Immune checkpoint inhibitor-induced hypophysitis: lessons learnt from a large cancer cohort

Immune checkpoint inhibitors (ICIs) can cause pituitary dysfunction due to hypophysitis. We aimed to characterize ICI-induced hypophysitis and examine its association with overall survival in this single-center retrospective cohort study of adult patients with cancer who received an ICI from January 1, 2012 through December 31, 2016. A total of 896 patients were identified who received ipilimumab alone (n=120); ipilimumab and nivolumab (n=50); ipilimumab before or after pembrolizumab (n=70); pembrolizumab alone (n=406); and nivolumab alone (n=250). Twenty-six patients (2.9%) developed hypophysitis after a median of 2.3 months. Median age at the start of ICI was 57.9 years and 54% were men. Hypophysitis occurred in 7.9% of patients receiving ipilimumab alone or in combination or sequence with a programmed cell death protein 1 inhibitor; 1.7% after pembrolizumab alone, never after nivolumab alone. Secondary adrenal insufficiency occurred in all hypophysitis cases. Use of ipilimumab alone or in combination was associated with pituitary enlargement on imaging and mass effects more frequently than pembrolizumab alone. Occurrence of hypophysitis was associated with improved overall survival by univariate analysis (median 50.7 vs 16.5 months; p=0.015) but this association was not observed in multivariable landmark survival analysis (HR for mortality 0.75; 95% CI 0.38 to 1.30; p=0.34) after adjusting for age, sex and malignancy type. To conclude, hypophysitis occurred most frequently after ipilimumab and manifested as anterior hypopituitarism affecting the corticotrophs more commonly than thyrotrophs and gonadotrophs. Mass effects and pituitary enlargement occurred more frequently in ipilimumab-induced hypophysitis. The association of hypophysitis with overall survival needs further investigation.

Lepton-flavour non-universality of $${\bar{B}}\rightarrow D^*\ell {{\bar{\nu }}}$$ angular distributions in and beyond the Standard Model

We analyze in detail the angular distributions in $${\bar{B}}\rightarrow D^*\ell {{\bar{\nu }}}$$ B ¯ → D ∗ ℓ ν ¯ decays, with a focus on lepton-flavour non-universality. We investigate the minimal number of angular observables that fully describes current and upcoming datasets, and explore their sensitivity to physics beyond the Standard Model (BSM) in the most general weak effective theory. We apply our findings to the current datasets, extract the non-redundant set of angular observables from the data, and compare to precise SM predictions that include lepton-flavour universality violating mass effects. Our analysis shows that the number of independent angular observables that can be inferred from current experimental data is limited to only four. These are insufficient to extract the full set of relevant BSM parameters. We uncover a $$\sim 4\sigma $$ ∼ 4 σ tension between data and predictions that is hidden in the redundant presentation of the Belle 2018 data on $${\bar{B}}\rightarrow D^*\ell {{\bar{\nu }}}$$ B ¯ → D ∗ ℓ ν ¯ decays. This tension specifically involves observables that probe $$e-\mu $$ e - μ lepton-flavour universality. However, we find inconsistencies in these data, which renders results based on it suspicious. Nevertheless, we discuss which generic BSM scenarios could explain the tension, in the case that the inconsistencies do not affect the data materially. Our findings highlight that $$e-\mu $$ e - μ non-universality in the SM, introduced by the finite muon mass, is already significant in a subset of angular observables with respect to the experimental precision.

Unilateral hydrocephalus from a gangliocytoma-somatotrophinoma: first reported case

