L'Oftalmopatia Basedowiana scompare mai? Risposte ad una vecchia domanda.

La storia naturale dell’Oftalmopatia Basedowiana (OB) è caratterizzata da una iniziale fase in cui segni e sintomi oculari peggiorano rapidamente fino a raggiungere un picco massimo di gravità, quindi si riducono progressivamente fino a raggiungere una condizione di stabilità, tuttavia, senza ritorno ad una condizione normale. Vi è, pertanto, la convinzione generale in campo medico-scientifico che l’OB sia una condizione “cronica”, senza possibilità di ritorno degli occhi dei pazienti ad una condizione pre-malattia. Il modo ideale per valutare tale aspetto sarebbe quello di esaminare obiettivamente i pazienti prima del manifestarsi dell’OB e dopo un lungo periodo di follow-up. Ovviamente questo non è possibile, ma ci sono solo due modi di rispondere a tale domanda, vale a dire la valutazione dei segni di OB basata su un'accurata valutazione oftalmologica e l'autovalutazione del paziente, con tutti i limiti che tali metodiche possono comportare. Nel tentativo di rispondere alla domanda se l’OB scompare e in che misura lo fa, abbiamo progettato uno studio prospettico-osservazionale in cui sia il punto di vista obiettivo del clinico sia il punto di vista soggettivo del paziente sono stati considerati. Lo scopo di questo studio è stato quello di valutare la scomparsa di OB sia dal punto di vista obiettivo del clinico che dal punto di vista soggettivo del paziente, indipendentemente dal trattamento effettuato, in pazienti consecutivi con una storia di OB di almeno 10 anni giunti nel nostro Centro per una visita di follow-up in un periodo di 5 anni. Abbiamo valutato complessivamente 99 pazienti che avevano ricevuto diversi tipi di trattamento per quanto riguarda la malattia tiroidea e l’OB. Alla fine del follow-up, l’OB poteva ritenersi scomparsa in base a criteri oggettivi in 8 pazienti (~8%) e in base a criteri soggettivi in 24 pazienti (~24%). Quando abbiamo considerato sia i criteri soggettivi che oggettivi congiuntamente, solo 2 pazienti (~2%) hanno soddisfatto tutti i criteri e potevano essere considerati liberi da malattia. L’OB è una malattia cronica nella stragrande maggioranza dei pazienti. Anche dopo molto tempo, la guarigione completa è rara, intesa come completa assenza di sintomi e segni di malattia, anche se una minoranza di pazienti ritiene di non avere più la malattia e una percentuale ancora minore di pazienti non presenta più segni di OB clinicamente rilevanti. Tali risultati, a nostro parere, danno informazioni rilevanti nella pratica clinica per quanto riguarda la gestione del paziente nel lungo periodo

Carcinoma anaplastico della tiroide: epidemiologia, diagnosi e trattamento. Esperienza in un centro di riferimento italiano.

