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      Pazopanib-induced posterior reversible encephalopathy syndrome with possible syndrome of inappropriate secretion of antidiuretic hormone: an incidental or pathophysiological association?

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          Abstract

          Introduction: Pazopanib is an oral protein kinase inhibitor (PKI) that targets vascular endothelial growth factor (VEGF) receptors, fibroblastic growth factor receptors, platelet-derived growth factor receptors, and stem cell factor that inhibits VEGF-induced cellular proliferation. Pazopanib is approved for use in advanced renal cell carcinoma and subtypes of advanced soft-tissue sarcoma (Deguchi et al., 2018). Major adverse drug reactions of pazopanib include hypertension, high-grade hyponatremia and posterior reversible encephalopathy syndrome (PRES) (Berardi et al., 2016; Deguchi et al., 2018). In clinical trials, few investigations have been conducted to determine the aetiology of PKI-associated hyponatremia, the mechanism remains therefore unknown. Only rare cases of PKI-induced syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (Largeau et al., 2019), and none with pazopanib, have been reported. PRES is a clinical and radiological entity where a bilateral white matter oedema, occurring predominantly in the posterior occipital and parietal lobes, is associated with several neurologic symptoms. Interestingly, a recent review suggests that SIADH could be a symptom of PRES (Largeau et al., 2019). To our knowledge, this is the first case published where pazopanib-induced PRES occurs contemporaneously with possible SIADH. Case presentation: This report was prepared in accordance with the CAse REport (CARE) guidelines (Riley et al., 2017). A 73-year-old woman presented with high blood pressure and frontal headache to the oncology unit. Her medical history was significant for stage IV clear cell renal carcinoma, chronic hypertension on irbesartan/hydrochlorothiazide, which were prescribed at the same dosing for more than a year. She was recently started on pazopanib at 600 mg/d for metastatic clear cell renal carcinoma then was reduced to 400 mg/d on day 7 due to high blood pressure ( Figure 1 ). On day 12 after pazopanib initiation, the patient developed severe frontal headache, nausea and high blood pressure (210/100 mmHg), leading to amlodipine therapy on day 14. The following day the patient was admitted in the oncology unit and reported headache, her blood pressure was 229/112 mmHg and heart rate was 90 beats per minute. Except a psychomotor retardation, neurological examination was without abnormality and the patient had no visual impairment. Figure 1 Clinical and biological time course. BP: Blood pressure. At admission (day 15) initial serum biochemistry was significant for a sodium of 126 mM, potassium of 2.9 mM, albumin of 46.5 g/L and 88 giga/L thrombocytopenia. Serum magnesium was not measured. Urinary electrolytes and serum osmolality were obtained to establish the aetiology of the patient’s euvolemic hyponatraemia. Plasma osmolality was 261.7 mOsm/kg. Urinary labs showed sodium of 51 mM, osmolality of 215 mOsm/kg and 2.6 g/L proteinuria. Thyroid stimulating hormone and serum cortisol were within normal limits, ruling out hypothyroidism and glucocorticoid deficiency, respectively. On day 16, the patient developed acute kidney failure where serum creatinine experienced a 1.4-fold increase from admission baseline. Brain magnetic resonance imaging (MRI) performed on day 16 showed typical imaging features of PRES with vasogenic oedema characterized by parieto-occipital hyperintense signal within the posterior white matter (Figure 2A and B ). Brain MRI did not reveal central progression of the cancer, nor infarction, nor hemorrhage. Figure 2 Brain MRI at onset of neurological disturbances (day 16 after pazopanib initiation) and 3-month follow-up. (A, B) Brain MRI at onset of neurological disturbances. MRI at onset of PRES showed hyperintensities in the left occipital (A, arrow) and the left parietal (B, arrow) regions involving the white matter in T2-FLAIR sequence. No diffusion abnormalities were found in the diffusion weighted imaging sequence and apparent diffusion coefficient was increased. These lesions were consistent with a vasogenic edema of PRES. Major differential diagnoses were excluded including posterior reversible vasoconstriction syndrome (time-of-flight MRI), cerebral bleeding (T2* MRI) and stroke. (C, D) 3-month follow-up brain MRI. New brain MRI 3 months later showing complete resolution of the lesions of PRES in the left occipital (C) and the left parietal regions (D). Treatments included pazopanib, amlodipine, irbesartan and hydrochlorothiazide discontinuation, administration of intravenous nicardipine (day 15) and fluid restriction (day 18). Antihypertensive therapy was switched to oral irbesartan and amlodipine