The importance of being integrative: a remarkable case of synonymy in the genus Viridiscus (Heterotardigrada: Echiniscidae)

There are two predominant sources of taxonomically useful morphological variability in the diverse tardigrade family Echiniscidae: the internal structure and surface sculpture of the cuticular plates covering the dorsum (sculpturing) and the arrangement and morphology of the trunk appendages (chaetotaxy). However, since the appendages often exhibit intraspecific variation (they can be reduced or can develop asymmetrically), sculpturing has been considered more stable at the species level and descriptions of new echiniscid species based solely on morphology are still being published. Here, we present a case study in which a detailed analysis of the morphology and multiple genetic markers of several species of the genus Viridiscus shows that cuticular sculpture may also exhibit considerable intraspecific variation and lead to false taxonomic conclusions. In a population collected from the eastern Nearctic, in the type locality of the recently described species V. miraviridis, individuals with transitional morphotypes between those reported for V. viridissimus and V. miraviridis were found. Importantly, all morphotypes within the viridissimus–miraviridis spectrum were grouped in a single monospecific clade according to rapidly evolving markers (ITS-1, ITS-2 and COI). Given the morphological and genetic evidence, we establish V. miraviridis as a junior synonym of V. viridissimus. This study explicitly demonstrates that a lack of DNA data associated with morphological descriptions of new taxa jeopardizes the efforts to unclutter tardigrade systematics. Additionally, V. perviridis and V. viridissimus are reported from Lâm Đồng Province in southern Vietnam, which considerably broadens their known geographic ranges.

INNV-11. COMPLETE RESPONSE TO SELPERCATINIB IN A PATIENT WITH RECURRENT GLIOBLASTOMA AND RET AMPLIFICATION

BACKGROUND Glioblastoma (GBM) is a malignant central nervous system tumor that remains largely incurable. Limited treatment options currently exist after disease progression on the standard of care first-line therapy. However, repurposing the use of approved therapies in patients with potentially targetable genomic alterations continues to be an emerging area of interest. Here, we present the first reported case of a patient with isocitrate dehydrogenase wild-type GBM with an underlying RET amplification who demonstrated a near-complete response (CR) while receiving therapy with the targeted RET inhibitor, selpercatinib. CLINICAL PRESENTATION A 48-year-old male with no significant past medical history presented with sudden onset of dizziness and confusion. Magnetic resonance imaging (MRI) revealed two rim enhancing lesions in the right parietal lobe and the patient underwent surgical resection with subsequent pathology revealing a GBM. Genomic analysis identified a RET amplification. After standard adjuvant therapy, the patient was treated with selpercatinib 160 mg twice daily as a continuous regimen with near CR on MRI after six weeks of treatment. The patient was continued on therapy for a total of eight months before having disease progression requiring discontinuation of selpercatinib and was then transitioned to the next line of therapy for disease stabilization. To better characterize the response, further whole-exome sequencing and analysis were performed on the original specimen. CONCLUSION Although selpercatinib is approved in RET-fusion positive lung and thyroid cancer, we present a remarkable case of a recurrent, RET-amplified GBM having a CR to selpercatinib. The case highlights the excellent blood-brain barrier penetration of selpercatinib, as well as its potential role in RET-amplified GBM. Larger biomarker-enriched studies are needed to confirm the results of this case report. However, given the rare incidence of RET alterations in GBM, findings from this report can help guide and support optimal treatment strategies for patients with RET-altered GBM.

The dynamics of the Campi Flegrei caldera magma chamber.

The Campi Flegrei volcanic system is certainly a remarkable case study for what concerns magma chamber dynamics. In fact, its magmatic and volcanic history appears to have been largely driven by chamber processes like fractional crystallization, magma mixing, and volatile degassing. These processes have been intensely investigated with a variety of approaches that are described in many chapters of this book, and more specifically, in Chapters 2 to 5. Here we employ physico-mathematical modelling and numerical simulations in order to study the dynamics of magma convection and mixing in a vertically extended, geometrically complex, compositionally heterogeneous magmatic system representing a schematic simplification of an overall picture emerging from previous studies at Campi Flegrei. Although clearly a simplification, a number of first order characteristics of possible real magmatic systems at Campi Flegrei are accounted for, including the more chemically evolved, partially degassed nature of magmas emplaced at shallow depths, and the likely occurrence of multiple reservoirs with different depth, size and shape which can be connected at certain stages during system evolution, allowing deeper, CO2-rich magmas to rise and rejuvenate the shallow magmas.

