Search

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.

Repurposing denosumab in lung cancer therapeutics capitalizes on its well-established role in preventing the skeletal related events (SREs) and its emerging, yet elusive, bone-independent role, assigned to inhibit the contribution of RANKL to cancer initiation and progression.The present review presents the available preclinical and clinical data indicating that denosumab may provide survival benefit to lung cancer patients beyond the counteraction of SREs.Despite the preliminary data heralding the potential of denosumab to increase overall survival in lung cancer, the embracement of this strategy in clinical practice cannot be advocated until large randomized clinical trials consolidate its safety and efficacy. Given the improvement of lung cancer prognosis ascribed to revolutionary targeted treatment agents, the possibility of denosumab-related increased risk of second primary malignancies merits further evaluation. Many challenges in endorsing denosumab as a strategy to treat lung cancer beyond SREs prevention are pending counteraction, including: (i) patient selection guided by validated predictive and prognostic biomarkers; (ii) assessment of long-term outcomes; (iii) evaluation of benefit-risk ratio; (iv) translational research; (v) combination of denosumab with other targeted therapies; (vi) integration of genomic biomarkers, immune-related biomarkers, and biomarkers of active RANKL pathway to guide the decision-making process.

Simple Summary To capitalize on the revolutionary anticancer efficacy of immune checkpoint inhibitors (ICPi) in an expanding list of tumors, including hematological malignancies, it is mandatory to mitigate the immune-related (ir) adverse events, among which prevail the ir thyroid disorders. Currently, most available data on ir thyroid disorders are derived from solid tumors. Our review provides a comprehensive and updated overview of ir thyroid disorders, dissecting several intriguing issues, namely: (i) the elusive biological background, (ii) the epidemiological profile, (iii) the clinical spectrum, (iv) the diagnostic and therapeutic algorithms, (v) the predictive value of antithyroid antibodies for the development of ir thyroid disorders, and (vi) the prognostic significance. To contribute to the decision-making, this review provides an on-hand presentation of the latest reviews, meta-analyses, and pharmacovigilance studies addressing ir thyroid disorders, as well as of the most widely applied treatment guidelines. The current challenges and future perspectives, as regards a tailored approach to ir thyroid disorders, are critically discussed. Abstract Background: Until more data are available to shed light on the thyroid disorders related to immune checkpoint inhibitors (ICPi) implemented for the treatment of hematological malignancies, the decision-making is guided by pertinent data derived mostly from solid tumors. Methods: The present review provides a comprehensive and updated overview of the thyroid disorders related to ICPi, namely to inhibitors of cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death (PD) 1 (PD-1), and the ligand of the latter (PD-L1). Results: With the increasing recognition of ir thyroid disorders, many outstanding issues have emerged. Ir thyroid disorders are reminiscent of, but not identical to, thyroid autoimmunity. Interclass and intraclass ICPi differences regarding thyroid immunotoxicity await interpretation. The available data concerning the predictive value of thyroid autoantibodies for the development of ir thyroid disorders are inconclusive. Mounting data indicate an association of ir thyroid disorders with ICPi efficacy, but a causative link is still lacking. The path forward is a tailored approach, entailing: (i) the validation of tumor-specific, patient-specific, and ICPi-specific predictive factors; (ii) appropriate patient selection; (iii) the uncoupling of antitumor immunity from immunotoxicity; (iv) a multidisciplinary initiative; and (v) global registry strategies. Conclusions: Untangling and harnessing the interrelationship of immuno-oncology with endocrinology underlying the ir thyroid disorders will yield the optimal patient care.

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.

The incorporation of immune checkpoint inhibitors in the oncologists' arsenal is a milestone in cancer therapeutics, though not being devoid of toxicities.Areas covered: The present review provides a comprehensive and up-to-date overview of the immune-related hypophysitis with focus on the elusive biological background, the wide spectrum of the epidemiological profile, the varying clinical aspects, and the diagnostic and therapeutic challenges.Expert opinion: Historically considered distinctive of anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibodies (mAbs), the immune-related hypophysitis is increasingly correlated with the anti-programmed cell-death (PD) protein 1 (PD-1)/anti-PD ligand 1 (PD-L1) mAbs. The distinct phenotype of hypophysitis related to anti-PD1/anti-PD-L1 mAbs is highlighted with focus on the immune-related isolated adrenocorticotropic (ACTH) deficiency. The immune-related central diabetes insipidus is discussed as a rare aspect of anti-CTL-A4 mAbs-induced hypophysitis, recently related to anti-PD1/anti-PD-L1 mAbs as well. The present review builds on existing literature concerning immune-related hypophysitis underscoring the pending issues still to be addressed, including (i) pathogenesis; (ii) correlation with preexisting autoimmunity; (iii) predictive value; (iv) utility of high-dose glucocorticoids; and (v) establishment of evidence-based diagnostic and therapeutic protocols. Increased awareness and constant vigilance are advocated as cornerstone of a multidisciplinary approach to ensure optimal patients' care.