on day 17. Despite this combination of antihypertensive agents, the patient’s blood pressure remained high until the normalization of natremia on day 21 ( Figure 1 ), 6 days after pazopanib discontinuation. The psychomotor retardation, headache and renal failure resolved on day 18. The patient was discharged 6 days after admission (day 21), with a serum sodium of 134 mM. One month after discharge, blood pressure and natremia were still normal. Hydrochlorothiazide was not reintroduced. After 2 months of drug discontinuation, pazopanib was restarted at 200 mg/d. A new brain MRI performed 3 months after discharge showed complete resolution of the PRES lesions (Figure 2C and D ). The patient no longer had hyponatremia, headache or other iterative neurological recurrence. Discussion: Drug-causality assessment in drug-induced PRES is difficult due to the fact that (1) the underlying diseases are also strongly linked to PRES (e.g., transplantation, active cancers, autoimmune disorders); (2) various drugs, often used in combination, can cause PRES; (3) delays of occurrence are extremely variable; and (4) incriminated drugs can be reintroduced without iterative PRES recurrence (Largeau et al., 2019). Nevertheless, the close temporal relationship (i.e., onset and improvement) between high blood pressure, hyponatremia, PRES and pazopanib treatment is consistent with the role of this drug. The role of hydrochlorothiazide in hyponatremia, administered and well tolerated for a long time (i.e., natremia of 136 mM before pazopanib initiation), is less evocative. The patient’s hyponatremia was consistent with drug-induced SIADH diagnostic criteria (i.e., euvolemic hyponatraemia with urine sodium > 40 mM and urine osmolality > 100 mOsm/kg, recovery after drug discontinuation and fluid restriction) whereas the recent use of the diuretic agent cannot allow to confirm this diagnosis (Ellison and Berl, 2007), without excluding it. Furthermore, other aetiology such as paraneoplastic syndrome, neurological and pulmonary disorders were ruled out. Pazopanib has been associated with both hyponatremia (Berardi et al., 2016) and PRES (Deguchi et al., 2018) but PRES with pazopanib-induced SIADH has to date never been reported. PRES associated with pazopanib is supposed to be precipitated by endothelial dysfunction and high blood pressure induced by anti-VEGF therapy (Deguchi et al., 2018). The mechanism of hyponatremia associated with pazopanib is unclear but the role of VEGF pathway in sodium homeostasis has been suggested (Berardi et al., 2016). Another hypothesis could be a SIADH mechanism. SIADH has been associated with other PKI (Largeau et al., 2019) and a pathophysiologic link between PRES and SIADH may explain the association of these two syndromes. Evidence for anti-VEGF therapy induced arginine vasopressin hypersecretion: Arginine vasopressin (AVP), also known as the antidiuretic hormone, is involved in the regulation of renal water reabsorption and urine protein excretion through renal V2 receptors. AVP also regulates arterial blood pressure and renal blood flow through vasoconstriction induced by V1a receptors activation (Largeau et al., 2019). SIADH, where hypersecretion of AVP occurs without osmotic stimulus, is characterized by hypotonic hyponatremia. The use of anti-VEGF therapy for 6 days in mice significantly increased the density of AVP-immunoreactive axonal terminals that were away from the vasculature (Furube et al., 2014). In addition, a 6-week treatment by anti-VEGF increased serum copeptin, a stable precursor of AVP, in a cohort of patients with metastatic colorectal cancer (Hagman et al., 2017). Given the fact that AVP is known to induce VEGF secretion (Tahara et al., 2011), anti-VEGF therapy induced AVP secretion could be considered as a positive feedback loop ( Figure 3 ). This control loop could explain the safety profile of anti-VEGF drugs (i.e., pre-eclampsia like syndrome with kidney failure and high blood pressure) with renal dysfunction/proteinuria and hypertension induced by the action of supraphysiologic concentration of AVP on V2 and V1a receptors, respectively (Largeau et al., 2019). These effects of anti-VEGF therapy on AVP axis could also explain the very high prevalence of hyponatremia with antiangiogenic PKI (32% with pazopanib (Berardi et al., 2016)) probably by SIADH mechanism, as in our case. Figure 3 Possible mechanism involved in anti-VEGF therapy-induced posterior reversible encephalopathy syndrome. Anti-VEGF therapy (1) leads to vasopressin neurons stimulation through a positive feedback loop (2); AVP release or direct V1a receptors activation leads to constriction of cerebral vessels and increased sympathetic tone, causing both endothelial dysfunction and cerebral ischemia; combination of these effects promotes dysregulation of ionic/water transglial and subsequent brain edema (3). In the periphery, AVP can induce endothelial dysfunction and