mRNA expression of caspase 14 in skin epithelial malignancies.

Introduction: The skin is the largest organ in the human body and it is also a complex organ. Its protective function is properly maintained due to its continuous renewal. Malignancies develop when the balance between proliferation and cell death is dysregulated in skin cells. Skin epithelial cancers are the most common neoplasms in humans. Although caspases are proteins which regulate the cell cycle and cell death, caspase 14 is a unique representative of the caspase family which does not participate in apoptosis. The detailed role of caspase 14 in skin epithelial malignancies has not been elucidated. Material and methods: We performed a prospective study aimed at the analysis of the mRNA expression of caspase 14 in groups of skin epithelial malignancies. We enrolled 56 patients (control group n = 21, study group n = 35). The mRNA expression of caspase 14 was lower in the non-lesional skin of patients with basal cell cancer or squamous cell cancer compared to a combined group of non-lesional samples from actinic keratosis patients and the control group. Results: The prognostic potential of caspase 14 mRNA is suggested when trying to identify patients predisposed to skin cancer. Moreover, the expression level was lower in combined groups of non-lesional skin obtained from patients with basal cell cancer (BCC)/squamous cell cancer (SCC) in comparison with lesional samples obtained from patients with BCC/SCC. Conclusions: We present primary results of a pilot study and define further goals for research continuation.

Real-life data of abiraterone acetate and enzalutamide treatment in post-chemotherapy metastatic castration-resistant prostate cancer in Poland.

Background: Abiraterone acetate (ABI) and Enzalutamide (ENZA) are second-generation hormone drugs that show breakthrough activity in post-chemotherapy, metastatic castration-resistant prostate cancer (mCRPC). The leading oncological and urological guidelines indicate both drugs with the same strong recommendation. There is a lack of randomized trials which compare the efficacy of ABI and ENZA. The current study aimed to compare the effectiveness of the drugs with an analysis of prognostic factors related to those drugs. Patients and methods: The study included 420 patients with docetaxel (DXL) pretreated mCRPC from seven Polish cancer centers. Patients were treated according to inclusion and exclusion criteria in the Polish national drug program (1000 mg ABI and 10 mg prednisone, n=76.2%; ENZA, 160 mg; n=23.8%). The study retrospectively analyzed the overall survival (OS), time to treatment failure (TTF), PSA 50% decline rate (PSA 50%) and selected clinic-pathological data. Results: In the study group, the median OS was 17 months (95% CI: 15.6-18.3). The median OS (26.1 vs. 15.7 mo.; p<0.001), TTF (14.2 vs. 7.6 mo.; p<0.001) and PSA 50% (87.5 vs. 56%; p<0.001) were higher in ENZA than in ABI treatment. Multivariate analysis shows that ENZA treatment and PSA nadir <17.35 ng/mL during or after DXL treatment were related to longer TTF. ENZA treatment, DXL dose ≥750 mg, PSA nadir <17.35 ng/mL during or after DXL treatment was related to longer OS. Conclusions: ENZA treatment may be related to more favorable oncological outcomes than ABI treatment in the studied Polish population of patients. A 50% decline in PSA is an indicator of longer TTF and OS. Due to the non-randomized and retrospective nature of the analysis, the current results require prospective validation.

Anticancer effect and safety of doxorubicin and nutraceutical sulforaphane liposomal formulation in triple-negative breast cancer (TNBC) animal model.

Female breast cancer is the most deadly cancer in women worldwide. The triple-negative breast cancer subtype therapies, due to the lack of specific drug targets, are still based on systemic chemotherapy with doxorubicin, which is burdened with severe adverse effects. To enhance therapeutic success and protect against systemic toxicity, drug carriers or combination therapy are being developed. Thus, an innovative liposomal formulation containing doxorubicin and the main nutraceutical, sulforaphane, has been developed. The anticancer efficacy and safety of the proposed liposomal formulation was evaluated in vivo, in a 4T1 mouse model of triple-negative breast cancer, and the mechanism of action was determined in vitro, using triple-negative breast cancer MDA-MB-231 and non-tumorigenic breast MCF-10A cell line. The elaborated drug carriers were shown to efficiently deliver both compounds into the cancer cell and direct doxorubicin to the cell nucleus. Incorporation of sulforaphane resulted in a twofold inhibition of tumor growth and the potential of up to a fourfold reduction in doxorubicin concentration due to the synergistic interaction between the two compounds. Sulforaphane was shown to increase the accumulation of doxorubicin in the nuclei of cancer cells, accompanied by inhibition of mitosis, without affecting the reactive oxygen species status of the cell. In normal cells, an antagonistic effect resulting in less cytotoxicity was observed. In vivo results showed that sulforaphane incorporation yielded not only cardioprotective, but also nephro- and hepatoprotective effects. The results of the research revealed the prospects of applying sulforaphane as a component of liposomal doxorubicin in triple-negative breast cancer chemotherapy.

