Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder involving skeletal dysplasia and heterotopic ossification (HO) of muscle and connective tissue. We aimed to define a novel biomarker in FOP that enables reliable assessment of musculoskeletal tissue integrity. Considering logistical difficulties that FOP patients often face, our goal was to identify an at-home biomarker technique. Electrical impedance myography (EIM) is a non-invasive, portable method that can inform on muscle health. 15 FOP patients (age 10–52) and 13 healthy controls were assessed. Using EIM, multiple muscle groups were characterized per participant in a 45-min period. The Cumulative Analogue Joint Involvement Scale (CAJIS) was implemented to determine mobility burden severity. We additionally evaluated physical activity levels via a Patient-Reported Outcomes Measurement Information System (PROMIS)-based questionnaire. Relative to controls, FOP patients demonstrated significantly lower regional and whole-body phase values at 50 kHz and 100 kHz, indicating more diseased muscle tissue. Lower whole-body phase and reactance values, and higher resistance values, were associated with greater FOP burden (CAJIS score range: 4–30) and lower physical activity levels at 50 kHz and 100 kHz. This study points to the potential utility of EIM as a clinical biomarker tool capable of characterizing muscle integrity in FOP.
Fibrous dysplasia (FD) is a rare, non-inherited bone disease occurring following a somatic gain-of-function R201 missense mutation of the guanine-nucleotide binding protein alpha subunit stimulating activity polypeptide 1 (GNAS) gene. The spectrum of the disease ranges from a single FD lesion to a combination with extraskeletal features; an amalgamation with café-au-lait skin hyperpigmentation, precocious puberty, and other endocrinopathies defines McCune–Albright Syndrome (MAS). Pain in FD/MAS represents one of the most prominent aspects of the disease and one of the most challenging to treat—an outcome driven by (i) the heterogeneous nature of FD/MAS, (ii) the variable presentation of pain phenotypes (i.e., craniofacial vs. musculoskeletal pain), (iii) a lack of studies probing pain mechanisms, and (iv) a lack of rigorously validated analgesic strategies in FD/MAS. At present, a range of pharmacotherapies are prescribed to patients with FD/MAS to mitigate skeletal disease activity, as well as pain. We analyze evidence guiding the current use of bisphosphonates, denosumab, and other therapies in FD/MAS, and also discuss the potential underlying pharmacological mechanisms by which pain relief may be achieved. Furthermore, we highlight the range of presentation of pain in individual cases of FD/MAS to further describe the difficulties associated with employing effective pain treatment in FD/MAS. Potential next steps toward identifying and validating effective pain treatments in FD/MAS are discussed, such as employing randomized control trials and probing new pain pathways in this rare bone disease.
Patients with fibrous dysplasia (FD) often present with craniofacial lesions that affect the trigeminal nerve system. Debilitating pain, headache, and migraine are frequently experienced by FD patients with poor prognosis, while some individuals with similar bone lesions are asymptomatic. The clinical and biological factors that contribute to the etiopathogenesis of pain in craniofacial FD are largely unknown. We present two adult females with comparable craniofacial FD lesion size and location, as measured by 18F-sodium fluoride positron emission tomography/computed tomography (PET/CT), yet their respective pain phenotypes differed significantly. Over 4 weeks, the average pain reported by Patient A was 0.4/0–10 scale. Patient B reported average pain of 7.8/0–10 scale distributed across the entire skull and left facial region. Patient B did not experience pain relief from analgesics or more aggressive treatments (denosumab). In both patients, evaluation of trigeminal nerve divisions (V1, V2, and V3) with CT and magnetic resonance imaging (MRI) revealed nerve compression and displacement with more involvement of the left trigeminal branches relative to the right. First-time employment of diffusion MRI and tractography suggested reduced apparent fiber density within the cisternal segment of the trigeminal nerve, particularly for Patient B and in the left hemisphere. These cases highlight heterogeneous clinical presentation and neurobiological properties in craniofacial FD and also, the disconnect between peripheral pathology and pain severity. We hypothesize that a detailed phenotypic characterization of patients that incorporates an advanced imaging approach probing the trigeminal system may provide enhanced insights into the variable experiences with pain in craniofacial FD.
Background Niemann–Pick disease type C (NPC) is a rare inherited lysosomal storage disease typified by accumulation of cholesterol and other lipids in late endosomes/lysosomes, thereby resulting in a spectrum of neurological, psychiatric, and systemic symptoms (notably liver disease). Though it is well-known that NPC exacts a physical and emotional toll on both patients and caregivers, the burden of NPC can vary between patients, while the challenges of living with NPC can evolve over time (i.e., from time of diagnosis to the present day). To further grasp patient and caregiver perceptions and experiences with NPC, we carried out focus group discussions with pediatric and adult individuals with NPC (N = 19), with partial or full representation of the patient by their caregiver. Furthermore, we utilized our NPC focus group discussion to provide guidance on study design parameters and feasibility of prospective investigations aiming to characterize the central manifestations of NPC using neuroimaging, specifically, magnetic resonance imaging (MRI) methodology. Results Focus group discussions revealed that neurological signs, including declining cognition, memory loss, and psychiatric symptoms, as well as increasingly impaired mobility and motor function, are among the most pressing past and current concerns for patients and caregivers. Moreover, several participants also expressed concern over a loss of independence, social exclusion, and uncertainty for what the future holds. Caregivers described the challenges that participation in research poses, which included logistical difficulties mainly due to traveling with medical equipment and the need for sedation in a minority of patients when undergoing MRI. Conclusions The findings derived from focus group discussions highlight the outstanding challenges that NPC patients and their caregivers face daily, while also providing direction on the potential scope and feasibility of future studies focusing on the central phenotypes of NPC.
Multiple myeloma (MM) is a haematologic malignancy resulting from the malignant overgrowth of monoclonal plasma cells in the bone marrow. Nearly 35,000 new cases are expected in the USA each year. In the last two decades there have been many clinical advances with the approvals of many new drugs and their combinations, which have improved survival statistics. Despite this, MM remains incurable, and patients with relapsed/refractory MM remain vulnerable. The development of chimeric antigen receptor T-cell (CAR-T) therapy has shown promising results utilizing several target antigens; of note, B-cell maturation antigen (BCMA) is most prominent, due to its universal expression on the surface of malignant plasma cells. While anti-BCMA CAR-T therapies are inspiring, most patients eventually relapse and require further treatment. With these patients progressing through standard-of-care therapies, and more recently through novel anti-BCMA CAR-T therapies, we are faced with exploring novel treatment regimens to challenge their diseases. In this review, we discuss the different mechanisms of resistance to anti-BCMA therapies, effective retreatment with anti-BCMA-targeted therapies in MM, and advances in therapies utilizing other novel targets for patients who have progressed through anti-BCMA treatment.
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