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  • A high serum lactate dehydrogenase (LDH) level is generally associated with an inferior outcome in patients with most tumour types. LDH is also known to have immunosuppressive and/or tumour-promoting effects, suggesting a potentially broader role for this enzyme in clinical oncology. In this Review, the authors provide a holistic overview of the current role of LDH in both cancer biology and oncology, and highlight possible areas of future research interest, including the development of novel therapies targeting LDH.

    • Giuseppina Claps
    • Sara Faouzi
    • Caroline Robert
    Review Article
  • Clinical research needs support from preclinical models that consider the biology and genetics of human cancers during treatment, such as patient-derived xenograft (PDX) models. The authors of this Review discuss how PDX models have been used in the past decade for precision oncology and present emerging approaches that could broaden the application of these models.

    • Eugenia R. Zanella
    • Elena Grassi
    • Livio Trusolino
    Review Article
  • Glioblastoma, the most common form of brain cancer in adults, has a dismal prognosis and has proven recalcitrant to novel targeted therapies and immunotherapies. Extrachromosomal DNAs (ecDNAs) harbouring oncogenes are increasingly recognized as important drivers of tumour development, evolution and resistance to treatment, particularly in patients with glioblastoma. In this Perspective, the authors summarize key reasons for the failed clinical translation of new therapies for glioblastoma, highlighting the important contributions of ecDNAs. They then focus on the opportunities and challenges of utilizing ecDNAs to improve the likelihood of success in the development of precision medicines for this disease.

    • Imran Noorani
    • Paul S. Mischel
    • Charles Swanton
  • Peritoneal surface malignancies (PSMs) typically have a poor prognosis, although considerable advances in the understanding and management of these malignancies have been made over the past decade. This Review comprehensively describes the improvements in knowledge of the biology, assessment and classification, perioperative and surgical management, systemic treatment and pre-emptive management of PSMs. The authors also outline future directions for research in this field.

    • Vahan Kepenekian
    • Aditi Bhatt
    • Olivier Glehen
    Review Article
  • The incidence of early-onset forms of many cancers (defined as cancers diagnosed in individuals <50 years of age) has increased in a number of countries over the past several decades. The underlying reasons for this apparent increase probably include greater use of screening programmes, but also changing patterns in early-life exposures. In this Review, the authors describe the emerging global increase in the incidence of early-onset cancers and suggest changes that might address this situation.

    • Tomotaka Ugai
    • Naoko Sasamoto
    • Shuji Ogino
    Review Article
  • The entry of cells into senescence can act as a barrier to tumorigenesis; however, in certain contexts senescent malignant and non-malignant cells can acquire pro-tumorigenic properties. The authors of this Review discuss the cell-intrinsic and cell-extrinsic mechanisms involved in both the antitumorigenic and tumour-promoting roles of senescent cells, and describe the potential of various senolytic and senomorphic therapeutic approaches in oncology.

    • Clemens A. Schmitt
    • Boshi Wang
    • Marco Demaria
    Review Article
  • Clinical trials of neoadjuvant therapy for melanoma have expanded rapidly over the past several years. Preliminary data demonstrate the prognostic value of pathological response, which might have clinical implications for refining the roles of surgery and adjuvant therapy. These clinical questions are under active investigation across many ongoing clinical trials.

    • Giorgos C. Karakousis
    • Tara C. Mitchell
    News & Views
  • Age is one of the strongest risk factors for cancer and also affects tumour biology, treatment recommendations and response to therapy. Although clinical oncology guidelines advocate against classifying patients on the basis of chronological age alone, most studies and published guidelines use discrete age cutoffs, often heterogeneously. Herein, we discuss age cutoffs from a historical and biological perspective, focusing on breast cancer.

    • Neil Carleton
    • Priscilla F. McAuliffe
  • The RAS oncogenes are among the most common drivers of tumour development and progression but have historically been considered undruggable. The development of direct KRAS inhibitors has changed this paradigm, although currently clinical use of these novel therapeutics is limited to a select subset of patients, and intrinsic or acquired resistance presents an inevitable challenge to cure. Herein, the authors provide an overview of the RAS pathway in cancer and review the ongoing efforts to develop effective therapeutic strategies for RAS-mutant cancers. They also discuss the current understanding of mechanisms of resistance to direct KRAS inhibitors and strategies by which they might be overcome.

    • Salman R. Punekar
    • Vamsidhar Velcheti
    • Kwok-Kin Wong
    Review Article
  • The development of covalent, allele-specific inhibitors of KRASG12C represents a major breakthrough in precision oncology. Herein we discuss recent data from the phase II KRYSTAL-1 trial of adagrasib in KRASG12C-mutated non-small-cell lung cancer (NSCLC). This trial showed responses in a subset of patients, including among those with brain metastases, and offers exploratory insights into potential biomarkers of response.

    • Yonina R. Murciano-Goroff
    • Piro Lito
    News & Views