Use of lenvatinib in the treatment of radioiodine-refractory differentiated thyroid cancer: a multidisciplinary perspective for daily practice

Differentiated thyroid cancer; Lenvatinib; ToxicityCáncer diferenciado de tiroides; Lenvatinib; ToxicidadCàncer diferenciat de tiroide; Lenvatinib; ToxicitatBackground Most thyroid cancers of follicular origin have a favorable outcome. Only a small percentage of patients will develop metastatic disease, some of which will become radioiodine refractory (RAI-R). Important challenges to ensure the best therapeutic outcomes include proper, timely, and appropriate diagnosis; decisions on local, systemic treatments; management of side effects of therapies; and a good relationship between the specialist, patients, and caregivers. Methods With the aim of providing suggestions that can be useful in everyday practice, a multidisciplinary group of experts organized the following document, based on their shared clinical experience with patients with RAI-R differentiated thyroid cancer (DTC) undergoing treatment with lenvatinib. The main areas covered are patient selection, initiation of therapy, follow-up, and management of adverse events. Conclusions It is essential to provide guidance for the management of RAI-R DTC patients with systemic therapies, and especially lenvatinib, since compliance and adherence to treatment are fundamental to achieve the best outcomes. While the therapeutic landscape in RAI-R DTC is evolving, with new targeted therapies, immunotherapy, etc., lenvatinib is expected to remain a first-line treatment and mainstay of therapy for several years in the vast majority of patients and settings. The guidance herein covers baseline work-up and initiation of systemic therapy, relevance of symptoms, multidisciplinary assessment, and patient education. Practical information based on expert experience is also given for the starting dose of lenvatinib, follow-up and monitoring, as well as the management of adverse events and discontinuation and reinitiating of therapy. The importance of patient engagement is also stressed.Eisai Europe sponsored the expert panel and editorial assistance providing medical writing support. Eisai Europe had no editorial control over this manuscript and the views expressed are those of the authors. JC, DD, CD, SL, ML, RNM, KN, SS,GS, and LDL received an honorarium from Eisai Europe for time attending the panel and for editorial contribution to the present manuscript. Beate Bartès, as president of Association Vivre sans Thyroïde, received a donation from Eisai Europe. Kate Farnell received, on behalf of Butterfly Thyroid Cancer Trust, a donation from Eisai Europe

Rapid Eye Movement Sleep Behavior Disorder:Abnormal Cardiac Image and Progressive Abnormal Metabolic Brain Pattern

BACKGROUND: Isolated rapid eye movement sleep behavior disorder (iRBD) is prodromal for α-synucleinopathies. OBJECTIVE: The aim of this study was to determine whether pathological cardiac [123 I]meta-iodobenzylguanidine scintigraphy ([123 I]MIBG) is associated with progression of [18 F]fluorodeoxyglucose-positron emission tomography-based Parkinson's disease (PD)-related brain pattern (PDRP) expression in iRBD. METHODS: Seventeen subjects with iRBD underwent [18 F]fluorodeoxyglucose-positron emission tomography brain imaging twice ~3.6 years apart. In addition, [123 I]MIBG and [123 I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane single-photon emission computed tomography ([123 I]FP-CIT-SPECT) at baseline were performed. Olfactory, cognitive, and motor functions were tested annually. RESULTS: Twelve of 17 subjects had pathological [123 I]MIBG. At baseline, 6 of 12 of these expressed the PDRP (suprathreshold PDRP z score). At follow-up, 12 of 17 subjects had suprathreshold PDRP z scores, associated with pathological [123 I]MIBG in 92% and with pathological [123 I]FP-CIT-SPECT in 75%. Subjects with pathological [123 I]MIBG had higher PDRP z score change per year (P = 0.027). Three subjects phenoconverted to PD; all had pathological [123 I]MIBG and [123 I]FP-CIT-SPECT, suprathreshold baseline PDRP z scores, and hyposmia. CONCLUSIONS: Pathological [123 I]MIBG was associated with progressive and suprathreshold PDRP z scores at follow-up. Abnormal [123 I]MIBG likely identifies iRBD as prodromal PD earlier than pathological [123 I]FP-CIT-SPECT. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Low fertility and population replacement in Scotland