acute hypertension (4); stimulation of V1a and V2 receptors leads to acute kidney failure and dilutional hyponatremia (5). AVP: Arginine vasopressin; VEGF: vascular epithelial growth factor. AVP as a possible trigger of anti-VEGF therapy induced PRES: PRES has been largely reported with the use of anti-VEGF agents (Shah, 2017). The mechanism by which antiangiogenics drugs lead to PRES remains elusive, although it is suggested that they induce endothelial dysfunction and high blood pressure. These effects could promote cerebrovascular autoregulation breakdown, leading to blood-brain barrier disruption and subsequent brain oedema. Endothelial dysfunction, defined as impaired vasodilatation phenotype and proinflammatory state of the endothelium, is an on-target effect of anti-VEGF drugs. The vasoconstrictive response to VEGF inhibitors is related to both reduced levels of the vasodilator nitric oxide and increase of vasoactive peptides (e.g., endothelin and AVP) (Hagman et al., 2017; Touyz et al., 2017). Nevertheless, this endothelial/hypertensive theory is challenged by the absence of hypertension in a substantial proportion of patients with PRES (Largeau et al., 2019), including anti-VEGF therapy-induced PRES (Shah, 2017). A recent review highlighted that AVP overstimulation seems to be involved in PRES development and subsequent symptoms, in particular because of both its pathophysiologic role in brain oedema formation and its involvement in most of PRES aetiologies (Largeau et al., 2019). AVP hypersecretion, known to up-regulate sodium–proton exchangers, Na+-K+-Cl– cotransporters and aquaporin 4, could be the trigger of PRES brain oedema through a dysregulation of ionic/water transglial flux induced by astrocytic ion channels dysfunction (i.e., astrocytic swelling due to the increase of sodium, chloride and water glial influx) (Largeau et al., 2019). In the periphery, AVP receptors stimulation could be responsible of symptoms usually reported in PRES such as acute hypertension (75–80%) and impaired renal function (55%) (Largeau et al., 2019) ( Figure 3 ). Interestingly, in our case, acute kidney failure occurred at the nadir of hyponatremia and blood pressure normalization occurred simultaneously with natremia normalization, supporting the central pathophysiological role of AVP in PRES symptoms. In 6 cases of pazopanib-induced PRES, duration from starting pazopanib to onset of PRES ranged from 9 days to 2 months (Deguchi et al., 2018). Interestingly, hyponatremia (Deguchi et al., 2018) and acute kidney failure (Asaithambi et al., 2013; Miaris et al., 2017) have also been described in these cases. The fact that pazopanib can be reintroduced without recurrence (Deguchi et al., 2018) suggests that other parameters, exogenous or endogenous, must be present to cause an increase in AVP beyond the threshold of PRES development. Another hypothesis, that cannot be ruled out, is that this adverse event is concentration-dependent, which would explain the absence of recurrence at reduced dosage. Potential relationship between PRES and SIADH: Taken together, overstimulation of the AVP axis occurs in SIADH and probably in PRES, suggesting a close connection between these two syndromes. PRES may be caused by the convergence of various processes involved in AVP release (e.g., underlying disease, drugs, nausea) associated with risk factors for endothelial dysfunction and high blood pressure. Therefore, AVP increase can stimulate its effectors both through central receptors (i.e., V1 receptors) and peripheral ones (i.e., V1 and V2 receptors). First, cerebrovascular stimulation of V1a receptors induces ionic/water transglial flux disruption through astrocytic ion channels dysfunction, leading to the brain edema of PRES. Second, elevated AVP levels can activate vascular V1a receptors and renal V2 receptors, leading to hypertension and dilutional hyponatremia, respectively ( Figure 3 ). Schematically, central activation of V1 receptors appears to be involved in the genesis of brain edema, while peripheral V1 and V2 receptors are more likely to be responsible for PRES symptoms. The predominant role of V1 receptors compared to V2 receptors would explain why not all occurrences of PRES are complicated by SIADH (Largeau et al., 2019). Conclusion: In pazopanib-induced hyponatremia, a SIADH mechanism should be considered. AVP could be the trigger of pazopanib-induced PRES. Concurrent SIADH in drug-induced PRES should be considered as a symptom. If this AVP theory is confirmed, a promising therapeutic approach would be to prevent the action of AVP on its effectors in PRES patients. Suppression of AVP hypersecretion with corticosteroids (potent inhibitors of central AVP release) and/or its pharmacologic effects by antagonizing AVP receptors with conivaptan (a dual V1a and V2 receptors antagonist) (Largeau et al., 2019), may deserve to be evaluated in the management of patients with PRES.