Neuropeptide Y and its receptors in prostate cancer: associations with cancer invasiveness and perineural spread.

PURPOSE: Neuropeptide Y (NPY) is a pleiotropic peptide, which is involved in many biological mechanisms important in regulation of cell growth and survival. The aim of this study was a comprehensive analysis of the NPY system in prostate pathology. METHODS: The study was based on immunohistochemical analysis of NPY and its receptors, Y1R, Y2R and Y5R, in tissue samples from benign prostate (BP), primary prostate cancer (PCa) and PCa bone metastases. Tissue microarray (TMA) technique was employed, with analysis of multiple cores from each specimen. Intensity of the immunoreactivity and expression index (EI), as well as distribution of the immunostaining in neoplastic cells and stromal elements were evaluated. Perineural invasion (PNI) and extraprostatic extension (EPE) were areas of special interests. Moreover, a transwell migration assay on the LNCaP PCa cell line was used to assess the chemotactic properties of NPY. RESULTS: Morphological analysis revealed homogeneous membrane and cytoplasmic pattern of NPY staining in cancer cells and its membrane localization with apical accentuation in BP glands. All elements of the NPY system were upregulated in pre-invasive prostate intraepithelial neoplasia, PCa and metastases. EI and staining intensity of NPY receptors were significantly higher in PCa then in BP with correlation between Y2R and Y5R. The strength of expression of the NPY system was further increased in the PNI and EPE areas. In bone metastases, Y1R and Y5R presented high expression scores. CONCLUSION: The results of our study suggest that the NPY system is involved in PCa, starting from early stages of its development to disseminated states of the disease, and participates in the invasion of PCa into the auto and paracrine matter.

The Effect of Low Doses of Acetylsalicylic Acid on the Occurrence of Rectal Aberrant Crypt Foci.

Background and Objectives: Aberrant crypt foci (ACF) are one of the earliest putative preneoplastic and, in some cases, neoplastic lesions in human colons. Many studies have confirmed the reduction of ACFs and colorectal adenomas after treatment with acetylsalicylic acid (ASA) commonly referred to as ASA; however, the minimum effective dose of ASA and the duration of use has not been fully elucidated. The objective of our study was to assess the significance of low dose ASA (75-mg internally once daily) to study the chemopreventive effect of ASA in ACF and adenomas development in patients taking this drug for a minimum period of 10 years. Materials and Methods: Colonoscopy, combined with rectal mucosa staining with 0.25% methylene blue, was performed on 131 patients. The number of rectal ACF in the colon was divided into three groups: ACF < 5; ACF 5−10; and ACF > 10. Patients were divided into two groups: the "With ASA" group (the study group subjects taking ASA 75-mg daily for 10 years); and "Without ASA" group (control group subjects not taking ASA chronically). The incidence of different types of rectal ACF and colorectal polyps in both groups of subjects was analysed and ascertained. Results: Normal ACF was found in 12.3% in the study group vs. 87.7% control group, hyperplastic 22.4% vs. 77.6%, dysplastic 25% vs. 75%, mixed 0% vs. 100%. Treatment with ASA affects the occurrence of colorectal adenomas. The amount of dysplastic ACFs was lower in the study group than in the control group. The increase in dysplastic ACFs decreases with age in both groups, with the increase greater in those not taking ASA. Conclusions: Patients who take persistent, chronic (>10 years) low doses of ASA have a lower total number of all types of rectal ACFs and adenomas compared to the control group.

The Nephrotoxicity of Drugs Used in Causal Oncological Therapies.

