Liver transplantation in metastatic colorectal cancer: are we ready for it?Ros, Javier; Salva, Francesc; Dopazo, Cristina; López, Daniel; Saoudi, Nadia; Baraibar, Iosune; Charco, Ramon; Tabernero, Josep; Elez, Elena
doi: 10.1038/s41416-023-02213-1pmid: 36879000
Colorectal cancer (CRC) is a prevalent disease worldwide, with more than 50% of patients developing metastases to the liver. Five-year overall survival remains modest among patients with metastatic CRC (mCRC) treated with conventional therapies however, liver transplantation in a highly selected population can improve clinical outcomes with an impressive 5-year overall survival of 83%. Despite liver transplantation appearing to be a promising therapeutical option for well-selected patients with mCRC with the liver-limited disease, these data come from small monocentric trials which included a heterogeneous population. Currently, several clinical trials are evaluating liver transplantation in this scenario, aiming for a more accurate patient selection by integrating liquid biopsy, tissue profiling, and nuclear medicine to the already known clinical biomarkers that eventually may lead to a survival improvement. In this paper, the clinical outcomes and inclusion criteria from the most relevant clinical trials and clinical series involving liver transplantation in patients with liver-limited disease colorectal cancer are reviewed as well as the trials currently recruiting.
Head and neck cancer patient-derived tumouroid cultures: opportunities and challengesBasnayake, B. W. M. Thilini J.; Leo, Paul; Rao, Sudha; Vasani, Sarju; Kenny, Lizbeth; Haass, Nikolas K.; Punyadeera, Chamindie
doi: 10.1038/s41416-023-02167-4pmid: 36765173
Head and neck cancers (HNC) are the seventh most prevalent cancer type globally. Despite their common categorisation, HNCs are a heterogeneous group of malignancies arising in various anatomical sites within the head and neck region. These cancers exhibit different clinical and biological manifestations, and this heterogeneity also contributes to the high rates of treatment failure and mortality. To evaluate patients who will respond to a particular treatment, there is a need to develop in vitro model systems that replicate in vivo tumour status. Among the methods developed, patient-derived cancer organoids, also known as tumouroids, recapitulate in vivo tumour characteristics including tumour architecture. Tumouroids have been used for general disease modelling and genetic instability studies in pan-cancer research. However, a limited number of studies have thus far been conducted using tumouroid-based drug screening. Studies have concluded that tumouroids can play an essential role in bringing precision medicine for highly heterogenous cancer types such as HNC.
Preclinical models in head and neck squamous cell carcinomaChaves, Patricia; Garrido, María; Oliver, Javier; Pérez-Ruiz, Elisabeth; Barragan, Isabel; Rueda-Domínguez, Antonio
doi: 10.1038/s41416-023-02186-1pmid: 36765175
Head and neck cancer is the sixth most frequent cancer type. Drug resistance and toxicity are common challenges of the existing therapies, making the development of reliable preclinical models essential for the study of the involved molecular mechanisms as well as for eventual intervention approaches that improve the clinical outcome. Preclinical models of head and neck squamous cell carcinoma have been traditionally based on cell lines and murine models. In this review, we will go over the most frequently used preclinical models, from immortalised-cell and primary tumour cultures in monolayer or 3D, to the currently available animal models. We will scrutinise their efficiency in mimicking the molecular and cellular complexity of head and neck squamous cell carcinoma. Finally, the challenges and the opportunities of other envisaged putative approaches, as well as the potential of the preclinical models to further develop personalised therapies will be discussed.
Azithromycin, a potent autophagy inhibitor for cancer therapy, perturbs cytoskeletal protein dynamicsTakano, Naoharu; Hiramoto, Masaki; Yamada, Yumiko; Kokuba, Hiroko; Tokuhisa, Mayumi; Hino, Hirotsugu; Miyazawa, Keisuke
doi: 10.1038/s41416-023-02210-4pmid: 36871041
BackgroundAutophagy plays an important role in tumour cell growth and survival and also promotes resistance to chemotherapy. Hence, autophagy has been targeted for cancer therapy. We previously reported that macrolide antibiotics including azithromycin (AZM) inhibit autophagy in various types of cancer cells in vitro. However, the underlying molecular mechanism for autophagy inhibition remains unclear. Here, we aimed to identify the molecular target of AZM for inhibiting autophagy.MethodsWe identified the AZM-binding proteins using AZM-conjugated magnetic nanobeads for high-throughput affinity purification. Autophagy inhibitory mechanism of AZM was analysed by confocal microscopic and transmission electron microscopic observation. The anti-tumour effect with autophagy inhibition by oral AZM administration was assessed in the xenografted mice model.ResultsWe elucidated that keratin-18 (KRT18) and α/β-tubulin specifically bind to AZM. Treatment of the cells with AZM disrupts intracellular KRT18 dynamics, and KRT18 knockdown resulted in autophagy inhibition. Additionally, AZM treatment suppresses intracellular lysosomal trafficking along the microtubules for blocking autophagic flux. Oral AZM administration suppressed tumour growth while inhibiting autophagy in tumour tissue.ConclusionsAs drug-repurposing, our results indicate that AZM is a potent autophagy inhibitor for cancer treatment, which acts by directly interacting with cytoskeletal proteins and perturbing their dynamics.
Risk stratification of oesophageal squamous cell carcinoma using change in total lesion glycolysis and number of PET-positive lymph nodesNose, Yohei; Makino, Tomoki; Tatsumi, Mitsuaki; Tanaka, Koji; Yamashita, Kotaro; Noma, Toshiki; Saito, Takuro; Yamamoto, Kazuyoshi; Takahashi, Tsuyoshi; Kurokawa, Yukinori; Nakajima, Kiyokazu; Eguchi, Hidetoshi; Doki, Yuichiro
doi: 10.1038/s41416-023-02151-ypmid: 36841907
BackgroundThe efficacy of neoadjuvant chemotherapy (NACT) correlates with patient survival in oesophageal squamous cell carcinoma (OSCC), but optimal evaluation of the treatment response based on PET-CT parameters has not been established.MethodsWe analysed 226 OSCC patients who underwent PET-CT before and after NACT followed by surgery. We assessed SUVmax, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) for the primary tumour and the number of PET-positive lymph nodes before and after NACT to predict patient survival.ResultsIn a stepwise analysis, we defined 60%, 80%, and 80% as the optimal cut-off values for SUVmax, MTV, and TLG reduction, respectively, to distinguish responders and non-responders to NACT. In the ROC analysis, the TLG reduction rate was the best predictor of recurrence among PET-CT parameters. The TLG responders achieved significantly more favourable prognoses than non-responders (2-year progression-free survival [PFS] rate: 64.1% vs. 38.5%; P = 0.0001). TLG reduction rate (HR 2.58; 95% CI 1.16–5.73) and the number of PET-positive lymph nodes after NACT (HR 1.79; 95% CI 1.04–3.08) were significant independent prognostic factors.ConclusionsTLG reduction is the best predictor of prognosis. Preoperative PET-CT evaluation of both the primary tumour and lymph nodes could accurately stratify risk in OSCC patients.