Prophylactic lymph node dissection in clinically N0 differentiated thyroid carcinoma: Example of personalized treatment

Considering the differentiated thyroid carcinoma (DTC) epidemic', the indolent nature of DTC imposes a treatment paradigm shift toward elimination of recurrence. Lymph node metastases in cervical compartments, encountered in 20-90% of DTC, are the main culprit of recurrent disease, affecting 5-30% of patients. Personalized risk-stratified cervical prophylactic lymph node dissection (PLND) at initial thyroidectomy in DTC with no clinical, sonographic or intraoperative evidence of lymph node metastases (clinically N0) has been advocated, though not unanimously. The present review dissects the controversy over PLND. Weighing the benefit yielded from PLND up against the PLND-related morbidity is so far hampered by the inconsistent profit yielded by PLND and the challenging patient selection. Advances in tailoring PLND are anticipated to empower optimal patient care. © 2020 Future Medicine Ltd

Parathyroid hormone related protein (PTHrP)-mediated hypercalcemia in malignancy associated with anti-PD-1 immune checkpoint inhibitor treatment and related inflammatory reactions

Over the last decade, the breakthrough of immune checkpoint inhibitors has revolutionized cancer therapeutics, an enterprise not devoid of a novel constellation of unique immune-related adverse events. In this article, we present the first two patients, one with metastatic urothelial bladder cancer and another one with inoperable non-small squamous cell lung carcinoma, with immune-related parathyroid hormone related protein (PTHrP)-mediated hypercalcemia concurrent with immune-related pneumonitis following administration of anti-PD-1 monoclonal antibody nivolumab. The second patient present immune-related colitis as well. In both patients the hypercalcemia developed when cancer was in remission, rendering unlikely the diagnosis of humoral hypercalcemia of malignancy. The time of onset of PTHrP-mediated hypercalcemia–11 weeks and 15 weeks after initiation of nivolumab for the first and second patient respectively– insinuated the immune-related origin of PTHrP. The concurrent immune-related pneumonitis raised the question of whether the immune-related inflammatory milieu in the context of pneumonitis could be the source of the immune-related PTHrP. In conclusion, increased awareness of nivolumab-related hypercalcemia –an extremely rare immune-related adverse event– could enable the identification of immune-related elevation of PTHrP. Moreover, our cases provide the rationale for further research in pursuit of not only the source of immune-related PTHrP expression, but also of a causative link connecting the inflammatory milieu of immune-related pneumonitis and/or immune-related colitis with PTHrP-mediated hypercalcemia. Finally, the correlation of immune-related adverse events observed herein with response to nivolumab is in line with previous reports, necessitating further consolidation. © 2019 Elsevier B.V

Repurposing denosumab in breast cancer beyond prevention of skeletal related events: Could nonclinical data be translated into clinical practice?

Introduction: Denosumab is a human monoclonal antibody inhibiting the receptor activator of nuclear factor kappa-B ligand (RANKL). Initially approved as antiosteοporotic agent, denosumab is being currently pursued as a candidate for drug repurposing in oncology, especially breast cancer. Areas covered: The present review provides an overview of the therapeutic potential of denosumab in breast cancer beyond prevention of skeletal-related events (SREs), with focus on prevention of carcinogenesis in BRCA mutation carriers and on adjuvant treatment in early breast cancer patients. Study search was conducted on the following electronic databases: PubMed, Google scholar, Scopus.com, ClinicalTrials.gov, and European Union Clinical Trials Register from 2008 until June 2020. Expert opinion: Nonclinical data have established links between RANKL signaling and breast cancer initiation and progression, rationalizing exploring the potential bone-independent anticancer role of denosumab beyond SREs prevention. Preclinical and preliminary clinical data show that denosumab may inhibit carcinogenesis in BRCA mutation carriers. Denosumab adjuvant in early breast cancer has been shown, though inconsistently, to provide a disease-free survival benefit for a subgroup of patients. Despite promising results, the incorporation of denosumab in preventive and therapeutic protocols of breast cancer beyond prevention of SREs cannot be endorsed until further research consolidates its efficacy. © 2020 Informa UK Limited, trading as Taylor & Francis Group

Endocrine adverse events related with immune checkpoint inhibitors: An update for clinicians