Initially endorsed as an antiosteoporotic agent, denosumab ‒ human monoclonal antibody inhibiting the receptor activator of nuclear factor kappa-B ligand (RANKL)‒ has currently shown an anticancer potential, rationalizing its exploitation in oncology. A prerequisite for leveraging denosumab in oncology is a favorable safety profile.The present review provides an overview of the adverse events of denosumab in oncology, with a focus on hypocalcemia, medication-related osteonecrosis of the jaw, atypical femoral fracture(s), post-denosumab vertebral fractures, increased risk of infections, and excess of second primary cancer. Representative studies addressing the safety and efficacy of denosumab compared to bisphosphonates in oncology are summarized. Critical gaps in the literature concerning the safety of denosumab in oncology are highlighted as opposed to plenty of available safety data on denosumab as an antiosteoporotic agent.Despite the generally acceptable safety profile of denosumab in oncology, many issues remain unresolved. Further research is mandatory to counteract current challenges, namely: (i) validation of risk factors for adverse events; (ii) elucidation of the pathophysiology of the adverse events in search of actionable molecular pathways; (iii) illumination of the association of denosumab with increased risk of infections and/or second primary cancer; (iv) establishment of optimal diagnostic, and therapeutic protocols.

(1) Background: the present review provides a comprehensive and up-to date overview of the potential exploitation of fasting as an anticancer strategy. The rationale for this concept is that fasting elicits a differential stress response in the setting of unfavorable conditions, empowering the survival of normal cells, while killing cancer cells. (2) Methods: the present narrative review presents the basic aspects of the hormonal, molecular, and cellular response to fasting, focusing on the interrelationship of fasting with oxidative stress. It also presents nonclinical and clinical evidence concerning the implementation of fasting as adjuvant to chemotherapy, highlighting current challenges and future perspectives. (3) Results: there is ample nonclinical evidence indicating that fasting can mitigate the toxicity of chemotherapy and/or increase the efficacy of chemotherapy. The relevant clinical research is encouraging, albeit still in its infancy. The path forward for implementing fasting in oncology is a personalized approach, entailing counteraction of current challenges, including: (i) patient selection; (ii) fasting patterns; (iii) timeline of fasting and refeeding; (iv) validation of biomarkers for assessment of fasting; and (v) establishment of protocols for patients’ monitoring. (4) Conclusion: prescribing fasting as anticancer medicine may not be far away if large randomized clinical trials consolidate its safety and efficacy.

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.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.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

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.

Simple Summary Leveraging lessons learned from the coronavirus disease 2019 (COVID-19) pandemic, resilient health systems focus on the preservation of the continuum of care of chronic diseases, especially of cancer, beyond addressing emergency health requirements. Obesity has a detrimental impact on COVID-19 and affects the epidemic of thyroid cancer (TC). TC, especially differentiated TC (DTC), is a notable paradigm of obesity-related cancers. Thus, obesity–COVID-19–(D)TC interplay can be a constant threat to public health. The present review dissects the COVID-19–(D)TC association in the setting of obesity and beyond, highlighting: (i) the interrelationship between immunity, inflammation, obesity, oxidative stress, and cancer underlying this association; (ii) the challenging management of (D)TC in the COVID-19 era; (iii) the impact of COVID-19 on (D)TC and vice versa; and (iv) the oncogenic potential of SARS-CoV-2. Future perspectives for understanding and harnessing the COVID-19–(D)TC association to inform decision-making are underlined. Abstract Background: Conceived of as the “silver lining” of the dark cloud of the coronavirus disease 2019 (COVID-19) pandemic, lessons taught by this catastrophe should be leveraged by medical authorities and policy makers to optimize health care globally. A major lesson is that resilient health systems should absorb sudden shocks incited by overwhelming health emergencies without compromising the continuum of care of chronic diseases, especially of cancer. Methods: The present review dissects the association between COVID-19 and thyroid cancer (TC), especially with differentiated TC (DTC), focusing on available data, knowledge gaps, current challenges, and future perspectives. Results: Obesity has been incriminated in terms of both COVID-19 severity and a rising incidence of TC, especially of DTC. The current conceptualization of the pathophysiological landscape of COVID-19–(D)TC association implicates an interplay between obesity, inflammation, immunity, and oxidative stress. Whether COVID-19 could aggravate the health burden posed by (D)TC or vice versa has yet to be clarified. Improved understanding and harnessing of the pathophysiological landscape of the COVID-19–(D)TC association will empower a mechanism-guided, safe, evidence-based, and risk-stratified management of (D)TC in the COVID-19 era and beyond. Conclusion: A multidisciplinary patient-centered decision-making will ensure high-quality (D)TC care for patients, with or without COVID-19.