Introduzione: il carcinoma anaplastico della tiroide (anaplastic thyroid cancer, ATC) è un raro tumore aggressivo che origina dalle cellule follicolari della tiroide, di cui, però, non conserva nessuna delle caratteristiche biologiche originarie. La prognosi è quasi invariabilmente infausta. La mortalità raggiunge il 90% e l’exitus, nella maggior parte dei casi, avviene entro 6 mesi dalla diagnosi, soprattutto per asfissia causata dall’invasione locale da parte della neoplasia. Il trattamento dell’ATC non è standardizzato, poiché non è chiaro se la terapia sia efficace nel prolungare la sopravvivenza. Gli sforzi terapeutici dovrebbero essere rivolti al controllo locale dalla malattia avendo come primo obiettivo la qualità della vita ed essendo la guarigione un evento eccezionale. In tale ottica, l’impiego isolato di chirurgia, radioterapia o chemioterapia, non risultano essere adeguati, mentre un approccio multimodale, che prevede, quando possibile, la combinazione di chirurgia e radiochemioterapia è auspicabile, in quanto potenzialmente in grado di ottenere la stabilizzazione del quadro a livello loco-regionale. Purtroppo, spesso, sia perché la presentazione clinica può essere molto variabile ostacolando la scelta del trattamento terapeutico ideale, sia perché la malattia è già molto avanzata alla diagnosi, non è possibile raggiungere gli effetti clinici sperati, ma solo risultati palliativi. Scopo dello studio: lo scopo primario del presente lavoro è stato quello di valutare gli aspetti epidemiologici, clinici e le modalità di diagnosi e di trattamento, in una casistica di pazienti trattati presso il Dipartimento di Endocrinologia di Pisa dal 1972 al 2012. Scopo secondario è stato quello di individuare la presenza di eventuali fattori clinico-epidemiologici predittivi dell’andamento clinico del nostro campione. Ulteriore scopo è stato la caratterizzazione dell’ATC da un punto di vista biologico-molecolare mediante l’analisi e la valutazione di alcune delle mutazioni già riscontrate nell’ATC e riportate in letteratura. Risultati: dall’analisi dei dati relativi al nostro campione, è emersa l’estrema variabilità degli aspetti clinici e biologici dell’ATC. In particolare, i dati clinici hanno evidenziato una lieve prevalenza del sesso femmine (56% dei pazienti) ed un’età media alla diagnosi di ~62 anni. La sopravvivenza media è stata di ~18 mesi, con una mediana di 6 mesi. Il trattamento iniziale, quando possibile, è stato di tipo chirurgico, nel 94% dei pazienti, altri presidi terapeutici utilizzati sono stati la radioterapia (nel 48% dei casi) e la chemioterapia (nel 68% dei casi). Tra le varie caratteristiche clinico-epidemiologiche che son state prese in considerazione, nessuna ha mostrato una correlazione significativa con la prognosi; al contrario le modalità terapeutiche che, pur non essendo in grado di modificare l’evoluzione finale della malattia, hanno significativamente migliorato la sopravvivenza dei nostri pazienti; in particolare, un approccio terapeutico multidisciplinare basato sulla chirurgia associata a radiochemioterapia si è rilevato il presidio in assoluto più efficace in grado di prolungare la sopravvivenza, probabilmente, aumentando il controllo della malattia, soprattutto, a livello loco-regionale. Per un sottogruppo di pazienti (20%) di cui disponevamo del tessuto tumorale, prelevato mediante biopsia durante l’intervento chirurgico, è stato possibile condurre l’analisi genetica: questa, pur non mostrando alterazioni in grado di caratterizzare l’ATC da un punto di vista molecolare, ha evidenziato l’associazione fra una minor sopravvivenza e la presenza di specifiche mutazioni geniche, indicando un loro possibile ruolo come fattori prognostici negativi in casi di ATC. Conclusioni: i pazienti con ATC hanno caratteristiche clinico-epidemiologiche molto variabili. Quando possibile, è opportuno eseguire un trattamento multimodale con chirurgia, radioterapia e chemioterapia: questo è l’unico elemento che correla con una maggior sopravvivenza. L’infiltrazione locale e le metastasi ematiche identificano un gruppo di ATC a peggior prognosi

Oxidative phosphorylation in bone cells

The role of energy metabolism in bone cells is an active field of investigation. Bone cells are metabolically very active and require high levels of energy in the form of adenosine triphosphate (ATP) to support their function. ATP is generated in the cytosol via glycolysis coupled with lactic acid fermentation and in the mitochondria via oxidative phosphorylation (OXPHOS). OXPHOS is the final convergent metabolic pathway for all oxidative steps of dietary nutrients catabolism. The formation of ATP is driven by an electrochemical gradient that forms across the mitochondrial inner membrane through to the activity of the electron transport chain (ETC) complexes and requires the presence of oxygen as the final electron acceptor. The current literature supports a model in which glycolysis is the main source of energy in undifferentiated mesenchymal progenitors and terminally differentiated osteoblasts, whereas OXPHOS appears relevant in an intermediate stage of differentiation of those cells. Conversely, osteoclasts progressively increase OXPHOS during differentiation until they become multinucleated and mitochondrial-rich terminal differentiated cells. Despite the abundance of mitochondria, mature osteoclasts are considered ATP-depleted, and the availability of ATP is a critical factor that regulates the low survival capacity of these cells, which rapidly undergo death by apoptosis. In addition to ATP, bioenergetic metabolism generates reactive oxygen species (ROS) and intermediate metabolites that regulate a variety of cellular functions, including epigenetics changes of genomic DNA and histones. This review will briefly discuss the role of OXPHOS and the cross-talks OXPHOS-glycolysis in the differentiation process of bone cells

Acromegaly in the setting of Tatton-Brown-Rahman Syndrome

Tatton-Brown-Rahman syndrome (TBRS) is a newly defined genetic entity characterized by overgrowth and intellectual disability, resulting from germline mutations in the gene encoding DNA methyltransferase 3 alpha (DNMT3A). Affected individuals with benign and malignant tumors have been reported; to our knowledge pituitary adenomas (and other tumors identified in our patient) have not yet been described in this syndrome

Does Graves' Orbitopathy Ever Disappear? Answers to an Old Question

There is a general belief that Graves' orbitopathy (GO) is a "chronic" disease, namely that patients' eyes do not return to how they were before GO appeared. Here, we investigate this issue from both the patient's and the physician's point of view

