. The present review aimed to summarize what is known regarding the underlying mechanisms related to the indolent course of subsets of prostate cancer, at various stages. The data suggested that no specific gene alteration by itself was responsible for carcinogenesis or disease aggressiveness. However, pathway analysis identified genetic aberrations in multiple critical pathways that tend to accumulate over the course of the disease. The progression from indolence into aggressive disease is associated with a complex interplay in which genetic and epigenetic factors are involved. The effect of the immune tumor microenvironment is also very important. Emerging evidence has suggested that the upregulation of pathways related to cellular aging and senescence can identify patients with indolent disease. In addition, a number of tumors enter a long-lasting quiescent state. Further research will determine whether halting tumor evolution is a feasible option, and whether the life of patients can be markedly prolonged by inducing tumor senescence or long-term dormancy., Competing Interests: All authors declare that they have no competing interests., (Copyright: © Sakellakis et al.)

Objective: Economic crisis and austerity has dramatic consequences for health care professionals' mental health. This study aimed to investigate the prevalence of burnout syndrome among doctors working in public or private oncology departments in Greece and its association with factors determined by economic crisis. Method : Medical or radiation oncologists who are members of the National Oncology Societies and practicing oncology at least for one year were enrolled in this study. An On-Line questionnaire consisting of the Maslach Burnout Inventory and an informative questionnaire was utilized. Results: Eighty-six On-Line questionnaires waere analyzed. Radiation oncologists had significantly higher Depersonalization (DP), whereas medical oncologists had significantly higher Emotional Exhaustion (EE) scores. Registrars had higher scores compared to consultants in all subscales of the burnout syndrome. Factors such as ''hospitals are not safe due to the lack or reductions in medical supplies and personnel shortage'' and ''receiving less than 50% of annual leave'' were associated with significantly higher levels of EE. Factors such as ''not afraid of moving abroad'' and ''receiving 100% of annual leave'' were associated with significantly higher levels of low Personal Accomplishments (PA). The principal component analysis yielded three principal components: 'future insecurity', 'feeling secure while working' and 'working conditions associated with burnout syndrome. Conclusion: Several factors associated with austerity resulting from economic crisis significantly influenced prevalence of burnout syndrome among oncologists in Greece. Further studies need to be conducted to mobilize policy makers to develop and implement policies to improve oncologists' mental health., (Copyright © 2022 Tehran University of Medical Sciences. Published by Tehran University of Medical Sciences.)

DNA methyltransferases (DNMTs) regulate gene expression by methylating cytosine residues within CpG dinucleotides. Aberrant methylation patterns have been shown in a variety of human tumours including prostate cancer. However, the expression of DNMTs in clinical samples across the spectrum of prostate cancer progression has not been studied before. Tissue microarrays were constructed from the prostatectomy specimens of 309 patients across the spectrum of prostate cancer progression: hormone-naïve low-grade prostate cancer (n=49), hormone-naïve high-grade prostate cancer (n=151), hormonally treated high-grade prostate cancer (n=65), and castrate-resistant prostate cancer (CRPC) including neuroendocrine carcinoma (n=44). Adjacent non-neoplastic parenchyma was also available in 100 patients. In 71 patients with high-grade carcinoma and lymph node metastasis, tissue from the metastasis was also available for analysis. Immunohistochemical staining was performed with antibodies against DNMT1, DNMT2, DNMT3A, DNMT3B, and DNMT3L. Our results showed that DNMT1 and DNMT3L were upregulated early in prostate cancer progression, whereas DNMT2 was upregulated as a response to androgen ablation. DNMT1, DNMT3A, and DNMT3B were higher in the late stages of prostate cancer progression, i.e., the emergence of castrate resistance and androgen-independent growth. Lastly, DNMT1, DNMT2, and DNMT3L were upregulated in lymph node metastases compared to primary carcinomas. Our results highlight a cascade of epigenetic events in prostate cancer progression., (Copyright © 2019 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Background/aim: The role of FOXP3+ Tregs and CD8+ T-cells in different stages and subtypes of breast carcinoma (BC) is yet to be fully defined, mainly because of methodological variations between studies. The aim of this study was to assess FOXP3+ and CD8+ intratumoral stromal TILs (sTILs) by a standardized method, in order to discern differences between the histological subtypes and BC stage and evaluate the applicability of the method., Patients and Methods: FOXP3+ and CD8+ sTILs were studied immunohistochemically in 207 BCs and counted on digital images, amounting to a standard stromal area of a 10×10 grid on ×40 magnification. The results were correlated with clinicopathological features and outcomes., Results: Tregs and CD8+ TILs were more abundant in HER2+ BCs (p=0.02, p=0.007, respectively), estrogen receptor (ER)-BCs (p<0.001, for both cell types), and triple-negative BCs (TNBCs) (p=0.01, p=0.006, respectively). Tregs and CD8+ TILs were associated with high grade (p<0.001 and p=0.002, respectively) and high Ki67 index (p<0.001, for both cell types). Lower CD8/FOXP3 ratio was associated with node metastases (p=0.007). Node metastases and advanced stage paralleled with decreased CD8+ sTILs (p=0.023, p=0.019, respectively). In the entire group and in ER- BCs, CD8+ TILs were associated with favorable distant metastasis-free survival (p=0.021, p<0.001, respectively), disease-free survival (p=0.022, p<0.001, respectively) and breast cancer specific survival (BCSS) (p=0.022, p=0.005). In ER-BCs, Tregs were associated with favorable BCSS (p=0.02)., Conclusion: Tregs and CD8+ TILs are higher in early-stage TNBCs and HER2+ BCs and diminish with progression to advanced stages. The findings provide support for immunotherapeutic manipulation of TILs, particularly in early stages of these BC subtypes. The evaluation methodology can be easily implemented for standardization of immunohistochemically-detected TILs., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Lung adenocarcinomas carrying epidermal growth factor receptor (EGFR) mutations have been identified as a unique group of entities that depend on EGFR for their proliferation and metastasis. The introduction of reversible EGFR tyrosine kinase inhibitors, such as erlotinib, has significantly affected the management of metastatic disease in this subset of patients. Interestingly, although erlotinib is highly effective in patients with EGFR mutations, it may occasionally prove useful, even in the absence of mutations. We herein present the course of two heavily pretreated patients who achieved remarkable disease stabilization over several years, despite harbouring no EGFR mutations. Our cases underscore the fact that further research is required to identify which subset of patients will benefit the most from this treatment, as a substantial minority may present with favourable outcomes.