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          CARE 2013 Explanations and Elaborations: Reporting Guidelines for Case Reports.

          Well-written and transparent case reports (1) reveal early signals of potential benefits, harms, and information on the use of resources; (2) provide information for clinical research and clinical practice guidelines (CPGs), and (3) inform medical education. High-quality case reports are more likely when authors follow reporting guidelines. During 2011-2012 a group of clinicians, researchers, and journal editors developed recommendations for the accurate reporting of information in case reports that resulted in the CARE (CAse REport) Statement and Checklist. They were presented at the 2013 International Congress on Peer Review and Biomedical Publication, have been endorsed by multiple medical journals, and translated into nine languages. This explanation and elaboration document has the objective to increase the use and dissemination of the CARE Checklist in writing and publishing case reports. Each item from the CARE Checklist is explained and accompanied by published examples. The explanations and examples in this document are designed to support the writing of high-quality case reports by authors and their critical appraisal by editors, peer reviewers, and readers. This article and the 2013 CARE Statement and Checklist, available from the CARE website [www.care-statement.org] and the EQUATOR Network, [www.equator-network.org] are resources for improving the completeness and transparency of case reports.
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            Recent Advances in Hypertension and Cardiovascular Toxicities With Vascular Endothelial Growth Factor Inhibition

            Physiologically, vascular endothelial growth factors (VEGF) and their receptors (VEGFR) play a critical role in vascular development, neogenesis, angiogenesis, endothelial function and vascular tone. Pathologically, VEGF-VEGFR signaling induces dysregulated angiogenesis, which contributes to the growth and spread of tumors. The development of VEGF-VEGFR inhibitors (VEGFIs) has thus proven to be a valuable strategy in the management of a number of malignancies, yielding improved survival outcomes. Not surprisingly, VEGFIs are now standard of care as first-line monotherapy for some cancers and the scope of this class of drugs is growing. However with the promise of improved outcomes, VEGFIs also led to clinically relevant toxicities, especially hypertension and cardiovascular disease (CVD). As such, cancer patients treated with VEGFIs may have improved cancer outcomes, but at the cost of an increased risk of CVD. Indeed, dose intensity and protracted use of these drugs can be limited by cardiovascular side effects and patients may require dose reduction or drug withdrawal, thus compromising anti-cancer efficacy and survival. Here we summarize the vascular biology of VEGF-VEGFR signaling and discuss the cardiovascular consequences and clinical impact of VEGFIs. New insights into molecular mechanisms whereby VEGFIs cause hypertension and heart disease are highlighted.
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              Risk of Hyponatraemia in Cancer Patients Treated with Targeted Therapies: A Systematic Review and Meta-Analysis of Clinical Trials

