Therapeutical Usefulness of PD-1/PD-L1 Inhibitors in Aggressive or Metastatic Pituitary Tumours.

Therapeutic options for pituitary neuroendocrine tumours (PitNETs) refractory to temozolomide are scarce. Immune checkpoint inhibitors (ICIs), particularly inhibitors of the programmed cell death-1 (PD-1) pathway and its ligand (PD-L1), have been experimentally used in aggressive or metastatic PitNETs. We aimed to study the therapeutic usefulness of anti-PD-1 drugs in patients with aggressive or metastatic PitNETs. Published cases and case series involving patients with PitNETs treated with PD-1/PD-L1 inhibitors were reviewed. Demographic data, clinical-pathological features, previous therapies, drug dosage and posology, and the best radiological and biochemical responses, as well as survival data, were evaluated. We identified 29 cases of aggressive (n = 13) or metastatic (n = 16) PitNETs treated with PD-1/PD-L1 inhibitors. The hypersecretion of adrenocorticotropic hormone (ACTH) was documented in eighteen cases (62.1%), seven were prolactinomas (24.1%), and four were non-functioning PitNETs. All patients underwent various therapies prior to using ICIs. Overall, a positive radiological response (i.e., partial/complete radiological response and stable disease) was observed in eighteen of twenty-nine cases (62.1%), of which ten and four were ACTH- and prolactin-secreting PitNETs, respectively. Hormonal levels reduced or stabilised after using ICIs in 11 of the 17 functioning PitNET cases with available data (64.7%). The median survival of patients treated with ICIs was 13 months, with a maximum of 42 months in two ACTH-secreting tumours. Among 29 patients with PitNETs treated with PD-1/PD-L1 inhibitors, the positive radiological and biochemical response rates were 62.1% and 64.7%, respectively. Altogether, these data suggest a promising role of ICIs in patients with aggressive or metastatic PitNETs refractory to other treatment modalities.

The Role of Programmed Cell Death Ligand 1 Expression in Pituitary Tumours: Lessons from the Current Literature.

BACKGROUND: Programmed cell death-1 (PD-1) and PD ligand-1 (PD-L1) expression predict the biological behaviour, aggressiveness, and response to immune checkpoint inhibitors in different cancers. We reviewed the published data on PD-L1 expression in pituitary tumours from the perspective of its biological role and prognostic usefulness. SUMMARY: A literature review focused on PD-L1 expression in pituitary tumours was performed. Six immunohistochemistry-based studies which assessed PD-L1 positivity in pituitary tumours were included, encompassing 704 patients. The cohort consisted of 384 (54.5%) nonfunctioning tumours and 320 (43.5%) functioning pituitary tumours. PD-L1 expression was positive in 248 cases (35.2%). PD-L1 positivity rate was higher in functioning than in nonfunctioning tumours (46.3% vs. 26.0%; p < 0.001) but also higher in growth hormone-secreting tumours (56.7%) and prolactinomas (53.6%) than in thyrotroph (33.3%) or corticotroph tumours (20.6%). While proliferative pituitary tumours showed higher rate of PD-L1 positivity than non-proliferative tumours (p < 0.001), no association with invasion or recurrence was found. KEY MESSAGES: PD-L1 is expressed in a substantial number of pituitary tumours, predominantly in the functioning ones. PD-L1 positivity rates were significantly higher in proliferative pituitary tumours in comparison to non-proliferative tumours, but no differences were found concerning invasive or recurrent pituitary tumours. More studies following homogeneous and standardised methodologies are needed to fully elucidate the role and usefulness of PD-L1 expression in pituitary tumours.

Acromegaly in humans and cats: Pathophysiological, clinical and management resemblances and differences.

OBJECTIVE: Acromegaly is a disorder associated with excessive levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). In general, GH/IGF-1 excess leads to morphologic craniofacial and acral changes as well as cardiometabolic complications, but the phenotypic changes and clinical presentation of acromegaly differ across species. Here, we review the pathophysiology, clinical presentation and management of acromegaly in humans and cats, and we provide a systematic comparison between this disease across these different species. DESIGN: A comprehensive literature review of pathophysiology, clinical features, diagnosis and management of acromegaly in humans and in cats was performed. RESULTS: Acromegaly is associated with prominent craniofacial changes in both species: frontal bossing, enlarged nose, ears and lips, and protuberant cheekbones are typically encountered in humans, whereas increased width of the head and skull enlargement are commonly found in cats. Malocclusion, prognathism, dental diastema and upper airway obstruction by soft tissue enlargement are reported in both species, as well as continuous growth and widening of extremities resulting in osteoarticular compromise. Increase of articular joint cartilage thickness, vertebral fractures and spine malalignment is more evident in humans, while arthropathy and spondylosis deformans may also occur in cats. Generalized organomegaly is equally observed in both species. Other similarities between humans and cats with acromegaly include heart failure, ventricular hypertrophy, diabetes mellitus, and an overall increased cardiometabolic risk. In GH-secreting pituitary tumours, local compressive effects and behavioral changes are mostly observed in humans, but also present in cats. Cutis verticis gyrata and skin tags are exclusively found in humans, while palmigrade/plantigrade stance may occur in some acromegalic cats. Serum IGF-1 is used for acromegaly diagnosis in both species, but an oral glucose tolerance test with GH measurement is only useful in humans, as glucose load does not inhibit GH secretion in cats. Imaging studies are regularly performed in both species after biochemical diagnosis of acromegaly. Hypophysectomy is the first line treatment for humans and cats, although not always available in veterinary medicine. CONCLUSION: Acromegaly in humans and cats has substantial similarities, as a result of common pathophysiological mechanisms, however species-specific features may be found.