Statins for Graves' orbitopathy (STAGO): a phase 2, open-label, adaptive, single centre, randomised clinical trial

Background A protective action of statins on development of Graves' orbitopathy suggests that statins might be used for treatment of the disease. We aimed to assess the efficacy of the addition of a statin, atorvastatin, to intravenous glucocorticoids (ivGCs) on Graves' orbitopathy outcomes in patients with hypercholesterolaemia. Methods We did a randomised, open-label, phase 2, adaptive, clinical trial at a single, tertiary, referral hospital in Pisa, Italy. Patients with moderate-to-severe, active Graves' orbitopathy, with a low-density lipoprotein cholesterol concentration between 2·97 and 4·88 mmol/L were eligible for inclusion. Patients were randomly assigned (1:1) in 11 blocks of eight, using a computer-based system, to the ST group or the NST group. The ST group received ivGCs (methylprednisolone 500 mg once a week for 6 weeks followed by 250 mg once a week for an additional six weeks) for 12 weeks and oral atorvastatin (20 mg once a day) for 24 weeks. The NST group only received the ivGC regimen. Patients were unmasked to group allocation; however, the ophthalmological investigator was masked to randomisation. The primary endpoint was the Graves' orbitopathy outcome (composite evaluation of exophthalmos, clinical activity score, eyelid aperture, and diplopia) at 24 weeks in the modified intention-to-treat (ITT) population (patients who attended the week 12 visit). Patients were considered responders when at least two of the following criteria were fulfilled in the most affected eye, without worsening in any of the same measures in both eyes: (1) reduction in exophthalmos of 2 mm or more, with no increase by 2 mm or more in the other eye; (2) reduction of clinical activity score by two or more points; (3) reduction in eyelid aperture by 2 mm or more, with no increase by 2 mm or more in the other eye; and (4) disappearance or improvement (change from constant to inconstant, intermittent, or absent, or from inconstant to intermittent or absent) of diplopia, and (5) improvement in visual acuity by 0·2 decimals or more. The trial is registered with EUDRACT, 2018-001317-33, and ClinicalTrials.gov, NCT03110848. Findings Between June 1, 2020, and Nov 30, 2020, 119 patients were screened for inclusion, of whom 88 (74%) patients were enrolled and randomly assigned to one of the two treatment groups (44 [50%] to the ST group and 44 [50%] to the NST group). Eight (9%) patients did not attend the 12 week visit; 80 (91%) patients (18 [23%] men and 62 [78%] women) were included in the modified ITT population (41 [51%] in the ST group and 39 [49%] in the NST group]. The proportion of Graves' orbitopathy composite evaluation responders at 24 weeks was higher in the ST group (21 [51%] of 41 patients) than the NST group (11 [28%] of 39 patients; attributable risk 0·23 [95% CI 0·02–0·44]; p=0·042). 26 adverse events occurred in 21 (24%) of 88 patients in the safety population. One (2%) of 44 patients in each group required treatment discontinuation, with no serious adverse events and no difference between groups. Interpretation Addition of oral atorvastatin to an ivGC regimen improved Graves' orbitopathy outcomes in patients with moderate-to-severe, active eye disease who were hypercholesterolaemic. Future phase 3 studies, which could potentially recruit patients regardless of low-density lipoprotein cholesterol concentration, are required to confirm this association

Natural history of graves’ orbitopathy after treatment

Intravenous glucocorticoids are used for Graves’ orbitopathy, alone or associated with/followed by additional treatments (orbital radiotherapy, orbital decompression, palpebral or eye surgery). However, the relation between associated/additional treatments and other variables with Graves’ orbitopathy outcome following intravenous glucocorticoids is not clear. Thus, the present study was conducted to investigate retrospectively the impact of associated/additional treatments and other variables on Graves’ orbitopathy outcome after intravenous glucocorticoids. We evaluated 226 untreated Graves’ orbitopathy patients. Following first observation, patients were given intravenous glucocorticoids and re-examined after a median of 46.5 months. The end-points were the relation between Graves’ orbitopathy outcome, outcome of NOSPECS score and of the single Graves’ orbitopathy features with several variables, including associated/additional treatments. All Graves’ orbitopathy features improved significantly after treatment. Overall, Graves’ orbitopathy improved in ~60 % of patients (responders), whereas it was stable or worsened in ~40 % of patients (non-responders). Time between first and last observation and clinical activity score at first observation correlated significantly with Graves’ orbitopathy outcome. The outcomes of NOSPECS, eyelid aperture, clinical activity score and diplopia correlated with time between the first and last observation. The NOSPECS outcome correlated with gender. The outcomes of proptosis, eyelid aperture and visual acuity correlated with orbital decompression. The outcome of diplopia correlated with orbital radiotherapy. Taking into account the limitations of retrospective investigations, our findings confirm that time (i.e. the natural history of Graves’ orbitopathy) is a key factor in determining the long-term outcome of Graves’ orbitopathy, radiotherapy is effective for diplopia, and orbital decompression is followed by an amelioration of several Graves’ orbitopathy features

