The Cyclin-dependent kinase 1: more than a cell cycle regulatorMassacci, Giorgia; Perfetto, Livia; Sacco, Francesca
doi: 10.1038/s41416-023-02468-8pmid: 37898722
The Cyclin-dependent kinase 1, as a serine/threonine protein kinase, is more than a cell cycle regulator as it was originally identified. During the last decade, it has been shown to carry out versatile functions during the last decade. From cell cycle control to gene expression regulation and apoptosis, CDK1 is intimately involved in many cellular events that are vital for cell survival. Here, we provide a comprehensive catalogue of the CDK1 upstream regulators and substrates, describing how this kinase is implicated in the control of key ‘cell cycle-unrelated’ biological processes. Finally, we describe how deregulation of CDK1 expression and activation has been closely associated with cancer progression and drug resistance.
The prognostic impact of peritoneal tumour DNA in gastrointestinal and gynaecological malignancies: a systematic reviewAllan, Zexi; Witts, Sasha; Tie, Jeanne; Tebbutt, Niall; Clemons, Nicholas J.; Liu, David S.
doi: 10.1038/s41416-023-02424-6pmid: 37700064
Peritoneal metastases from various abdominal cancer types are common and carry poor prognosis. The presence of peritoneal disease upstages cancer diagnosis and alters disease trajectory and treatment pathway in many cancer types. Therefore, accurate and timely detection of peritoneal disease is crucial. The current practice of diagnostic laparoscopy and peritoneal lavage cytology (PLC) in detecting peritoneal disease has variable sensitivity. The significant proportion of peritoneal recurrence seen during follow-up in patients where initial PLC was negative indicates the ongoing need for a better diagnostic tool for detecting clinically occult peritoneal disease, especially peritoneal micro-metastases. Advancement in liquid biopsy has allowed the development and use of peritoneal tumour DNA (ptDNA) as a cancer-specific biomarker within the peritoneum, and the presence of ptDNA may be a surrogate marker for early peritoneal metastases. A growing body of literature on ptDNA in different cancer types portends promising results. Here, we conduct a systematic review to evaluate the prognostic impact of ptDNA in various cancer types and discuss its potential future clinical applications, with a focus on gastrointestinal and gynaecological malignancies.
Liquid biopsy: creating opportunities in brain spaceTrivedi, Rakesh; Bhat, Krishna P.
doi: 10.1038/s41416-023-02446-0pmid: 37752289
In recent years, liquid biopsy has emerged as an alternative method to diagnose and monitor tumors. Compared to classical tissue biopsy procedures, liquid biopsy facilitates the repetitive collection of diverse cellular and acellular analytes from various biofluids in a non/minimally invasive manner. This strategy is of greater significance for high-grade brain malignancies such as glioblastoma as the quantity and accessibility of tumors are limited, and there are collateral risks of compromised life quality coupled with surgical interventions. Currently, blood and cerebrospinal fluid (CSF) are the most common biofluids used to collect circulating cells and biomolecules of tumor origin. These liquid biopsy analytes have created opportunities for real-time investigations of distinct genetic, epigenetic, transcriptomics, proteomics, and metabolomics alterations associated with brain tumors. This review describes different classes of liquid biopsy biomarkers present in the biofluids of brain tumor patients. Moreover, an overview of the liquid biopsy applications, challenges, recent technological advances, and clinical trials in the brain have also been provided.
Generation of evidence-based carboplatin dosing guidelines for neonates and infantsBarnett, Shelby; Makin, Guy; Tweddle, Deborah A.; Osborne, Caroline; Veal, Gareth J.
doi: 10.1038/s41416-023-02456-ypmid: 37816842
BackgroundTo optimally dose childhood cancer patients it is essential that we apply evidence-based dosing approaches. Carboplatin is commonly dosed to achieve a cumulative target exposure (AUC) in children, with target AUC values of 5.2–7.8 mg/ml.min defined. To achieve these exposures patients are dosed at 6.6 mg/kg/day or 4.4 mg/kg for patients <5 kg. The current study uses real world clinical pharmacology data to optimise body weight-based doses to effectively target AUCs of 5.2–7.8 mg/ml.min in infants.MethodsCarboplatin exposures were determined across 165 treatment cycles in 82 patients ≤10 kg. AUC and clearance values were determined by Bayesian modelling from samples collected on day 1. These parameters were utilised to assess current dosing variability, determine doses required to achieve target AUC values and predict change in AUC using the modified dose.ResultsNo significant differences in clearance were identified between patients <5 kg and 5–10 kg. Consequently, for patients <5 kg, 4.4 mg/kg dosing was not sufficient to achieve a target AUC of 5.2 mg/ml.min, with <55% of patients within 25% of this target. Optimised daily doses for patients ≤10 kg were 6 mg/kg and 9 mg/kg for cumulative carboplatin target exposures of 5.2 and 7.8 mg/ml.min, respectively.ConclusionsAdoption of these evidence-based carboplatin doses in neonates and infants will reduce drug exposure variability and positively impact treatment.
Long-term, continuous infusion of single-agent dinutuximab beta for relapsed/refractory neuroblastoma: an open-label, single-arm, Phase 2 studyLode, Holger N.; Ehlert, Karoline; Huber, Stephanie; Troschke-Meurer, Sascha; Siebert, Nikolai; Zumpe, Maxi; Loibner, Hans; Ladenstein, Ruth
doi: 10.1038/s41416-023-02457-xpmid: 37813959
BackgroundShort-term infusions of dinutuximab beta plus isotretinoin and cytokines administered in previous immunotherapy studies in neuroblastoma were associated with severe pain. Here, long-term, continuous infusion of single-agent dinutuximab beta was evaluated in patients with relapsed/refractory neuroblastoma.MethodsIn this open-label, single-arm, Phase 2 study, patients with either refractory or relapsed high-risk neuroblastoma received dinutuximab beta by continuous infusion over 10 days of each cycle, for up to five cycles. The primary endpoint was objective response rate 24 weeks after the end of cycle 5. Secondary endpoints included adverse events, intravenous morphine use, best response, duration of response, and three-year progression-free and overall survival.ResultsOf the 40 patients included, 38 had evaluable response. Objective response rate was 26% and best response rate 37%. Median duration of response was 238 days (IQR 108–290). Three-year progression-free and overall survival rates were 31% (95% CI 17–47) and 66% (95% CI 47–79), respectively. Prophylactic intravenous morphine use and duration of use decreased with increasing cycles. The most common grade 3 treatment-related adverse events were pain, diarrhea, and hypokalemia.ConclusionLong-term continuous infusion of single-agent dinutuximab beta is tolerable and associated with clinically meaningful responses in patients with relapsed/refractory high-risk neuroblastoma.Clinical trial registrationThe study is registered with ClinicalTrials.gov (NCT02743429) and EudraCT (2014-000588-42).