Introduction: Small cell carcinoma constitutes the most aggressive type of lung cancer, with the greatest propensity for early disseminated disease. Although commonly neglected due to its rarity and the presence of other comorbidities, cases of iris metastasis from small cell lung cancer have been reported in the literature., Case Presentation: We present the case of a 76-year-old female. Once diagnosed, the patient already had disseminated disease with metastatic foci found in the spleen, liver, and brain. The patient received six cycles of combination carboplatin/etoposide chemotherapy, followed by cranial irradiation. After an initial response, two months after the completion of cranial irradiation, the patient complained of visual impairment and was referred to an ophthalmologist. A diagnosis of secondary glaucoma was made, caused by metastasis to the left iris., Conclusions: Physicians should be aware of this rare site of metastasis. Early diagnosis is of paramount importance in order to effectively prevent the significant morbidity this condition can cause if left untreated.

Object: The aim of the study was to investigate whether there are seasonal differences in the occurrence of carcinomatous meningitis (CM), with a greater prevalence of the disease in months with higher temperatures., Methods: The authors searched the records of all patients with a diagnosis of CM from 1998 until 2013 at the University Hospital of Patras, Greece. The date of hospitalization was extracted for each patient. The cases were divided into 2 categories depending on the time of CM diagnosis. Based on the official data regarding the annual temperature distribution in this region, the authors divided the patients into 2 groups. The first group consisted of cases diagnosed with CM from October 15 to April 15 (cold climate and shorter daytime duration), whereas the second group comprised patients diagnosed between April 15 and October 15 (warm climate and longer daytime duration)., Results: Overall, 44 confirmed cases of CM were found. The most common type of malignancy associated with the development of CM was breast cancer (27 patients), while the second most common tumor was lung carcinoma (11 patients). The median interval between the time of initial cancer diagnosis and CM was 4.5 years. Thirty-one patients were diagnosed with CM during the period between April 15 and October 15, while the remaining 13 patients developed CM between October 15 and April 15, a significant difference (p = 0.01)., Conclusions: Significantly more patients developed CM during the warm season of the year. To the authors' knowledge, this is the first study to provide evidence for the potential seasonal variability in CM incidence. However, these results should be validated prospectively in larger cohorts.

The diagnosis of multiple primary malignancies (MPMs) in a patient has been reported rather frequently during the past decade. Here we present two cases with three synchronous primary malignant tumors. The first patient is a 66-year-old male with synchronous colorectal cancer, renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC). The second patient is a 64-year-old female with breast cancer, transitional cell carcinoma of the ureter and endometrial cancer. MPMs seem to be diagnosed in a higher incidence than that predicted only by the influence of hazard and, whenever found, they raise questions regarding not only possible common etiologic factors or same pathogenetic mechanisms but also they cause a lot of troubles to both clinicians and patients because the therapeutic options usually become limited.

Aim: We evaluated whether the concurrent β-blocker use in early breast cancer patients influenced the outcome in terms of preventing tumor recurrence after adjuvant chemotherapy., Methods: We retrospectively reviewed the medical records of 610 patients with breast cancer. Thereafter, we compared overall disease-free survival (DFS) between β-blocker users and nonusers., Results: Those not receiving β-blockers had a relatively longer mean DFS (10.8 vs. 9.7 years), although the difference did not reach statistical significance (p = 0.651). When the survival analysis was adjusted for age, tumor stage, hormone receptor status and HER2 status, the results remained unaltered, suggesting that β-blocker use did not significantly improve overall DFS (HR, 0.849; 95% CI, 0.537-1.343; p = 0.485)., Conclusion: Our findings failed to confirm previous results indicating a potential antitumor effect of β-blockers., (© 2015 S. Karger AG, Basel.)