Lenvatinib and other tyrosine kinase inhibitors for the treatment of radioiodine refractory, advanced, and progressive thyroid cancer

Lenvatinib is a small oral molecule able to inhibit three of the extracellular and intracellular molecules involved in the modulation of angiogenesis and lymphangiogenesis: vascular endothelial growth factor receptor 1–3, fibroblast growth factor receptor 1–4, and platelet-derived growth factor receptor alpha. Since it is also able to inhibit the REarranged during Transfection oncogene and the protooncogene c-KIT, this drug can also be used to control tumor cell proliferation. The maximum tolerated dose, as demonstrated in Phase I studies, is 25 mg daily. The drug is rapidly absorbed with maximum concentrations achieved within 3 and 5 hours after administration in fasting and nonfasting treated patients, respectively. The most common adverse events, reported in Phase I study and confirmed in the subsequent Phase II and III studies, are hypertension, proteinuria, and gastrointestinal symptoms such as nausea, diarrhea, and stomatitis. In Phase I studies, efficacy of lenvatinib in solid tumors was demonstrated, and these encouraging results have led to the development of a Phase II study using lenvatinib in advance radioiodine-refractory differentiated thyroid cancer (DTCs) patients. Since an overall response rate of 50% was reported, this study also confirmed the efficacy of lenvatinib in DTCs patients with an acceptable toxicity profile. Recently, a Phase III study in patients with DTCs (SELECT study) demonstrated the lenvatinib efficacy in prolonging progression-free survival with respect to the placebo (18.3 vs 3.6 months; P65 years). The study confirmed that the most common side effects of this drug are hypertension, diarrhea, decreased appetite, weight loss, nausea, and proteinuria. In this review, we report the results of the main studies on lenvatinib efficacy in patients with advanced and progressive thyroid cancer, mainly in DTCs but also in medullary and anaplastic thyroid cancer. We also compared the efficacy of lenvatinib with that of other tyrosine kinase inhibitors, mainly sorafenib, already tested in the same type of patient population

VARIABLES AFFECTING THE LONG TERM OUTCOME OF GRAVES' ORBITOPATHY FOLLOWING HIGH DOSE INTRAVENOUS GLUCOCORTICOID PULSE THERAPY IN PATIENTS NOT TREATED WITH ORBITAL RADIOTHERAPY

OBJECTIVE: Intravenous (iv) glucocorticoids (GC) (ivGC) are used for active Graves orbitopathy (GO), but factors affecting GO outcome are poorly understood. We performed a retrospective study to investigate the variables affecting GO after ivGC. METHODS: We evaluated 83 consecutive GO patients treated with ivGC but not orbital radiotherapy (ORT) and re-examined them after a median of 47 months. The endpoints were the relationships between GO outcome or additional treatments with age, sex, smoking habits, thyroid volume, thyroid treatment, time since thyroid treatment, antithyroid-stimulating hormone receptor antibodies (TRAb), GO duration, GO features, and follow-up time. RESULTS: GO features improved after treatment, resulting in moderate and marked amelioration in ~75% and ~41% of patients respectively. By multivariate analysis, a moderate GO improvement correlated with diplopia at first observation, which was more severe in responders. A marked GO improvement correlated with time between first and last observation and time after thyroid treatment, which were longer in responders. This likely reflected the combination of an early effect of GC and a late, spontaneous improvement of GO, as shown by analyses of GO outcome at various time points. Additional treatments after ivGC correlated by multivariate analysis with eyelid aperture, diplopia and NOSPECS score (NOSPECS stands for no GO signs [N], only eyelid sign [O], soft tissue involvement [S], proptosis [P], extraocular motility restriction [E], corneal involvement [C], and sight loss [S]) at first observation, which were more severe in responders. CONCLUSION: Our study shows that response to ivGC increases with time, likely reflecting the known tendency of GO to improve spontaneously, and is more pronounced when GO is more severe to begin with, which is associated with more additional treatments. ABBREVIATIONS: ANOVA = analysis of variance CAS = clinical activity score GC = glucocorticoids GO = Graves orbitopathy 131I = radioactive iodine iv = intravenous ivGC = high-dose intravenous glucocorticoid pulse therapy MMI = methimazole OD = orbital decompression ORT = orbital radiotherapy TRAb = antithyroid-stimulating hormone receptor antibodies