Lenvatinib is a multi-kinase inhibitor approved for patients with radioactive iodine (RAI)–resistant differentiated thyroid cancer (DTC). Before the drug approval from the Italian National Regulatory ...Agency, a compassionate use programme has been run in Italy. This retrospective study aimed to analyse data from the first series of patients treated with lenvatinib in Italy.
The primary aim was to assess the response rate (RR) and progression-free survival (PFS). Secondary end-points include overall survival (OS) and toxicity data.
From November 2014 to September 2016, 94 patients were treated in 16 Italian sites. Seventeen percent of patients had one or more comorbidities, hypertension being the most common (60%). Ninety-eight percent of patients were treated by surgery, followed by RAI in 98% of cases. Sixty-four percent of patients received a previous systemic treatment. Lenvatinib was started at 24 mg in 64 subjects. Partial response and stable disease were observed in 36% and in 41% of subjects, respectively; progression was recorded in 14% of patients. Drug-related side-effects were common; the most common were fatigue (13.6%) and hypertension (11.6%). Overall, median PFS and OS were 10.8 months (95% confidence interval CI, 7.7–12.6) and 23.8 months (95% CI, 19.7–25.0) respectively.
Lenvatinib is active and safe in unselected, RAI-refractory, progressive DTC patients in real-life setting. RR and PFS seem to be less favourable than those observed in the SELECT trial, likely due to a negative selection that included heavily pretreated patients or with poor performance status.
•Patients with metastatic differentiated thyroid cancer (DTC) have poor survival rate.•Lenvatinib improved clinical outcomes in patient with metastatic radioactive iodine-refractory DTC.•Lenvatinib is active and safe, even in a real-life patient population.•Older patients show survival benefit from lenvatinib, without safety concern.
Summary
Context
Bilateral macronodular adrenal hyperplasia (BMAH) is a rare form of Cushing's syndrome (CS). A variety of in vivo tests to identify aberrant receptor expression have been proposed to ...guide medical treatment. Unilateral adrenalectomy (UA) may be effective in selected patients, but little is known about recurrence during follow‐up.
Objective
To describe a series of patients with BMAH and CS treated by different approaches, with a particular focus on the benefit of UA.
Design and patients
We retrospectively assessed 16 patients with BMAH and CS (11 females, five males), analysing the in vivo cortisol response to different provocative tests. Twelve of the 16 patients underwent UA and were monitored over the long term.
Results
Based on in vivo test results, octreotide LAR or propranolol was administered in one case of food‐dependent CS and two patients with a positive postural test. A significant improvement in biochemical values was seen in all patients but with limited clinical response. UA was performed in 12 patients, producing long‐term remission in three (106 ± 28 months; range: 80–135), recurrence in eight (after 54 ± 56 months; range 12–180) and persistence in one other. Four patients subsequently underwent contralateral adrenalectomy for overt CS, one received ketoconazole, and four other patients remain under observation for subclinical CS.
Conclusions
Medical treatment based on cortisol response to provocative tests had a limited role in our patients, whereas UA was useful in some of them. Although recurrence is likely, the timing of onset is variable and close follow‐up is mandatory to identify it.
ARMC5
mutations have recently been identified as a common genetic cause of primary bilateral macronodular adrenal hyperplasia (PBMAH). We aimed to assess the prevalence of
ARMC5
germline mutations ...and correlate genotype with phenotype in a large cohort of PBMAH patients. A multicenter study was performed, collecting patients from different endocrinology units in Italy. Seventy-one PBMAH patients were screened for small mutations and large rearrangements in the
ARMC5
gene: 53 were cortisol-secreting (two with a family history of adrenal hyperplasia) and 18 were non-secreting cases of PBMAH. Non-mutated and mutated patients’ clinical phenotypes were compared and related to the type of mutation. A likely causative germline
ARMC5
mutation was only identified in cortisol-secreting PBMAH patients (one with a family history of adrenal hyperplasia and ten apparently sporadic cases). Screening in eight first-degree relatives of three index cases revealed four carriers of an
ARMC5
mutation. Evidence of a second hit at somatic level was identified in five nodules. Mutated patients had higher cortisol levels (
p
= 0.062), and more severe hypertension and diabetes (
p
< 0.05). Adrenal glands were significantly larger, with a multinodular phenotype, in the mutant group (
p
< 0.01). No correlation emerged between type of mutation and clinical parameters.
ARMC5
mutations are frequent in cortisol-secreting PBMAH and seem to be associated with a particular pattern of the adrenal masses. Their identification may have implications for the clinical care of PBMAH cases and their relatives.
Background
: Adrenal lesions are discovered in acromegaly more frequently than in general population, without relationship with primary disease. Some patients, carriers of aryl hydrocarbon receptor ...interacting protein (AIP) gene mutations, developed an adrenal neoplasm.
