Background: Radiolabeled fibroblast activation protein (FAP) ligands, a novel class of tracers for PET/CT imaging, have demonstrated very promising results in various oncological, as well as in some benign, diseases with long-term potential to supplant the current pan-cancer agent [¹⁸F]FDG in some cancer types. Pancreatic ductal carcinoma (PDAC) belongs to the group of epithelial malignancies with a strong so-called “desmoplastic reaction”, leading to a prominent tumor stroma with cancer-associated fibroblasts that exhibit a marked overexpression of fibroblast activation protein (FAP). The first clinical experiences in PDAC with ⁶⁸Ga-labeled FAP ligands suggested superior sensitivity to [¹⁸F]FDG. However, there is limited data with ¹⁸F-labeled FAP derivatives, i.e. [¹⁸F]FAPI-74, yet prospective single- and multicenter trials are already ongoing. In this proof-of-concept study, we sought to evaluate the biodistribution, tumor uptake, and lesion detectability in patients with PDAC using [¹⁸F]FAPI-74 PET/CT as compared to [¹⁸F]FDG PET/CT scans for staging. Methods: This study includes 7 patients (median age 69) who underwent both [¹⁸F]FDG PET/CT with contrast-enhancement and [¹⁸F]FAPI-74 PET with low-dose CT for primary staging (n = 3) and therapy response control after neoadjuvant (n = 1) or re-staging after palliative therapy (n = 3). The mean interval between PET scans was 11 ± 4 days (range 1–15 days). The [¹⁸F]FDG and [¹⁸F]FAPI-74 PET/CT scans were acquired at 64 ± 4.1 min (range 61–91 min) and 66.4 ± 6.3 min (range 60–76 min), respectively, after administration of 200 ± 94 MBq (range 79–318 MBq) and 235 ± 88 MBq (range 90–321 MBq), respectively. Quantification of tracer uptake was determined with SUV_max and SUV_mean. Furthermore, the tumor-to-background ratio (TBR) was derived by dividing the SUV_max of tumor lesions by the SUV_max of adipose tissue, skeletal muscle, and blood pool. Results: Overall, 32 lesions were detected in 7 patients including primary (n = 7), lung (n = 7), bone (n = 3), lymph node (n = 13), and peritoneal metastases (n = 2). [¹⁸F]FAPI-74 detected 22% more lesions compared with [¹⁸F]FDG with a better TBR and visual lesion delineation. In one patient the primary lesion could be detected unequivocally with [¹⁸F]FAPI-74 but was missed by [¹⁸F]FDG imaging. Altogether, most of the lesions demonstrated markedly elevated uptake of [¹⁸F]FAPI-74 with a simultaneous lower uptake in the background, providing a very high visual contrast. Conclusion: To the best of our knowledge, this is the first, prospective, intra-individual investigation comparing [¹⁸F]FAPI-74 with [¹⁸F]FDG imaging in PDAC with encouraging results. These pivotalresults supporta larger, multicentric, prospective study to determine the value of [¹⁸F]FAPI-74 in detecting and staging PDAC in comparison with current standard of care imaging.

PET imaging of neuroendocrine tumours (NET) is well established for staging and therapy follow-up. The short half-life, increasing costs, and regulatory issues significantly limit the availability of approved imaging agents, such as [⁶⁸Ga]Ga-DOTA-TATE. Al[¹⁸F]F-NOTA-Octreotide provides a similar biodistribution and tumour uptake, can be produced on a large scale and may improve access to precision imaging. Here we prospectively compared the clinical utility of [⁶⁸Ga]Ga-DOTA-TATE and Al[¹⁸F]F-NOTA-Octreotide in the Latin-American population. Our results showed that in patients with stage IV NETs [⁶⁸Ga]Ga-DOTA-TATE presents higher physiological uptake than Al[¹⁸F]F-NOTA-Octreotide in the liver, hypophysis, salivary glands, adrenal glands (all p < 0.001), pancreatic uncinated process, kidneys, and small intestine (all p < 0.05). Nevertheless, despite the lower background uptake of Al[¹⁸F]F-NOTA-Octreotide, comparative analysis of tumour-to-liver (TLR) and tumour-to-spleen (TSR) showed no statistically significant difference for lesions in the liver, bone, lymph nodes, and other tissues. Only three discordant lesions in highly-metastases livers were detected by [⁶⁸Ga]Ga-DOTA-TATE but not by Al[¹⁸F]F-NOTA-Octreotide and only one discordant lesion was detected by Al[¹⁸F]F-NOTA-Octreotide but not by [⁶⁸Ga]Ga-DOTA-TATE. Non-inferiority analysis showed that Al[¹⁸F]F-NOTA-Octreotide is comparable to [⁶⁸Ga]Ga-DOTA-TATE. Hence, our results demonstrate that Al[¹⁸F]F-NOTA-Octreotide provided excellent image quality, visualized NET lesions with high sensitivity and represents a highly promising, clinical alternative to [⁶⁸Ga]Ga-DOTA-TATE.