              Background Hyponatraemia has been reported with targeted therapies in cancer patients. Aim of the study was to perform an up-to-date meta-analysis in order to determine the incidence and relative risk (RR) in cancer patients treated with these agents. Materials and Methods The scientific literature regarding hyponatraemia was extensively reviewed using MEDLINE, PubMed, Embase and Cochrane databases. Eligible studies were selected according to PRISMA statement. Summary incidence, RR, and 95% Confidence Intervals were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies. Results 4803 potentially relevant trials were identified: of them, 13 randomized phase III studies were included in this meta-analysis. 6670 patients treated with 8 targeted agents were included: 2574 patients had hepatocellular carcinoma, whilst 4096 had other malignancies. The highest incidences of all-grade hyponatraemia were observed with the combination of brivanib and cetuximab (63.4) and pazopanib (31.7), while the lowest incidence was reported by afatinib (1.7). The highest incidence of high-grade hyponatraemia was reported by cetuximab (34.8), while the lowest incidences were reported by gefitinib (1.0). Summary RR of developing all-grade and high-grade hyponatraemia with targeted agents was 1.36 and 1.52, respectively. The highest RRs of all-grade and high-grade hyponatraemia were associated with brivanib (6.5 and 5.2, respectively). Grouping by drug category, the RR of high-grade hyponatraemia with angiogenesis inhibitors was 2.69 compared to anti-Epidermal Growth Factor Receptors agents (1.12). Conclusion Treatment with biological therapy in cancer patients is associated with a significant increased risk of hyponatraemia, therefore frequent clinical monitoring should be emphasized when managing targeted agents.
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                Author and article information

                Journal
                Neural Regen Res
                Neural Regen Res
                NRR
                Neural Regeneration Research
                Wolters Kluwer - Medknow (India )
                1673-5374
                1876-7958
                June 2020
                10 December 2019
                : 15
                : 6
                : 1166-1168
                Affiliations
                [1]CHR d’Orléans, Service d’Oncologie Médicale, Orléans, France
                [2]CHRU de Tours, Centre d’Investigation Clinique - CIC INSERM 1415, Tours, France
                [3]CHRU de Tours, Service de Pharmacosurveillance, Centre Régional de Pharmacovigilance Centre-Val de Loire, Tours, France
                [4]Université de Tours, INSERM, Centre d’étude des pathologies respiratoires (CEPR) - UMR 1100, CHRU de Tours, Service de Médecine Intensive Réanimation, CIC INSERM 1415, réseau CRICS-TRIGGERSEP, Tours, France
                [5]CHR d’Orléans, Service de Neuroradiologie, Orléans, France
                Author notes
                [* ] Correspondence to: Bérenger Largeau, berenger.largeau@ 123456etu.univ-tours.fr .

                Author contributions: JWS, CM and JM were involved in the management of this patient and the preparation of this manuscript. BL, FBS and SE were intimately involved in all stages of the interpretation and drafting made to this manuscript. All the authors of the aforementioned manuscript have been equally involved in the authorship, editing and design of the case report .

                Author information
                http://orcid.org/0000-0002-6824-7283
                Article
                NRR-15-1166
                10.4103/1673-5374.270420
                7034268
                31823899
                01837da8-2076-4a50-8735-2990c7f7c748
                Copyright: © Neural Regeneration Research

                This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

                History
                : 15 August 2019
                : 19 August 2019
                : 10 October 2019
                Categories
                Imaging in Neural Regeneration

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