Aim
: To evaluate the role of metabolic and genetic aspects and the follow-up of adrenal nodules in acromegaly.
Material and methods
: We studied 69 acromegalic patients (30 male and 39 female, 56±15 yr) who had been referred to the Endocrinology Unit of Padua. In all patients we determined body mass index (BMI) and waist-to-hip ratio (WHR); we performed an oral glucose tolerance test (OGTT) whenever possible. If adrenal computed tomography revealed a lesion, the patient underwent an endocrine and genetic study.
Results
: Adrenal lesions were identified in 14 patients and were not related to gender, duration of disease, GH or IGF-I concentrations, basal and after-OGTT glucose and insulin levels, log(HOMA-IR) and Quantitative Insulin Sensitivity Check Index (QUICKI) values, whereas BMI and WHR were higher in patients with adrenal lesions. Baseline endocrine and radiological study revealed benign lesions; during mean 4-yr follow-up none of the patients showed hormone excess, even though some lesions increased in size. We did not find any mutation in AIP gene, except heterozygous silent alteration (T48T).
Conclusions
: The frequency of non-functioning adrenal lesions in acromegaly is not associated with the considered aspects, except BMI and WHR. The prolonged follow-up showed that these lesions have a tendency to increase in size independently of the control of acromegaly, so a morphological follow-up is recommended.
Adult-onset GH deficiency (GHD), mostly due to organic lesions of the pituitary-hypothalamic region, is frequently associated with multiple anterior pituitary deficiencies that need long-term ...substitutive treatment. The GH-IGF-I axis may play an important role in modulating peripheral metabolism of hormones (adrenal, thyroid, and sex hormones) and these interactions may have clinically significant implications on the phenotypes of adult GHD patients and on the effects of the combined replacement hormonal treatment of this condition. By accelerating the peripheral metabolism of cortisol, GH therapy may precipitate adrenal insufficiency in susceptible hypopituitary patients; estrogen replacement blunts the response to GH in women whereas in men with androgen substitution the responsivity increases over time. Endocrinologists should be mindful of these phenomena when starting patients with hypopituitarism on GH replacement therapy.
BACKGROUNDAdrenal lesions are discovered in acromegaly more frequently than in general population, without relationship with primary disease. Some patients, carriers of aryl hydrocarbon receptor ...interacting protein (AIP) gene mutations, developed an adrenal neoplasm. AIMTo evaluate the role of metabolic and genetic aspects and the follow-up of adrenal nodules in acromegaly. MATERIAL AND METHODSWe studied 69 acromegalic patients (30 male and 39 female, 56 ± 15 yr) who had been referred to the Endocrinology Unit of Padua. In all patients we determined body mass index (BMI) and waist-to-hip ratio (WHR); we performed an oral glucose tolerance test (OGTT) whenever possible. If adrenal computed tomography revealed a lesion, the patient underwent an endocrine and genetic study. RESULTSAdrenal lesions were identified in 14 patients and were not related to gender, duration of disease, GH or IGF-I concentrations, basal and after-OGTT glucose and insulin levels, log(HOMA-IR) and Quantitative Insulin Sensitivity Check Index (QUICKI) values, whereas BMI and WHR were higher in patients with adrenal lesions. Baseline endocrine and radiological study revealed benign lesions; during mean 4-yr follow-up none of the patients showed hormone excess, even though some lesions increased in size. We did not find any mutation in AIP gene, except heterozygous silent alteration (T48T). CONCLUSIONSThe frequency of non-functioning adrenal lesions in acromegaly is not associated with the considered aspects, except BMI and WHR. The prolonged follow-up showed that these lesions have a tendency to increase in size independently of the control of acromegaly, so a morphological follow- up is recommended.
Summary
Context
Bilateral macronodular adrenal hyperplasia (
BMAH
) is a rare form of Cushing's syndrome (
CS
). A variety of
in vivo
tests to identify aberrant receptor expression have been proposed ...to guide medical treatment. Unilateral adrenalectomy (
UA
) may be effective in selected patients, but little is known about recurrence during follow‐up.
Objective
To describe a series of patients with
BMAH
and
CS
treated by different approaches, with a particular focus on the benefit of
UA
.
Design and patients
We retrospectively assessed 16 patients with
BMAH
and
CS
(11 females, five males), analysing the
in vivo
cortisol response to different provocative tests. Twelve of the 16 patients underwent
UA
and were monitored over the long term.
Results
Based on
in vivo
test results, octreotide
LAR
or propranolol was administered in one case of food‐dependent
CS
and two patients with a positive postural test. A significant improvement in biochemical values was seen in all patients but with limited clinical response.