It has been argued that Scotland faces population ageing and decline that will have potentially serious economic and social consequences, and that the origin of these processes lie in its low and declining fertility rates. After considering alternatives to the total period rate measure of fertility, empirical evidence and theoretical argument about low fertility and its consequences is briefly reviewed. The paper argues that low fertility in general may not be the problem it is often purported to be, that Scotland has relatively high fertility, and that pro-natalist policies are neither desirable nor necessary. It suggests that low fertility and population ageing may be viewed as positive developments, and that within Europe, Scotland is distinguished more by its excess of early deaths than by any shortage of births.Peer reviewe

Use of lenvatinib in the treatment of radioiodine-refractory differentiated thyroid cancer: a multidisciplinary perspective for daily practice

Background: Most thyroid cancers of follicular origin have a favorable outcome. Only a small percentage of patients will develop metastatic disease, some of which will become radioiodine refractory (RAI-R). Important challenges to ensure the best therapeutic outcomes include proper, timely, and appropriate diagnosis; decisions on local, systemic treatments; management of side effects of therapies; and a good relationship between the specialist, patients, and caregivers. Methods: With the aim of providing suggestions that can be useful in ev eryday practice, a multidisciplinary group of experts organized the following document, based on their shared clinical experience with patients with RAI-R differentiat ed thyroid cancer (DTC) undergoing treatment with lenvatinib. The main areas covered are patient selection, initiation of therapy, follow-up, and management of adverse events. Conclusions: It is essential to provide guidance for the management of RAI-R DTC patients with systemic therapies, and especially lenvatinib, since compliance and adherence to treatment are fundamental to achieve the best outcomes. Whil e the therapeutic landscape in RAI-R DTC is evolving, with new targeted therapies, immunotherapy, etc., lenvatinib is expected to remain a first-line treatment and mainstay of therapy for several years in the vast majority of patients and settings. The guidance herein covers baseline work-up and initiation of systemic therapy, relevance of symptoms, multidisciplinary assessment, and patient education. Practical information based on expert experience is also given for the starting dose of lenvatinib, follow-up and monitoring, as well as the management of adverse events and discontinuation and reinitiating of therapy. The importance of patient engagement is also stressed

The surfactant protein C mutation A116D alters cellular processing, stress tolerance, surfactant lipid composition, and immune cell activation

<p>Abstract</p> <p>Background</p> <p>Surfactant protein C (SP-C) is important for the function of pulmonary surfactant. Heterozygous mutations in <it>SFTPC</it>, the gene encoding SP-C, cause sporadic and familial interstitial lung disease (ILD) in children and adults. Mutations mapping to the BRICHOS domain located within the SP-C proprotein result in perinuclear aggregation of the proprotein. In this study, we investigated the effects of the mutation A116D in the BRICHOS domain of SP-C on cellular homeostasis. We also evaluated the ability of drugs currently used in ILD therapy to counteract these effects.</p> <p>Methods</p> <p>SP-C^A116Dwas expressed in MLE-12 alveolar epithelial cells. We assessed in vitro the consequences for cellular homeostasis, immune response and effects of azathioprine, hydroxychloroquine, methylprednisolone and cyclophosphamide.</p> <p>Results</p> <p>Stable expression of SP-C^A116Din MLE-12 alveolar epithelial cells resulted in increased intracellular accumulation of proSP-C processing intermediates. SP-C^A116Dexpression further led to reduced cell viability and increased levels of the chaperones Hsp90, Hsp70, calreticulin and calnexin. Lipid analysis revealed decreased intracellular levels of phosphatidylcholine (PC) and increased lyso-PC levels. Treatment with methylprednisolone or hydroxychloroquine partially restored these lipid alterations. Furthermore, SP-C^A116Dcells secreted soluble factors into the medium that modulated surface expression of CCR2 or CXCR1 receptors on CD4⁺lymphocytes and neutrophils, suggesting a direct paracrine effect of SP-C^A116Don neighboring cells in the alveolar space.</p> <p>Conclusions</p> <p>We show that the A116D mutation leads to impaired processing of proSP-C in alveolar epithelial cells, alters cell viability and lipid composition, and also activates cells of the immune system. In addition, we show that some of the effects of the mutation on cellular homeostasis can be antagonized by application of pharmaceuticals commonly applied in ILD therapy. Our findings shed new light on the pathomechanisms underlying SP-C deficiency associated ILD and provide insight into the mechanisms by which drugs currently used in ILD therapy act.</p