In recent years, a dynamic development of oncology has been observed, resulting from the increasingly frequent occurrence of neoplasms and therefore, increasing population of patients. The most effective form of therapy for cancer patients is complex multidisciplinary specialized disease management, including nephro-oncology care. Different forms of renal function impairment are frequently diagnosed in cancer patients. They are caused by different co-morbidities existing before starting the oncologic treatment as well as the direct undesirable effects of this therapy which may cause temporary or irreversible damage of the urinary system-especially kidneys. According to different therapeutic programs, in such cases the degree of renal damage is often crucial for the possibility of further anti-cancer treatment. Medical personnel responsible for delivering care to oncology patients should be properly educated on current methods of prevention and treatment of renal complications resulting from anti-cancer therapy. The development of oncologic medicines design, including especially immuno-oncological agents, obliges us to learn new patomechanisms determining potential adverse effects, including renal complications. This publication is focused on the most important undesirable nephrotoxic effects of the frequently used anti-cancer drugs.

Antibody-Drug Conjugates in Uro-Oncology.

Currently available treatment options for patients with refractory metastatic prostate, bladder, or kidney cancers are limited with the prognosis remaining poor. Advances in the pathobiology of tumors has led to the discovery of cancer antigens that may be used as the target for cancer treatment. Antibody-drug conjugates (ADCs) are a relatively new concept in cancer treatment that broaden therapeutic landscape. ADCs are examples of a 'drug delivery into the tumor' system composed of an antigen-directed antibody linked to a cytotoxic drug that may release cytotoxic components after binding to the antigen located on the surface of tumor cells. The clinical properties of drugs are influenced by every component of ADCs. Regarding uro-oncology, enfortumab vedotin (EV) and sacituzumab govitecan (SG) are currently registered for patients with locally advanced or metastatic urothelial cancer following previous treatment with an immune checkpoint inhibitor (iCPI; programmed death receptor-1 [PD-1] or programmed death-ligand 1 [PD-L1]) inhibitor) and platinum-containing chemotherapy. The EV-301 trial showed that EV significantly prolonged the overall survival compared with classic chemotherapy. The TROPHY-U-01 trial conducted to evaluate SG demonstrated promising results as regards the objective response rate and duration of response. The safety and efficacy of ADCs in monotherapy and polytherapy (mainly with iCPIs) for different cancer stages and tumor types are assessed in numerous ongoing clinical trials. The aim of this review is to present new molecular biomarkers, specific mechanisms of action, and ongoing clinical trials of ADCs in genitourinary cancers. In the expert discussion, we assess the place of ADCs in uro-oncology and discuss their clinical value.

Investigation of Neural Microenvironment in Prostate Cancer in Context of Neural Density, Perineural Invasion, and Neuroendocrine Profile of Tumors.

BACKGROUND: Cancer stroma contains the neural compartment with specific components and action. Neural microenvironment processing includes among others axonogenesis, perineural invasion (PNI), neurosignaling, and tumor cell neural/neuroendocrine differentiation. Growing data suggest that tumor-neural crosstalk plays an important function in prostate cancer (PCa) biology. However, the mechanisms involved in PNI and axonogenesis, as well as their patho-clinical correlations in this tumor are unclear. METHODS: The present study was carried out on FFPE samples of 73 PCa and 15 benign prostate (BP) cases. Immunohistochemistry with neural markers PGP9.5, TH, and NFP was performed on constructed TMAs and selected tissue sections. The analyzed parameters of tumor innervation included small nerve density (ND) measured on pan-neural marker (PGP9.5) and TH s4tained slides, as well assessment of PNI presence and morphology. The qualitative and topographic aspects were studied. In addition, the expression of neuroendocrine marker chromogranin and NPY was assessed with dedicated indexes. The correlations of the above parameters with basic patho-clinical data such as patients' age, tumor stage, grade, angioinvasion, and ERG status were examined. RESULTS: The study showed that innervation parameters differed between cancer and BP. The neural network in PCa revealed heterogeneity, and ND PGP9.5 in tumor was significantly lower than in its periphery. The density of sympathetic TH-positive fibers and its proportion to all fibers was lower in cancer than in the periphery and BP samples. Perineural invasion was confirmed in 76% of cases, usually multifocally, occurring more commonly in tumors with a higher grade. NPY expression in PCa cells was common with its intensity often rising towards PNI. ERG+ tumors showed higher ND, more frequent PNI, and a higher stage. Moreover, chromogranin-positive cells were more pronounced in PCa with higher NPY expression. CONCLUSIONS: The analysis showed an irregular axonal network in prostate cancer with higher neural density (panneural and adrenergic) in the surroundings and the invasive front. ND and PNI interrelated with NPY expression, neuroendocrine differentiation, and ERG status. The above findings support new evidence for the presence of autocrine and paracrine interactions in prostate cancer neural microenvironment.