Designated as scientific breakthrough of current decade, immune checkpoint inhibitors attenuate the cytotoxic T-lymphocyte-Associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1)/ligand 1 (PD-L1) pathways, depriving cancer cells of a key strategy of evasion from immunosurveillance. The reinvigoration of immune response translates into clinical success, inevitably entwined with a novel constellation of immune-related adverse events. The present review dissects the endocrine immune-related adverse events, emphasizing their unique profile featured by unpredictable onset, irreversibility, nonspecific symptoms, wide clinical spectrum and sophisticated diagnostic work-up. Guidelines advocate individualized decision-making process guided by clinicians' judgement. Future perspective should be governed by five principles-prevention, anticipation, detection, treatment, monitoring-aiming to gain the optimal profit diminishing immunotoxicity. © 2020 Future Medicine Ltd

Harnessing the versatile role of OPG in bone oncology: counterbalancing RANKL and TRAIL signaling and beyond

More than 2 decades ago, the discovery of osteoprotegerin (OPG) as inhibitor of the receptor of activator of nuclear factor Kb (RANK) ligand (RANKL) revolutionized our understanding of bone biology and oncology. Besides acting as decoy receptor for RANKL, OPG acts as decoy receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). OPG, RANKL, and TRAIL are ubiquitously expressed, stimulating per se pivotal signaling cascades implicated in cancer. In the context of cancer cell–bone cell interactions, cancer cells skew the OPG/RANKL/RANK (RANKL cognate receptor) balance towards bone destruction and tumor growth through favoring the RANKL/RANK interface, circumventing OPG. Numerous preclinical and clinical studies demonstrate the dual role of OPG in cancer: antitumor and tumor-promoting. OPG potentially conveys an antitumor signal through inhibiting the tumor-promoting RANKL signaling—both the osteoclast-dependent and the osteoclast-independent—and the tumor-promoting TRAIL signaling. On the other hand, the presumed tumor-promoting functions of OPG are: (i) abrogation of TRAIL-induced apoptosis of cancer cells; (ii) abrogation of RANKL-induced antitumor immunity; and (iii) stimulation of oncogenic and prometastatic signaling cascades downstream of the interaction of OPG with diverse proteins. The present review dissects the role of OPG in bone oncology. It presents the available preclinical and clinical data sustaining the dual role of OPG in cancer and focuses on the imbalanced RANKL/RANK/OPG interplay in the landmark “vicious cycle” of skeletal metastatic disease, osteosarcoma, and multiple myeloma. Finally, current challenges and future perspectives in exploiting OPG signaling in bone oncology therapeutics are discussed. © 2019, Springer Nature B.V

Osteoporosis entwined with cardiovascular disease: The implication of osteoprotegerin and the example of statins

Beyond being epiphenomenon of shared epidemiological factors, the integration of Osteoporosis (OP) with Cardiovascular Disease (CVD)-termed “calcification paradox”-reflects a continuum of aberrant cardiometabolic status. The present review provides background knowledge on “calcification paradox”, focusing on the endocrine aspect of vasculature orchestrated by the osteoblastic molecular fingerprint of vascular cells, acquired via imbalance among established modulators of mineralization. Osteoprotegerin (OPG), the well-established osteoprotective cytokine, has recently been shown to exert a vessel-modifying role. Prompted by this notion, the present review interrogates OPG as the potential missing link between OP and CVD. However, so far, the confirmation of this hypothesis is hindered by the equivocal role of OPG in CVD, being both proatherosclerotic and antiatherosclerotic. Further research is needed to illuminate whether OPG could be a biomarker of the “calcification paradox”. Moreover, the present review brings into prominence the dual role of statins-cardioprotective and osteoprotective-as a potential illustration of the integration of CVD with OP. Considering that the statins-induced modulation of OPG is central to the statins-driven osteoprotective signalling, statins could be suggested as an illustration of the role of OPG in the bone/vessels crosstalk, if further studies consolidate the contribution of OPG to the cardioprotective role of statins. Another outstanding issue that merits further evaluation is the inconsistency of the osteoprotective role of statins. Further understanding of the varying bone-modifying role of statins, likely attributed to the unique profile of different classes of statins defined by distinct physicochemical characteristics, may yield tangible benefits for treating simultaneously OP and CVD. © 2021 Bentham Science Publishers

Sulforaphane and iberin are potent epigenetic modulators of histone acetylation and methylation in malignant melanoma