Lymphotoxin β receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE−/− mice

Atherosclerosis involves a macrophage-rich inflammation in the aortic intima. It is increasingly recognized that this intimal inflammation is paralleled over time by a distinct inflammatory reaction in adjacent adventitia. Though cross talk between the coordinated inflammatory foci in the intima and the adventitia seems implicit, the mechanism(s) underlying their communication is unclear. Here, using detailed imaging analysis, microarray analyses, laser-capture microdissection, adoptive lymphocyte transfers, and functional blocking studies, we undertook to identify this mechanism. We show that in aged apoE−/− mice, medial smooth muscle cells (SMCs) beneath intimal plaques in abdominal aortae become activated through lymphotoxin β receptor (LTβR) to express the lymphorganogenic chemokines CXCL13 and CCL21. These signals in turn trigger the development of elaborate bona fide adventitial aortic tertiary lymphoid organs (ATLOs) containing functional conduit meshworks, germinal centers within B cell follicles, clusters of plasma cells, high endothelial venules (HEVs) in T cell areas, and a high proportion of T regulatory cells. Treatment of apoE−/− mice with LTβR-Ig to interrupt LTβR signaling in SMCs strongly reduced HEV abundance, CXCL13, and CCL21 expression, and disrupted the structure and maintenance of ATLOs. Thus, the LTβR pathway has a major role in shaping the immunological characteristics and overall integrity of the arterial wall

Inconsistencies

No abstract available

Etablierung und Qualitätskontrolle der Radioligandentherapie mit Yttrium-90 und Lutetium-177 zur Behandlung neuroendokriner Tumoren am Uniklinikum Marburg