Caspase-14-From Biomolecular Basics to Clinical Approach. A Review of Available Data.

Caspase-14 is a unique member of the caspase family-a family of molecules participating in apoptosis. However, it does not affect this process but regulates another form of programmed cell death-cornification, which is characteristic of the epidermis. Therefore, it plays a crucial role in the formation of the skin barrier. The cell death cycle has been a subject of interest for researchers for decades, so a lot of research has been done to expand the understanding of caspase-14, its role in cell homeostasis and processes affecting its expression and activation. Conversely, it is also an interesting target for clinical researchers searching for its role in the physiology of healthy individuals and its pathophysiology in particular diseases. A summary was done in 2008 by Denecker et al., concentrating mostly on the biotechnological aspects of the molecule and its physiological role. However, a lot of new data have been reported, and some more practical and clinical research has been conducted since then. The majority of studies tackled the issue of clinical data presenting the role of caspase in the etiopathology of many diseases such as retinal dysfunctions, multiple malignancies, and skin conditions. This review summarizes the available knowledge on the molecular and, more interestingly, the clinical aspects of caspase-14. It also presents how theoretical science may pave the way for medical research. Methods: The authors analyzed publications available on PubMed until 21 March 2021, using the search term "caspase 14".

Attitudes of Patients with Cancer towards Vaccinations-Results of Online Survey with Special Focus on the Vaccination against COVID-19.

Recently developed COVID-19 vaccines significantly reduce the risk of severe coronavirus disease, which is essential in the particularly vulnerable cancer patient population. There is a growing anti-vaccine concern that may affect the success of the fight against the SARS-CoV2 pandemic. To evaluate opinions and attitudes toward vaccination, we conducted an anonymous online survey among Polish patients diagnosed with cancer. We analyzed how socio-demographic factors, type of cancer, comorbidities, previous influenza vaccinations, and information sources affect the general willingness and opinions about vaccinations, emphasizing vaccination against COVID-19. Six hundred thirty-five patients (80.2% female) participated in the study. A positive attitude towards vaccination was presented by 73.7%, neutral by 17.8%, while negative by 8.5%. Willingness to get vaccinated was declared by 60.3%, 23.5% were unwilling, and 16.2% were undecided. Significant predictors of willingness were education, marital status, active anti-cancer treatment, previous influenza vaccination, and positive attitude towards vaccinations. Patients with cancer have concerns regarding safety, effectiveness, and the process of development of the COVID-19 vaccine. Overall, patients with cancer present positive attitudes towards COVID-19 vaccination but required sufficient information on its efficacy and side effects.

Poly(ADP-Ribose) Polymerase Inhibitors in Prostate Cancer: Molecular Mechanisms, and Preclinical and Clinical Data.

Genomic instability is one of the hallmarks of cancer. The incidence of genetic alterations in homologous recombination repair genes increases during cancer progression, and 20% of prostate cancers (PCas) have defects in DNA repair genes. Several somatic and germline gene alterations drive prostate cancer tumorigenesis, and the most important of these are BRCA2, BRCA1, ATM and CHEK2. There is a group of BRCAness tumours that share phenotypic and genotypic properties with classical BRCA-mutated tumours. Poly(ADP-ribose) polymerase inhibitors (PARPis) show synthetic lethality in cancer cells with impaired homologous recombination genes, and patients with these alterations are candidates for PARPi therapy. Androgen deprivation therapy is the mainstay of PCa therapy. PARPis decrease androgen signalling by interaction with molecular mechanisms of the androgen nuclear complex. The PROFOUND phase III trial, comparing olaparib with enzalutamide/abiraterone therapy, revealed increased radiological progression-free survival (rPFS) and overall survival (OS) among patients with metastatic castration-resistant prostate cancer (mCRPC) with BRCA1, BRCA2 or ATM mutations. The clinical efficacy of PARPis has been confirmed in ovarian, breast, pancreatic and recently also in a subset of PCa. There is growing evidence that molecular tumour boards are the future of the oncological therapeutic approach in prostate cancer. In this review, we summarise the data concerning the molecular mechanisms and preclinical and clinical data of PARPis in PCa.

Impact of COVID-19 on anxiety levels among patients with cancer actively treated with systemic therapy.

