Nature Reviews Disease Primers最新文献

Polycythaemia vera (PV) is a haematological malignancy in the myeloproliferative neoplasm family. PV is typically characterized by erythrocytosis and often leukocytosis and thrombocytosis¹. Clinical features include reduced life expectancy due to hazards of thrombosis (often in atypical sites), haemorrhage and transformation to myelofibrosis and less frequently to a form of acute myeloid leukaemia called blast phase. Almost two decades ago, the JAK2^V617F mutation in exon 14 of JAK2 was described, and is known to be present in more than 95% of patients with PV. Testing for the JAK2^V617F mutation is used in the diagnosis of PV, and the quantity of the mutation (that is, the variant allele frequency) is linked to prognosis and the risk of complications. As such, reduction of JAK2^V617F variant allele frequency is currently being evaluated as a treatment target. Recommendations for PV treatment include control of vascular risk factors, therapeutic phlebotomy and low-dose aspirin in all patients. Currently, patients at higher risk of thrombosis (aged over 60 years and/or with a history of thrombosis) are offered cytoreductive agents. Hydroxyurea or interferons remain the preferred first-line cytoreductive agents, with the JAK1 and JAK2 inhibitor, ruxolitinib, currently approved for the treatment of patients who are resistant to, or intolerant of, hydroxyurea. Future recommendations might be to treat the majority of patients with these agents as long-term benefits of treatment begin to emerge.

Craniosynostosis is characterized by the premature fusion of one or more major cranial sutures at birth or soon after. Single-suture non-syndromic craniosynostosis (NSC) is the most common form of craniosynostosis and includes the sagittal, metopic, unicoronal and unilambdoid subtypes. Characterized by an abnormal head shape specific to the fused suture type, NSC can cause increased intracranial pressure. Cranial sutures either originate from the neural crest or arise from mesoderm-derived mesenchymal stem cells. A mixture of environmental and genetic factors contributes to NSC, with genetic causes following a largely polygenic model. Physical examination is used to identify the majority of patients, but accompanying radiographic imaging can be confirmatory. The three major surgical techniques in use to treat NSC are cranial vault remodelling, strip craniectomy and spring-assisted cranioplasty. Surgical intervention is ideally performed in the first year of life, with a mortality of <1%. Health-care disparities contribute to delayed initial presentation and timely repair. Optimal timing of surgery and comparative outcomes by surgical technique remain under active study. School-age children with treated NSC on average have subtle, but lower cognitive and behavioural performance. However, patient-reported quality of life outcomes are comparable to those in control individuals.

Cutaneous melanoma is a common cancer in Australia and New Zealand, Europe, and North America, and its incidence is still increasing in many regions. Ultraviolet (UV) radiation exposure (for example, through excessive sunlight exposure) remains the primary risk factor for melanoma; however, public awareness campaigns have led to a marked reduction in mortality. In addition to genetic damage from UV radiation, specific genetic alterations have been linked to melanoma. The stage of the tumour at the time of diagnosis is of greater importance for melanoma prognosis than in almost any other cancer. Context-dependent genetic mutations that attenuate tumour-suppressive mechanisms or activate growth-promoting signalling pathways are crucial factors in the development of cutaneous melanoma. In addition to external factors such as UV radiation, the tumour microenvironment can contribute to melanoma progression, invasion and metastasis. Cutaneous melanoma treatment has improved considerably over the past decade with the discovery and development of immune checkpoint inhibitors and therapy targeting BRAF and MEK. Over the next decade, several priorities are likely to influence melanoma research and management, including the continued advance of precision medicine methods to identify the most suitable patients for the most effective treatment, with the aim of improving clinical outcomes.

Achilles tendon pathologies are prevalent, impacting ~6% of the general population and up to 50% of elite endurance runners over their lifetimes. These conditions substantially affect quality of life and work productivity, leading to substantial societal costs. Achilles tendinopathy (AT) is a condition marked by localized pain and functional impairment related to mechanical loading. AT can considerably impair participation and potentially also performance in sports and daily activities. The aetiology of AT is multifactorial and repetitive overloading of the tendon is often observed as the inciting factor by health professionals. However, AT can also be associated with adverse effects of certain medication, ageing and various comorbidities. Characteristic tendon changes include proteoglycan accumulation, fluid accumulation with swelling and hypervascularization. Tissue disorganization advances as pathological changes in matrix structure are driven by altered cellular function and makeup, often accompanied by persistent inflammation. Treatment strategies include various interventions, although these can be protracted and challenging for both patients and health-care providers, often with high failure rates. Current research focuses on understanding the pathological processes at the cellular and molecular levels to distinguish between disease categories and to investigate the role of inflammation, metabolic maladaptation and mechanical stress. Emerging therapeutic approaches need to be developed to address these underlying mechanisms. These approaches focus on optimizing rehabilitation protocols and advancing the development of adjunct therapies, such as advanced therapy medicinal products, alongside the integration of precision medicine to improve treatment outcomes.