Marinos Papadopoulos Vretos : ‘Le trait d’union entre Paris et Athènes, l’intermédiaire naturel entre la Grèce et les Philhellènes des bords de la Seine’ (Victor Fournel, L’Espérance, 1858)

Marinos Papadopoulos Vretos (Corfu, 1828–Paris, 1871) represents a remarkable case of a conscious cultural mediator between Greece and France, during a critical time (1850–1870). Through a variety of print media (Greek, French or bilingual), he sought to inform the French-language public about the cultural identity of modern Greeks and to confute the distorted image provided by travel literature. Thanks to his excellent education in French, he managed to penetrate the French press, writing about Greek issues. He mobilised around him a network of French philhellenes, Hellenists and journalists who rebroadcasted his positions. Through his Greek-language Εθνικόν Ημερολόγιον [National Almanac], he ‘coordinated’ an important discussion on the language question, preparing the road for the foundation of the Association pour l’encouragement des études grecques.

Exotic Nonleaves with Infinitely Many Ends

We show that any simply connected topological closed $4$-manifold punctured along any compact, totally disconnected tame subset $\Lambda $ admits a continuum of smoothings, which are not diffeomorphic to any leaf of a $C^{1,0}$ codimension one foliation on a compact manifold. This includes the remarkable case of $S^4$ punctured along a tame Cantor set. This is the lowest reasonable regularity for this realization problem. These results come from a new criterion for nonleaves in $C^{1,0}$ regularity. We also include a new criterion for nonleaves in the $C^2$-category. Some of our smooth nonleaves are “exotic”, that is, homeomorphic but not diffeomorphic to leaves of codimension one foliations on a compact manifold, being the 1st examples in this class.

Multiple endocrinopathies, hypercalcaemia and pancreatitis following combined immune checkpoint inhibitor use- case report and review of literature

Background Immune checkpoint inhibitors (ICIs) are a novel class of oncological agents which are used to treat a number of malignancies. To date seven agents have been approved by the Food and Drug Administration (FDA) to treat both solid and haematological malignancies. Despite their efficacy they have been associated with a number of endocrinopathies. We report a unique case of hypophysitis, thyroiditis, severe hypercalcaemia and pancreatitis following combined ICI therapy. Case presentation A 46-year old Caucasian female with a background history of malignant melanoma and lung metastases presented to the emergency department with lethargy, nausea, palpitations and tremors. She had been started on a combination of nivolumab and ipilimumab 24 weeks earlier. Initial investigations revealed thyrotoxicosis with a thyroid stimulating hormone (TSH) of < 0.01 (0.38–5.33) mIU/L, free T4 of 66.9 (7–16) pmol/.L. TSH receptor and thyroperoxidase antibodies were negative. She was diagnosed with thyroiditis and treated with a beta blocker. Six weeks later she represented with polyuria and polydipsia. A corrected calcium of 3.54 (2.2–2.5) mmol/l and parathyroid hormone (PTH) of 9 (10–65) pg/ml confirmed a diagnosis of non-PTH mediated hypercalcaemia. PTH-related peptide and 1, 25-dihydroxycholecalciferol levels were within the normal range. Cross-sectional imaging and a bone scan out ruled bone metastases but did reveal an incidental finding of acute pancreatitis – both glucose and amylase levels were normal. The patient was treated with intravenous hydration and zoledronic acid. Assessment of the hypothalamic-pituitary-adrenal (HPA) axis uncovered adrenocorticotrophic hormone (ACTH) deficiency with a morning cortisol of 17 nmol/L. A pituitary Magnetic Resonance Image (MRI) was unremarkable. Given her excellent response to ICI therapy she remained on ipilimumab and nivolumab. On follow-up this patient’s thyrotoxicosis had resolved without anti-thyroid mediations – consistent with a diagnosis of thyroiditis secondary to nivolumab use. Calcium levels normalised rapidly and remained normal. ACTH deficiency persisted, and she is maintained on oral prednisolone. Conclusion This is a remarkable case in which ACTH deficiency due to hypophysitis; thyroiditis; hypercalcaemia and pancreatitis developed in the same patient on ipilimumab and nivolumab combination therapy. We postulate that hypercalcaemia in this case was secondary to a combination of hyperthyroidism and secondary adrenal insufficiency.