UA
was performed in 12 patients, producing long‐term remission in three (106 ± 28 months; range: 80–135), recurrence in eight (after 54 ± 56 months; range 12–180) and persistence in one other. Four patients subsequently underwent contralateral adrenalectomy for overt
CS
, one received ketoconazole, and four other patients remain under observation for subclinical
CS
.
Conclusions
Medical treatment based on cortisol response to provocative tests had a limited role in our patients, whereas
UA
was useful in some of them. Although recurrence is likely, the timing of onset is variable and close follow‐up is mandatory to identify it.
This review aims to provide an update on our current knowledge of the various effects of pesticide cocktails. We have collected data from studies conducted in mammalian models in vitro and in vivo ...that was published between 2000 and 2014. All ecotoxicological studies were voluntarily excluded. Cocktail effects were classified according to how they had been classified by each author. The frequency of the various cocktail effects and the classes and chemical families of pesticides involved in the observed effects were assessed. When focusing on the function of pesticides (i.e. herbicide, insecticide or fungicide), 46% of the mixtures contained insecticides alone, 15% fungicides alone, and 4.5% herbicides alone. Mixtures with effects associated with neurotoxicity were mainly composed of insecticides, and most studies on the effects of fungicide mixtures (90%) were associated with effects on endocrine regulation and/or reproduction. Dose addition was observed with each kind of mixture except herbicide combinations. In contrast, synergic interactions or greater-than-additive effects were mainly reported for insecticide mixtures. There were few examples of potentiating and antagonistic interactions. We have identified chemical families of compounds specifically involved in synergy, addition, potentiation and antagonism, and those that do not interact when combined. The chemical families identified as being involved in synergy are in agreement with data from another recently published compilation of ecotoxicological studies. For most mixtures investigated, further validation data is still needed from experiments using other compounds and other experimental models but this update provides useful information to help in human health risk assessments.
•Here we provide an update of our current knowledge on pesticide cocktail effects.•47% of the compiled studies reported an additive effect.•36% of the compiled studies described interactions between compounds.•Pesticides interact in various ways but lead mainly to synergic effects.•Mixture effects vary according to the dose and/or physiological target.
•Agent-based modelling is a powerful tool for evaluating the impact of the circular economy (CE).•Agent-based CE literature is fragmented and lacks a comprehensive framework.•Our systemic review ...finds three main themes in the literature.•We develop an integrated framework for agent-based model that complements general equilibrium models.•Our insights contribute to the theory and open future avenues of research.
Circular Economy (CE) is a popular topic for governments and businesses around the world; yet, only a few comprehensive and economy-wide frameworks exist, and the consequences of the CE on economic systems stay unclear. With this systematic review, we put under scrutiny the existing contributions to Circular Economy (CE) that apply the Agent-based modelling methodology. There is an open gap in the CE literature regarding the use of ABM. The research question that guides this systematic review concerns the potential benefit of ABM for CE and how to use this methodology in the context of CE. We put in evidence three thematic areas, two agents and one process, namely producers, i.e. firms and industrial systems, consumers, i.e. households and waste disposal, and the diffusion of innovation. We infer that the former three thematic strands of literature can be further synthetized together to form a general model of the Circular Economy. This development is crucial to properly evaluate how the agent's heterogeneity affects the diffusion and the consequences of the adoption of CE practices on the economy. Research has widely applied ABM simulations to consider the impact of heterogeneity amongst individuals and their behavioural interactions on the evolution of complex systems, yet very little did it systematically about CE. Our results complement those of Computable General Equilibrium models. The review provides an interpretative framework, suggests valuable future research directions within the new comprehensive thematic area, and contributes to the theoretical and managerial discussion on agent-based modelling in the circular economy.
Long-term exposure to ambient air pollutant concentrations is known to cause chronic lung inflammation, a condition that may promote increased severity of COVID-19 syndrome caused by the novel ...coronavirus (SARS-CoV-2). In this paper, we empirically investigate the ecologic association between long-term concentrations of area-level fine particulate matter (PM
2.5
) and excess deaths in the first quarter of 2020 in municipalities of Northern Italy. The study accounts for potentially spatial confounding factors related to urbanization that may have influenced the spreading of SARS-CoV-2 and related COVID-19 mortality. Our epidemiological analysis uses geographical information (e.g., municipalities) and negative binomial regression to assess whether both ambient PM
2.5
concentration and excess mortality have a similar spatial distribution. Our analysis suggests a positive association of ambient PM
2.5
concentration on excess mortality in Northern Italy related to the COVID-19 epidemic. Our estimates suggest that a one-unit increase in PM
2.5
concentration (µg/m
3
) is associated with a 9% (95% confidence interval: 6–12%) increase in COVID-19 related mortality.
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