Background: The gastrin-releasing peptide receptor (GRPr) is highly overexpressed in several solid tumors, including treatment-naïve and recurrent prostate cancer. [⁶⁸Ga]Ga-RM2 is a well-established radiotracer for PET imaging of GRPr, and [¹⁷⁷Lu]Lu-RM2 has been proposed as a therapeutic alternative for patients with heterogeneous and/or low expression of PSMA. In this study, we aimed to evaluate the expression of GRPr and PSMA in a group of patients diagnosed with castration-resistant prostate cancer (mCRPC) by means of PET imaging. Methods: Seventeen mCRPC patients referred for radio-ligand therapy (RLT) were enrolled and underwent [⁶⁸Ga]Ga-PSMA-11 and [⁶⁸Ga]Ga-RM2 PET/CT imaging, 8.8 ± 8.6 days apart, to compare the biodistribution of each tracer. Uptake in healthy organs and tumor lesions was assessed by SUV values, and tumor-to-background ratios were analyzed. Results: [⁶⁸Ga]Ga-PSMA-11 showed significantly higher uptake in tumor lesions in bone, lymph nodes, prostate, and soft tissues and detected 23% more lesions compared to [⁶⁸Ga]Ga-RM2. In 4/17 patients (23.5%), the biodistribution of both tracers was comparable. Conclusions: Our results show that in our cohort of mCRPC patients, PSMA expression was higher compared to GRPr. Nevertheless, RLT with [¹⁷⁷Lu]Lu-RM2 may be an alternative treatment option for selected patients or patients in earlier disease stages, such as biochemical recurrence.

To capture the global gene network regulating the differentiation of immature T cells in an unbiased manner, large-scale forward genetic screens in zebrafish were conducted and combined with genetic interaction analysis. After ENU mutagenesis, genetic lesions associated with failure of T cell development were identified by meiotic recombination mapping, positional cloning, and whole genome sequencing. Recessive genetic variants in 33 genes were identified and confirmed as causative by additional experiments. The mutations affected T cell development but did not perturb the development of an unrelated cell type, growth hormone-expressing somatotrophs, providing an important measure of cell-type specificity of the genetic variants. The structure of the genetic network encompassing the identified components was established by a subsequent genetic interaction analysis, which identified many instances of positive (alleviating) and negative (synthetic) genetic interactions. Several examples of synthetic lethality were subsequently phenocopied using combinations of small molecule inhibitors. These drugs not only interfered with normal T cell development, but also elicited remission in a model of T cell acute lymphoblastic leukaemia. Our findings illustrate how genetic interaction data obtained in the context of entire organisms can be exploited for targeted interference with specific cell types and their malignant derivatives.

The stability of cellular phenotypes in developing organisms depends on error-free transmission of epigenetic and genetic information during mitosis. Methylation of cytosine residues in genomic DNA is a key epigenetic mark that modulates gene expression and prevents genome instability. Here, we report on a genetic test of the relationship between DNA replication and methylation in the context of the developing vertebrate organism instead of cell lines. Our analysis is based on the identification of hypomorphic alleles of dnmt1, encoding the DNA maintenance methylase Dnmt1, and pole1, encoding the catalytic subunit of leading-strand DNA polymerase epsilon holoenzyme (Pole). Homozygous dnmt1 mutants exhibit genome-wide DNA hypomethylation, whereas the pole1 mutation is associated with increased DNA methylation levels. In dnmt1/pole1 double-mutant zebrafish larvae, DNA methylation levels are restored to near normal values, associated with partial rescue of mutant-associated transcriptional changes and phenotypes. Hence, a balancing antagonism between DNA replication and maintenance methylation buffers against replicative errors contributing to the robustness of vertebrate development.

In Chile, like in other Latin American countries, cancer incidence is rising rapidly with a massive social and economic burden, and this situation has worsened after the COVID19 outbreak. In 1986 the Chilean government created two antineoplastic drugs for adults (PANDA) and children (PINDA). Later, several cancers, cancer prevention plans and palliative services were covered by the GES/AUGE plan. However, the lack of a national cancer register, disparities in coverage and centralisation of specialists and oncologic infrastructure made the creation of a new National Cancer Plan necessary. Civil society, particularly non-governmental organisations (NGOs), pushed for a National Cancer Law as the legal framework for the National Cancer Plan. Their role is crucial to expose the patient perspective. Likewise, the collaborative work with clinic specialists, scientific societies, government and stakeholders is essential to face a multifactorial disease such as cancer. In this article, we analyse the role of civil society, particularly NGOs, in developing the Chilean National Cancer Plan and the National Cancer law. Through public consultation (including the Massachusetts Institute of Technology-COLAB platform, telephone and online surveys), we show that the community's main concerns were treatment financing, coverage, transparency of public policies, integral cancer care, health promotion and prevention. Historically, NGOs have played an assistant role; however, this is changing towards a more preponderant role in public policies, as seen in other developed countries, giving the strength to the civil society to collaborate in the construction of patient-centred cancer policies. Key words: Cancer policies, Cancer law, NGO, Chile, civil society.