Objective(s): Growing evidence supports that isothiocyanates exert a wide range of bioactivities amongst of which is their capacity to interact with the epigenetic machinery in various cancers including melanoma. Our aim was to characterise the effect of sulforaphane and iberin on histone acetylation and methylation as a potential anti-melanoma strategy. Methods: We have utilised an in vitro model of malignant melanoma [consisting of human (A375, Hs294T, VMM1) and murine (B16F-10) melanoma cell lines as well as a non-melanoma (A431) and a non-tumorigenic immortalised keratinocyte (HaCaT) cell line] exposed to sulforaphane or iberin. Cell viability was evaluated by the Alamar blue assay whilst total histone deacetylases and acetyltransferases activities were determined by the Epigenase HDAC Activity/Inhibition and EpiQuik HAT Activity/Inhibition assay kits, respectively. The expression levels of specific histone deacetylases and acetyltransferases together with those of lysine acetylation and methylation marks were obtained by western immunoblotting. Results: Overall, both sulforaphane and iberin were able to (1) reduce cell viability, (2) decrease total histone deacetylase activity and (3) modulate the expression levels of various histone deacetylases as well as acetyl and methyl transferases thus modulating the acetylation and methylation status of specific lysine residues on histones 3 and 4 in malignant melanoma cells. Conclusions: Our findings highlight novel insights as to how sulforaphane and iberin differentially regulate the epigenetic response in ways compatible with their anticancer action in malignant melanoma. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature

Assessment of Methodological Pipelines for the Determination of Isothiocyanates Derived from Natural Sources

Isothiocyanates are biologically active secondary metabolites liberated via enzymatic hydrolysis of their sulfur enriched precursors, glucosinolates, upon tissue plant disruption. The importance of this class of compounds lies in their capacity to induce anti-cancer, anti-microbial, anti-inflammatory, neuroprotective, and other bioactive properties. As such, their isolation from natural sources is of utmost importance. In this review article, an extensive examination of the various parameters (hydrolysis, extraction, and quantification) affecting the isolation of isothiocyanates from naturally-derived sources is presented. Overall, the effective isolation/extraction and quantification of isothiocyanate is strongly associated with their chemical and physicochemical properties, such as polarity-solubility as well as thermal and acidic stability. Furthermore, the successful activation of myrosinase appears to be a major factor affecting the conversion of glucosinolates into active isothiocyanates. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

Benzyl and phenethyl isothiocyanates as promising epigenetic drug compounds by modulating histone acetylation and methylation marks in malignant melanoma

Melanoma is an aggressive skin cancer with increasing incidence rates globally. On the other hand, isothiocyanates are derived from cruciferous vegetables and are known to exert a wide range of anti-cancer activities including, among others, their ability to interact with the epigenome in order to supress cancer progression. The aim of this study was to determine the role of phenethyl and benzyl isothiocyanates in modulating histone acetylation and methylation as a potential epigenetic therapeutic strategy in an in vitro model of malignant melanoma. We report that both isothiocyanates induced cytotoxicity and influenced acetylation and methylation status of specific lysine residues on histones H3 and H4 by modulating the expression of various histone acetyltransferases, deacetylases and methyltransferases in malignant melanoma cells. Our data highlight novel insights on the interaction of isothiocyanates with components of the histone regulatory machinery in order to exert their anti-cancer action in malignant melanoma. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature

Novel docosahexaenoic acid ester of phloridzin inhibits proliferation and triggers apoptosis in an in vitro model of skin cancer

Skin cancer is among the most common cancer types accompanied by rapidly increasing incidence rates, thus making the development of more efficient therapeutic approaches a necessity. Recent studies have revealed the potential role of decosahexaenoic acid ester of phloridzin (PZDHA) in suppressing proliferation of liver, breast, and blood cancer cell lines. In the present study, we investigated the cytotoxic potential of PZDHA in an in vitro model of skin cancer consisting of melanoma (A375), epidermoid carcinoma (A431), and non-tumorigenic (HaCaT) cell lines. Decosahexaenoic acid ester of phloridzin led to increased cytotoxicity in all cell lines as revealed by cell viability assays. However, growth inhibition and induction of both apoptosis and necrosis was more evident in melanoma (A375) and epidermoid carcinoma (A431) cells, whereas non-tumorigenic keratinocytes (HaCaT) appeared to be more resistant as detected by flow cytometry. More specifically, PZDHA-induced cell cycle growth arrest at the G2/M phase in A375 and A431 cells in contrast to HaCaT cells, which were growth arrested at the G0/G1 phase. Elevated intracellular generation of reactive oxygen species ROS was detected in all cell lines. Overall, our findings support the potential of PZDHA as a novel therapeutic means against human skin cancer. © 2018 by the authors