The immune checkpoint inhibitors (ICPi) revolutionize the cancer therapeutics, though not being devoid of toxicity. The immune-related primary adrenal insufficiency (PAI) is a rare, yet potentially life-threatening, adverse event, posing diagnostic and therapeutic challenges. We report the first case of reversible PAI related to nivolumab (programmed cell-death 1 protein inhibitor) in a 42-year-old male with metastatic rectal adenocarcinoma. PAI manifested as profound fatigue, disorientation, hypotension, hyperpigmentation of palmar creases, and hyponatremia without hyperkalemia 16 weeks after initiation of nivolumab. Due to impending adrenal crisis, intravenous stress doses of hydrocortisone and hydration with normal saline were initiated. When the state of patient was stabilized, PAI was confirmed through 250 μg Synacthen test 24 h after temporary cessation of hydrocortisone. Hydrocortisone was fixed at maintenance dose, while mineralocorticoid substitution was not required. PAI was ascribed to nivolumab based on history, physical examination, and laboratory work-up with emphasis on positivity of anti-21-hydroxylase antibodies and exclusion of other causes of PAI by normal imaging of adrenal glands on computed tomography (CT). Reevaluation of adrenal function during follow up demonstrated complete recovery. A review of literature concerning the immune-related PAI indicated that the complete recovery of adrenal function, the normal CT imaging, and the positivity of anti-21-hydroxylase antibodies observed in our patient are exceptional findings of immune-related PAI. Finally, heightened suspicion of immune-related PAI in case of hyponatremia without hyperkalemia and constant vigilance for diagnosis of rare, but real, reversibility of immune-related PAI are of paramount importance.

Cancer immunotherapy is a breakthrough strategy entwined with toxicity. Immune-related hypophysitis is conventionally considered distinctive of cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors. Immune-related central diabetes insipidus (CDI) is exceptional. CDI rarely manifests as hypernatremia, which is almost always euvolemic. We report a 71-years-old male patient with advanced lung cancer who experienced severe chronic hypernatremia presented as alterations in mental status five months after initiation of treatment with the anti-PD-1 checkpoint inhibitor nivolumab. Combination of persistenthypernatremia, polyuria, high plasma osmolality and hyposthenuria raised suspicion of diabetes insipidus, prompting measurement of serum concentration of arginine vasopressin(AVP). The inappropriately undetectable serum levels of AVP confirmed central diabetes insipidus (CDI). Nivolumab-related hypophysitis was recognized as possible cause of CDI. Further hormonal assessment excluded any endocrinopathy indicating disorder of posterior pituitary. Pituitary MRI was normal with persistence of hyperintensity of posterior pituitary on T1-weighted images (bright spot). The patient was scheduled to receive 1-deamino-8-D-arginine vasopressin (DDAVP), but he died suddenly due to cardiac arrest before initiation of treatment. Our report describes the first case of nivolumab related CDI, building on existing literature through: (I) underscoring hypovolemic hypernatremia as CDI manifestation; (ii) bringing into spotlight the rare anti-PD-1 treatment related hypophysitis; (iii) enriching the limited evidence on immune-related CDI. Increased awareness of nivolumab related CDI will enable prompt recognition and therapeutic intervention.

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.