Langerhans Cell Histiocytosis (LCH) is an orphan disease of clonal dendritic cells which may affect any organ of the body. Most of the knowledge about the diagnosis and therapy is based on pedriatic studies. Adult LCH patients are often evaluated by physicians who focus on only the most obviously affected organ without sufficient evaluation of other systems, resulting in patients being underdiagnosed and/or incompletely staged. Furthermore they may be treated with pediatric-based therapies which are less effective and sometimes more toxic for adults. The published literature on adult LCH cases lacks a comprehensive discussion on the differences between pediatric and adult patients and there are no recommendations for evaluation and comparative therapies. In order to fill this void, a number of experts in this field cooperated to develop the first recommendations for management of adult patients with LCH. Key questions were selected according to the clinical relevance focusing on diagnostic work up, therapy, and follow up. Based on the available literature up to December 2012, recommendations were established, drafts were commented by the entire group, and redrafted by the executive editor. The quality of evidence of the recommendations is predominantly attributed to the level of expert opinion. Final agreement was by consensus.

Langerhans cell histiocytosis (LCH) can affect children and adults with a wide variety of clinical manifestations, including unifocal, single-system multifocal, single-system pulmonary (smoking-associated), or multisystem disease. The existing paradigms in the management of LCH in adults are mostly derived from the pediatric literature. Over the last decade, the discovery of clonality and MAPK-ERK pathway mutations in most cases led to the recognition of LCH as a hematopoietic neoplasm, opening the doors for treatment with targeted therapies. These advances have necessitated an update of the existing recommendations for the diagnosis and treatment of LCH in adults. This document presents consensus recommendations that resulted from the discussions at the annual Histiocyte Society meeting in 2019, encompassing clinical features, classification, diagnostic criteria, treatment algorithm, and response assessment for adults with LCH. The recommendations favor the use of 18F-Fluorodeoxyglucose positron emission tomography-based imaging for staging and response assessment in the majority of cases. Most adults with unifocal disease may be cured by local therapies, while the first-line treatment for single-system pulmonary LCH remains smoking cessation. Among patients not amenable or unresponsive to these treatments and/or have multifocal and multisystem disease, systemic treatments are recommended. Preferred systemic treatments in adults with LCH include cladribine or cytarabine, with the emerging role of targeted (BRAF and MEK inhibitor) therapies. Despite documented responses to treatments, many patients struggle with a high symptom burden from pain, fatigue, and mood disorders that should be acknowledged and managed appropriately.

Denosumab is a potent antiresorptive agent that substantially increases bone mineral density and reduces fracture rates at all skeletal sites for as long as it is administered. However, its favorable skeletal effects reverse quickly upon its discontinuation, because of a vast increase of osteoclast number and activity, which leads to a subsequent profound increase of bone turnover above pre-treatment values, a phenomenon commonly described as “rebound phenomenon”. More importantly, most patients experience rapid, profound bone loss due to this burst of bone resorption that may lead in a minority of these patients to occurrence of fractures, especially multiple vertebral fractures. Therefore, subsequent antiresorptive treatment is mandatory, although the optimal regimen is yet to be clarified. In the present review, we outline what is currently known regarding the negative effects of denosumab discontinuation on different aspects of bone status, the factors that may affect them, and strategies to prevent them.

Cessation of denosumab treatment is associated with increases in bone turnover above baseline values and rapid bone loss. We investigated the efficacy of zoledronate to prevent this bone loss in women with postmenopausal osteoporosis who were treated with denosumab (mean duration 2.2 years) and discontinued treatment after achieving osteopenia. Women were randomized to receive a single 5-mg infusion of zoledronate (ZOL) (n = 27) or two additional 60-mg injections of denosumab (Dmab) (n = 30). Both groups were followed for a total period of 24 months. At 24 months lumbar spine–bone mineral density (LS-BMD) was not different from baseline in the ZOL group, but decreased in the Dmab group by (mean ± SD) 4.82% ± 0.7% (p < 0.001) from the 12-month value; the difference in BMD changes between the two groups, the primary endpoint of the study, was statistically significant (p = 0.025). Results of femoral neck (FN)-BMD changes were similar. ZOL infusion was followed by small but significant increases in serum procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) during the first year and stabilization thereafter. In the Dmab group, bone turnover marker values did not change during the first 12 months but increased significantly at 15 months and in the majority of women these remained elevated at 24 months. Neither baseline nor 12-month bone turnover marker values were associated with BMD changes in either group of women. In the Dmab group, three patients sustained vertebral fractures (two patients multiple clinical, one patient morphometric) whereas one patient in the ZOL group sustained clinical vertebral fractures 12 months after the infusion. In conclusion, a single intravenous infusion of ZOL given 6 months after the last Dmab injection prevents bone loss for at least 2 years independently of the rate of bone turnover. Follow-up is recommended, because in a few patients ZOL treatment might not have the expected effect at 2 years. © 2019 American Society for Bone and Mineral Research.

Neuroendocrine tumours (NETs) constitute a heterogeneous group of tumours that frequently express cell membrane-specific peptide receptors, such as somatostatin receptors (SSTRs), and of which gastroenteropancreatic (GEP), carcinoid and pancreatic islet cell tumours exhibit the highest expression of SSTRs. Radiolabelled receptor-binding somatostatin analogues (octreotide and lanreotide) act as vehicles to guide radioactivity to tissues expressing SSTRs, and can thus be used for their diagnosis and treatment. After the localization of NETs bearing SSTRs with ¹¹¹In-octreotide (OctreoScan), a number of radioisotopes with different physical properties have been used for their treatment. The administration of high doses of the Auger electron and γ-emitter ¹¹¹In-diethylenetriaminepenta-acetic acid (DTPA)⁰,octreotide in patients with metastatic tumours has been associated with considerable symptomatic improvement but relatively few and short-lived objective tumour responses. The use of another radiolabelled somatostatin analogue coupled with ⁹⁰Y, a pure β-emitter, ⁹⁰Y-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA)⁰,Tyr³,octreotide (⁹⁰Y-DOTATOC, OctreoTher), was associated with 10–30% objective tumour response rates, and appears to be particularly effective in larger tumours. ¹¹¹In- and ⁹⁰Y-DOTA-lanreotide has also been used for the treatment of NETs although its therapeutic efficacy is probably inferior to that of octreotide-based radiopharmaceuticals. More recently, treatment with ¹⁷⁷Lu-DOTA⁰,Tyr³octreotate (¹⁷⁷Lu-DOTATATE), which has a higher affinity for the SSTR subtype 2, resulted in approximately 30% complete or partial tumour responses; this radiopharmaceutical is particularly effective in smaller tumours. Furthermore, treatment using both ⁹⁰Y-DOTATOC and ¹⁷⁷Lu-DOTA⁰,Tyr³octreotate seems promising, as the combination of these radiopharmaceuticals could be effective in tumours bearing both small and large lesions. Tumour regression is positively correlated with a high level of uptake on ¹¹¹In-octreotide scintigraphy, limited tumour mass and good performance status. In general, better responses have been obtained in GEP tumours than other NETs. The side effects of this form of therapy are relatively few and mild, particularly when kidney-protective agents are used. Treatment with radiolabelled somatostatin analogues presents a promising tool for the management of patients with inoperable or disseminated NETs, and particularly GEP tumours.