BACKGROUND: Life-threatening diseases have a negative impact on emotional well-being and psychosocial functioning. This study aimed to assess the relationship between the level of anxiety caused by a neoplasm and the threat of coronavirus infection among patients with cancer actively treated with systemic therapy during the COVID-19 pandemic. Additionally, we searched for clinical factors associated with a higher level of anxiety. METHODS: In this multicentre, prospective, non-interventional study conducted in Poland, we enrolled 306 actively treated patients with cancer and collected their clinical data, including age, gender, cancer type and treatment intention. The fear/anxiety of SARS-CoV-2 were rated in Fear of COVID-19 Scale (SRA-FCV-19S) and Numerical Anxiety Scale (SRA-NAS). The fear and anxiety associated with cancer (CRA) were rated with the NAS (CRA-NAS). RESULTS: The mean level of SRA-FCV-19S was 18.5±7.44, which was correlated with the SRA-NAS (r=0.741, p<0.001). SRA-FCV-19S was significantly higher in women versus men (20.18±7.56 vs 16.54±6.83; p<0.001) and was tumour type-dependent (p=0.037), with the highest anxiety observed in patients with breast cancer (17.63±8.75). In the multivariate analysis, only the female gender was significantly associated with higher SRA. CRA-NAS was higher in women versus men (7.07±2.99 vs 5.47±3.01; p<0.001), in patients treated with curative versus palliative intention (7.14±3.06 vs 5.99±3.06; p=0.01) and in individuals aged ≤65 years versus >65 years (6.73±2.96 vs 5.66±3.24; p=0.007). CONCLUSIONS: For an actively treated patient with cancer, cancer remains the main life-threatening disease during the COVID-19 pandemic. The need for more attentive psychological care should be provided especially to female patients, patients with breast cancer, those under 65 years of age and treated with curative intention, as these factors are associated with a higher level of anxiety.

Complexity of Neural Component of Tumor Microenvironment in Prostate Cancer.

The tumor microenvironment (TME) plays an essential role in the development and progression of neoplasms. TME consists of the extracellular matrix and numerous specialized cells interacting with cancer cells by paracrine and autocrine mechanisms. Tumor axonogenesis and neoneurogenesis constitute a developing area of investigation. Prostate cancer (PC) is one of the most common malignancies in men worldwide. During the past years, more and more studies have shown that mechanisms leading to the development of PC are not confined only to the epithelial cancer cell, but also involve the tumor stroma. Different nerve types and neurotransmitters present within the TME are thought to be important factors in PC biology. Moreover, perineural invasion, which is a common way of PC spreading, in parallel creates the neural niche for malignant cells. Cancer neurobiology seems to have become a new discipline to explore the contribution of neoplastic cell interactions with the nervous system and the neural TME component, also to search for potential therapeutic targets in malignant tumors such as PC.

Malignant Gliomas as Second Neoplasms in Pediatric Cancer Survivors: Neuropathological Study.

This study presents a unique series of malignant supratentorial gliomas in children previously cured from non-CNS primary cancer. On neuroimaging these tumors were not specific, so the patients were suspected of cerebral recurrence of their primary neoplasm: leukemia in four children and sarcoma in one child. Histologically, the group contained four glioblastomas and one anaplastic astrocytoma. Three patients underwent neurosurgical resection, while the other two underwent stereotactic diagnostic biopsy only. Despite combined oncological treatment, four children died during 20 months, and only one glioblastoma patient continued to live for another twelve years. Microscopically, the neoplasms consisted of small cells with some morphologic features of astrocytic lineage, having scanty or prominent processes. Microvascular proliferation and focal or diffuse necrosis were encountered in four cases. The GFAP reactivity in neoplastic cells was low or nil, together with the expression of Olig2, vimentin, and nestin. In two cases a subpopulation of synaptophysin-positive cells was present. Molecular immunohistochemical profiling revealed the expression of phosphorylated forms of PI3Kp110 and AKT, in parallel to a strong PTEN and p53 positivity. The tumors were of IDH1R132H-wild type and immunoreactive for ATRX, HER3, and EGFR. Secondary malignant gliomas in pediatric cancer survivors pose a diagnostic challenge. The present study shows that these tumors are of IDH wild type, PI3K/AKT-activated, having no PTEN and EGFR mutations. Therefore, the biopsy of brain tumors in such patients is crucial both for accurate diagnosis and material preservation for molecular typing.