Summary Although pituitary macroadenomas often cause mass effects on surrounding structures, it is extremely rare for pituitary lesions to disturb cerebrospinal fluid circulation. Sellar gangliocytoma-pituitary adenomas (SGPAs) are also extremely rare. Here we report the unique case of a man with the unusual combination of acromegaly from an SGPA, who presented with unilateral hydrocephalus. A 60-year-old man presented with rapid neurological deterioration, bitemporal hemianopia, and acromegalic features. Neuroimaging revealed a large sellar lesion extending superiorly into the left foramen of Monro, causing acute obstructive unilateral hydrocephalus. External ventricular drain placement improved consciousness immediately. Biochemical assessment confirmed acromegaly. Following trans-sphenoidal debulking, histology revealed a mixed gangliocytoma/sparsely-granulated somatotrophinoma. Despite the residual disease, his vision recovered remarkably, low-dose cabergoline controlled residual excess growth hormone (GH) secretion, and the residual tumour has remained extremely stable over 2 years. Hydrocephalus is an extremely rare complication of pituitary lesions, and unilateral hydrocephalus has never been reported previously. GH secretion in SGPAs is more common than for pituitary adenomas in general, raising questions regarding the aetiology and therapeutic approach to this rare combination tumour. Learning points Pituitary tumours most commonly present with symptoms related to endocrine disturbance or mass effects upon visual pathways (e.g. optic chiasm, nerves in the lateral cavernous sinus). However, extremely rarely, pituitary masses may disrupt cerebrospinal fluid (CSF) circulation resulting in hydrocephalus. Sellar gangliocytomas are very rare tumours and most of them are hybrid tumours with pituitary adenomas (SGPAs). SGPAs are typically indolent and may be functioning or non-functioning tumours. Growth hormone (GH)-producing SGPAs are less likely to respond to somatostatin agonists than classic somatotrophinomas. Primary surgical debulking via a trans-sphenoidal approach was effective in this individual, leading to the restoration of CSF circulation and improvement in visual disturbance, while also negating the need for permanent CSF diversion despite the residual tumour burden.

Effect of Water Chemistry, Land Use Patterns, and Geographic Distances on the Spatial Distribution of Bacterioplankton Communities in an Anthropogenically Disturbed Riverine Ecosystem

The spatial distribution of bacterioplankton communities in rivers is driven by multiple environmental factors, including local and regional factors. Local environmental condition is associated with effect of river water chemistry (through species sorting); ecological process in region is associated with effects of land use and geography. Here, we investigated variation in bacterioplankton communities (free-living, between 0.22 and 5 μm) in an anthropogenically disturbed river using high-throughput DNA sequencing of community 16S rRNA genes in order to investigate the importance of water chemistry, land use patterns, and geographic distance. Among environmental factors, sulfate (SO42–), manganese (Mn), and iron (Fe) concentrations were the water chemistry parameters that best explained bacterioplankton community variation. In addition, forest and freshwater areas were the land use patterns that best explained bacterioplankton community variation. Furthermore, cumulative dendritic distance was the geographic distance parameter that best explained bacterial community variation. Variation partitioning analysis revealed that water chemistry, land use patterns, and geographic distances strongly shaped bacterioplankton communities. In particular, the direct influence of land use was prominent, which alone contributed to the highest proportion of variation (26.2% in wet season communities and 36.5% in dry season communities). These results suggest that the mechanisms of species sorting and mass effects together control bacterioplankton communities, although mass effects exhibited higher contributions to community variation than species sorting. Given the importance of allochthonous bacteria input from various land use activities (i.e., mass effects), these results provide new insights into the environmental factors and determinant mechanisms that shape riverine ecosystem communities.

Mass Effects

In the last two decades, community ecology has matured to consider biotic communities as a product of both local and regional processes. Therefore, local communities are currently thought to be connected by the dispersal of organisms, thereby forming a metacommunity. A metacommunity is organized by multiple processes, including environmental filtering, biotic interactions, dispersal, and ecological drift. Thus, spatial variations in local diversity (i.e., alpha diversity) and community composition (i.e., beta diversity) result from the relative roles of these major processes. In turn, these processes are mediated by organisms’ characteristics, environmental heterogeneity, and the connectivity between localities in a metacommunity. For a given environmental gradient, the role of environmental filtering is likely to be dependent on the dispersal rates shown by organisms. Unsuitable habitat patches (i.e., sinks), in terms of biotic and abiotic characteristics, may be occupied by different species due to high dispersal rates from suitable habitat patches (i.e., sources). Thus, mass effects occur when species are established at localities where their populations cannot be self-maintained. Even though it may be difficult to prove the action of mass effects per se, given the complex interactions between different mechanisms shaping biotic communities, there is some empirical evidence supporting their importance in nature. In addition, high dispersal rates that lead to mass effects may have important implications for biomonitoring and biodiversity conservation. This is because species occurring at sites beyond their niche requirements may provide false information about a site’s ecological quality or result in misleading plans to conserve species at sites where they cannot persist in the absence of continuous influx of propagules.