The isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) enzymes are involved in key metabolic processes in human cells, regulating differentiation, proliferation, and oxidative damage response. IDH mutations have been associated with tumor development and progression in various solid tumors such as glioma, cholangiocarcinoma, chondrosarcoma, and other tumor types and have become crucial markers in molecular classification and prognostic assessment. The intratumoral and serum levels of D-2-hydroxyglutarate (D-2-HG) could serve as diagnostic biomarkers for identifying IDH mutant (IDHmut) tumors. As a result, an increasing number of clinical trials are evaluating targeted treatments for IDH1/IDH2 mutations. Recent studies have shown that the focus of these new therapeutic strategies is not only the neomorphic activity of the IDHmut enzymes but also the epigenetic shift induced by IDH mutations and the potential role of combination treatments. Here, we provide an overview of the current knowledge about IDH mutations in solid tumors, with a particular focus on available IDH-targeted treatments and emerging results from clinical trials aiming to explore IDHmut tumor-specific features and to identify the clinical benefit of IDH-targeted therapies and their combination strategies. An insight into future perspectives and the emerging roles of circulating biomarkers and radiomic features is also included.

Head and neck cancers (HNCs) arise from anatomically adjacent sites and subsites, with varying etiological factors, diagnostic strategies, prognoses, and treatment approaches. While conventional squamous cell carcinoma (SCC) is the most common histology in the head and neck district, HNCs encompass a variety of rare histopathological entities, categorized into epithelial tumors such as salivary gland cancers, sinonasal tumors, neuroendocrine tumors, malignant odontogenic tumors, and SCC variants versus non-epithelial tumors including soft tissue sarcomas, mucosal melanomas, and hematological malignancies. Rare HNCs (R-HNCs) represent a diagnostic and clinical challenge, requiring histopathological expertise, the availability of peculiar molecular analysis, and the personalization of local and systemic treatments, all guided by a multidisciplinary tumor board. Here, we provide a comprehensive literature review on R-HNCs, emphasizing key histopathological and molecular characteristics that are crucial for guiding treatment decisions. An insight about the latest developments in systemic treatments is also reported.

Background: Salivary gland cancers (SGCs) are a rare and heterogeneous group of malignancies, accounting for approximately 5% of head and neck cancers. Despite their rarity, advances in molecular profiling have revealed a variety of genetic and molecular pathways, many of which are potentially actionable with targeted therapies. Methods: We reviewed the current literature involving the molecular landscape of SGCs, encompassing the diagnostic and prognostic value of tissue and liquid biomarkers and the potential therapeutic targets across various histological subtypes. Results: Our review highlights key molecular diagnostic findings such as the CRTC1-MAML2 fusion in mucoepidermoid carcinoma and MYB-NFIB rearrangements in adenoid cystic carcinoma, but also targetable alterations such as HER2 and AR positivity in salivary duct carcinoma and ETV6-NTRK3 fusion in secretory carcinoma. Liquid biopsy (both blood- or salivary-based), including circulating tumor DNA, circulating tumor cells, and miRNAs, offers novel, noninvasive approaches for disease monitoring and personalized treatment. Emerging therapies such as HER2 inhibitors, androgen deprivation therapy, and TRK inhibitors underscore the shift towards precision oncology in managing these malignancies. Conclusions: Despite promising advances, challenges remain due to the rarity and phenotypic heterogeneity of SGCs, emphasizing the need for molecularly stratified clinical trials. This review presents an overview of tissue and liquid biomarkers, focusing on molecular targets and therapeutic innovations that lay the foundation for improved diagnostic and treatment strategies for SGCs.

Background: Growth Differentiation Factor 15 (GDF15) has emerged as a key biomarker and therapeutic target in oncology, with roles extending beyond cancer cachexia. Elevated GDF15 levels correlate with poor prognosis across several solid tumors, including colorectal, gastric, pancreatic, breast, lung, prostate, and head and neck cancers. GDF15 modulates tumor progression through PI3K/AKT, MAPK/ERK, and SMAD2/3 signaling, thereby promoting epithelial-to-mesenchymal transition, metastasis, immune evasion, and chemoresistance via Nrf2 stabilization and oxidative stress regulation. Methods: We performed a narrative review of the literature focusing on the role of GDF15 in solid tumors, with a particular emphasis on head and neck cancers. Results: In head and neck squamous cell carcinoma (HNSCC), GDF15 overexpression is linked to aggressive phenotypes, radioresistance, poor response to induction chemotherapy, and failure of immune checkpoint inhibitors (ICIs). Similar associations are observed in colorectal, pancreatic, and prostate cancer, where GDF15 contributes to metastasis and therapy resistance. Targeting the GDF15-GFRAL axis appears therapeutically promising: the monoclonal antibody ponsegromab improved cachexia-related outcomes in the PROACC-1 trial, while visugromab combined with nivolumab enhanced immune response in ICI-refractory tumors. Conclusions: Further investigation is warranted to delineate the role of GDF15 across malignancies, refine patient selection, and evaluate combinatorial approaches with existing treatments.

Patients with head and neck cancer (HNC) bear a significant load, due to both disease-related symptoms and to toxicities associated with treatments. Evaluating quality of life (QoL) is crucial to gauge the physical and psychological impact on these patients. Our primary aim was to assess whether QoL has been incorporated as an endpoint in phase II and III clinical trials for HNC patients in the last 15 years. We investigated publications from 11 major journals to identify randomized and non-randomized phase II and phase III clinical trials assessing locoregional and systemic treatments as either single or multimodal strategies, published from 2008 to March 2023 in patients with HNC. We screened 2045 studies and we selected 158 articles that met the eligibility criteria including a total of 31.734 patients. Globally, QoL was the primary end point in 2 publications (1 %), secondary in 38 (24 %), and exploratory in 7 (4 %). The quota of primary publications with QoL among endpoints increased over time: 14 (17 %) publications between 2008 and 2015 and 33 (42 %) between 2016 and 2023. Notably, in phase III trials, QoL was included among endpoints in 30 (49 %) publications, whereas in phase II studies, QoL was present in 17 (17 %). In HNC, the assessment of QoL as an endpoint in clinical trials is still missing, even in phase III trials. Efforts should be focused on the adoption of Patient-Reported Outcomes (PROs) in trials to improve the definition of treatment value in this vulnerable population.