Neuroendokrine Tumoren sind seltene und sehr heterogene Neoplasien. Ein Großteil der Patienten weist bei Diagnosestellung bereits eine Fermetastasierung auf, so dass keine Möglichkeit mehr für eine kurative chirurgische Therapie besteht. Auch die Anzahl systemischer Therapieoptionen ist begrenzt. Die medikamentöse Therapie mit Somatostatinanaloga hat neben der Symptomkontrolle auch eine erwiesene antiproliferative Wirkung und findet bei der Behandlung von NET-Patienten einen breiten Einsatz. Eine Chemotherapie ist aufgrund des meist langsamen Wachstums der neuroendokrinen Tumore nur eingeschränkt anwendbar. Eine gängige Kombination bei höher proliferativen Tumoren ist Cisplatin und Etoposid, neue Ansätze umfassen Streptozocin, 5-FU und Doxorubicin. Eine weitere Option ist eine Therapie mit molekularem Targeting beispielsweise der Angiogenese, von mTOR, von Tyrosinkinasen oder Wachstumsfaktoren. Sowohl der Tyrosinkinaseinhibitor Sunitinib, als auch der mTOR-Inhibitor Everolimus werden bereits zur Therapie pankreatischer neuroendokriner Tumore eingesetzt. Eine wichtige Säule der systemischen Therapie ist die Radionuklidtherapie, bei der über Somatostatinrezeptoren, welche von vielen der neuroendokrinen Tumoren überexprimiert werden, ein Radionuklid in die Tumorzellen aufgenommen wird und dort zu DNA-Doppelstrangbrüchen führt. An dem Universitätsklinikum in Marburg wurden von 2009 bis 2012 35 Patienten mit metastasierten neuroendokrinen Tumoren mit einer Radionuklidtherapie behandelt. Die verwendeten Radiopharmaka waren hierbei entweder Yttrium-90-DOTATOC oder Lutetium-177-DOTATOC. Ziel dieser Arbeit war die Analyse der Qualität und Sicherheit dieser Therapie und der Vergleich mit den publizierten Ergebnissen anderer Zentren. Hierfür erfolgte eine retrospektive Analyse der Patientendaten. Bezüglich der Patientencharakteristika ergab sich kein wesentlicher Unterschied zwischen beiden Gruppen. Die akuten Nebenwirkungen der Therapie, bei denen es sich vor allem um Übelkeit, Erbrechen und eine Exazerbation von tumorassoziierten Schmerzen handelte, traten vermehrt bei den mit Yttrium-90 therapierten Patienten auf und waren gut therapierbar. Eine Nephrotoxizität Grad 3 oder 4 trat bei 4 Patienten der Yttrium-90-Therapiegruppe und 2 Patienten der Lutetium-177-Therapiegruppe auf, wobei diese bei 2 Patienten der Yttrium-90-Gruppe über den gesamten Beobachtungszeitraum persistierte. Hämatotoxische Effekte der Therapie waren meist passager und überwiegend leichtgradig. Beide Therapiegruppen zeigten milde Thrombozytopenien bis 12 Monate nach dem letzten Therapiezyklus. Eine schwere Thrombozytopenie trat nur bei einem Patienten der Lutetium-177-Gruppe auf. Leukozytopenien waren ebenfalls mild und bei je ein bis zwei Patienten pro Therapiegruppe innerhalb der ersten 6 Monate zu verzeichnen. Einzig für das Auftreten von Anämien zeigte sich ein signifikanter Unterschied zwischen beiden Gruppen mit einem deutlich höheren Anteil von bis zu 90% in der Yttrium-90-Gruppe. Die unerwünschte Wirkung auf die Erythropoese hielt in dieser Gruppe bis zum Ende des Beobachtungszeitraumes an. Hinweise auf eine hepatotoxische Wirkung der Therapie ergaben sich nicht. Das Therapieansprechen wurde in drei Subanalysen ausgewertet: biochemisches, morphologisches und klinisches Ansprechen. Für das biochemische Ansprechen wurde ein Absinken der Tumormarker unter 50% als Zeichen eines Progress und die Werte zwischen diesen als stabiler Verlauf gewertet. Für Chromogranin A ergab sich in der Yttrium-Gruppe ein Gesamtansprechen von 85%, in der Lutetium-Gruppe von 67%. Das biochemische Ansprechen für Serotonin betrug 90% in der Yttrium- und 92% in der Lutetium-Gruppe. Für die bildmorphologische Auswertung des Tumorwachstums anhand der RECIST-Kriterien ergab sich in der Yttrium-90-Gruppe mit 40% regressiven und 27% stabilen Befunden ein Gesamtansprechen von 67%. In der Lutetium-177-Gruppe zeigte sich ein Gesamtansprechen von 85% mit einem Anteil von 20% an regressiven und 65% stabilen Krankheitsverläufen. Eine klinische Verbesserung nach der Radionuklidtherapie ergab sich in der Yttrium-90-Gruppe zu 67% und in der Lutetium-177-Gruppe zu 45%. Ein signifikanter Unterschied für das Therapieansprechen zwischen beiden Gruppen bestand nicht. Auch zeigte sich kein Vorteil in Bezug auf das Überleben, was zum Abschluss der Datenerhebung bei je 79% in beiden Gruppen lag. Die in der Klinik für Nuklearmedizin durchgeführte Radionuklidtherapie mit Yttrium-90-DOTATOC und Lutetium-177-DOTATOC entspricht in ihrem Nebenwirkungsprofil und Antitumoreffekt den Ergebnissen aktueller internationaler Studien und ist eine sichere und nebenwirkungsarme Therapieoption für Patienten mit metastasierten neuroendokrinen Tumoren. Trotz der vielversprechenden bisherigen Ergebnisse gibt es noch Raum für eine weitere Optimierung der Radionuklidtherapie. Zukünftige Entwicklungen umfassen zum einen den Einsatz von individualisierten Verfahren zur Dosimetrie und die Entwicklung von neuen nephroprotektiven Substanzen, um die toxischen Effekte der Therapie weiter zu minimieren. Zum anderen werden neue Somatostatinanaloga und –antagonisten mit verbesserten Bindungseigenschaften und einem größeren Spektrum an Ziel-Rezeptoren entwickelt. Andere präklinische und klinische Studien befassen sich gegenwärtig mit der Untersuchung von neoadjuvanten Radiosensitizern, der Kombination der Radionuklidtherapie mit einer Chemotherapie oder der Kombination von Yttrium-90 und Lutetium-177, um eine stärkere Wirkung auf die Tumorzellen zu erzielen

Pediatric papillary thyroid cancer : Current management challenges

Although with a standardized incidence of 0.54 cases per 100,000 persons, differentiated thyroid cancer (DTC) is a rare disease in children and adolescents, it nonetheless concerns ~1.4% of all pediatric malignancies. Furthermore, its incidence is rising. Due to the rarity and long survival of pediatric DTC patients, in most areas of treatment little evidence exists. Treatment of pediatric DTC is therefore littered with controversies, many questions therefore remain open regarding the optimal management of pediatric papillary thyroid cancer (PTC), and many challenges remain unsolved. In the present review, we aim to provide an overview of these challenging areas of patient and disease management in pediatric PTC patients. Data on diagnosis, surgery, radionuclide, and endocrine therapy are discussed, and the controversies therein are highlighted