Prophylactic cranial irradiation in extensive disease small cell lung cancer: An endless debate.

Extensive disease Small cell lung cancer (ED-SCLC) represents a very aggressive malignancy in which brain metastases (BM) are quite common. Clinical trials on prophylactic cranial irradiation (PCI) have showed a clear decrease in the risk of developing BM but conflicting results concerning a possible survival advantage. A landmark European Organisation for Research and Treatment of Cancer (EORTC) prospective trial, as well as multitude of retrospective series confirm survival benefit after PCI. Recently, a Japan Clinical Oncology Group (JCOG) study did not find such survival benefit, provided that non-irradiated patients are closely followed by MRI. Henceforth, the role of PCI in this population has been questioned, on the ground of the possible absence of survival benefit, leading to a gradual shift in oncology practice. We performed a review of the literature on the subject of PCI in ED-SCLC patients. We conclude that PCI could still play a crucial role in these patients, considering not only a possible survival benefit, but also alternative endpoints, such as improved local control, delay in the onset of symptomatic BM and lower toxicity of a prophylactic- rather than an eventual active-intent treatment. Individualized attitude should be discussed with patients, while addressing all arguments in favour and against PCI.

Postmastectomy radiotherapy in T1-2 patients with one to three positive lymph nodes - Past, present and future.

PAST: The role of post-mastectomy radiotherapy (PMRT) in patients with tumor <5 cm and one to three positive lymph nodes after axillary dissection (ALND) is vigorously debated. Initial doubts over the efficacy and safety of PMRT in these patients were partially overcome by improvement in technology and systemic treatments. Several randomized controlled clinical trials confirmed benefit of PMRT in N1 patients, which were meta-analyzed by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG). This meta-analysis provides the sole high-level evidence to guide clinical decision-making. PRESENT: Nevertheless, concerns have been evoked around these results, most notably concerning the patient selection bias and the era in which the patients were treated. More recent studies, albeit retrospective, are in contrast with this level I evidence, unequivocally reporting inferior recurrence rates in control arms than those of the EBCTCG meta-analysis. Taken together, these results suggest that one solution would not fit all N1 patients and that patient selection for PMRT shall be stratified upon risks factors. Most prominent of such factors identified are: patient age; number and ratio of positive lymph nodes; histological features such as lymphovascular invasion; and hormone receptor expression. FUTURE: A prospective randomized controlled trial SUPREMO will release its final results in 2023 and shed light onto the subject. Genomic tumor cell profiling will likely provide further guidelines in terms of risk stratification. SUPREMO translational sub-study will also offer material for genomic analyses. A cross-field tendency to forgo nodal dissection in favor of sentinel lymph node biopsy followed by nodal irradiation might eventually render the question of PMRT indication after ALND irrelevant.

Trichoplax adhaerens reveals a network of nuclear receptors sensitive to 9-cis-retinoic acid at the base of metazoan evolution.

Trichoplax adhaerens, the only known species of Placozoa is likely to be closely related to an early metazoan that preceded branching of Cnidaria and Bilateria. This animal species is surprisingly well adapted to free life in the World Ocean inhabiting tidal costal zones of oceans and seas with warm to moderate temperatures and shallow waters. The genome of T. adhaerens (sp. Grell) includes four nuclear receptors, namely orthologue of RXR (NR2B), HNF4 (NR2A), COUP-TF (NR2F) and ERR (NR3B) that show a high degree of similarity with human orthologues. In the case of RXR, the sequence identity to human RXR alpha reaches 81% in the DNA binding domain and 70% in the ligand binding domain. We show that T. adhaerens RXR (TaRXR) binds 9-cis retinoic acid (9-cis-RA) with high affinity, as well as high specificity and that exposure of T. adhaerens to 9-cis-RA regulates the expression of the putative T. adhaerens orthologue of vertebrate L-malate-NADP+ oxidoreductase (EC 1.1.1.40) which in vertebrates is regulated by a heterodimer of RXR and thyroid hormone receptor. Treatment by 9-cis-RA alters the relative expression profile of T. adhaerens nuclear receptors, suggesting the existence of natural ligands. Keeping with this, algal food composition has a profound effect on T. adhaerens growth and appearance. We show that nanomolar concentrations of 9-cis-RA interfere with T. adhaerens growth response to specific algal food and causes growth arrest. Our results uncover an endocrine-like network of nuclear receptors sensitive to 9-cis-RA in T. adhaerens and support the existence of a ligand-sensitive network of nuclear receptors at the base of metazoan evolution.

The nematode homologue of Mediator complex subunit 28, F28F8.5, is a critical regulator of C. elegans development.

The evolutionarily conserved Mediator complex is a critical player in regulating transcription. Comprised of approximately two dozen proteins, the Mediator integrates diverse regulatory signals through direct protein-protein interactions that, in turn, modulate the influence of Mediator on RNA Polymerase II activity. One Mediator subunit, MED28, is known to interact with cytoplasmic structural proteins, providing a potential direct link between cytoplasmic dynamics and the control of gene transcription. Although identified in many animals and plants, MED28 is not present in yeast; no bona fide MED28 has been described previously in Caenorhabditis elegans. Here, we identify bioinformatically F28F8.5, an uncharacterized predicted protein, as the nematode homologue of MED28. As in other Metazoa, F28F8.5 has dual nuclear and cytoplasmic localization and plays critical roles in the regulation of development. F28F8.5 is a vital gene and its null mutants have severely malformed gonads and do not reproduce. F28F8.5 interacts on the protein level with the Mediator subunits MDT-6 and MDT-30. Our results indicate that F28F8.5 is an orthologue of MED28 and suggest that the potential to link cytoplasmic and nuclear events is conserved between MED28 vertebrate and nematode orthologues.

Perilipin-related protein regulates lipid metabolism in C. elegans.

Perilipins are lipid droplet surface proteins that contribute to fat metabolism by controlling the access of lipids to lipolytic enzymes. Perilipins have been identified in organisms as diverse as metazoa, fungi, and amoebas but strikingly not in nematodes. Here we identify the protein encoded by the W01A8.1 gene in Caenorhabditis elegans as the closest homologue and likely orthologue of metazoan perilipin. We demonstrate that nematode W01A8.1 is a cytoplasmic protein residing on lipid droplets similarly as human perilipins 1 and 2. Downregulation or elimination of W01A8.1 affects the appearance of lipid droplets resulting in the formation of large lipid droplets localized around the dividing nucleus during the early zygotic divisions. Visualization of lipid containing structures by CARS microscopy in vivo showed that lipid-containing structures become gradually enlarged during oogenesis and relocate during the first zygotic division around the dividing nucleus. In mutant embryos, the lipid containing structures show defective intracellular distribution in subsequent embryonic divisions and become gradually smaller during further development. In contrast to embryos, lipid-containing structures in enterocytes and in epidermal cells of adult animals are smaller in mutants than in wild type animals. Our results demonstrate the existence of a perilipin-related regulation of fat metabolism in nematodes and provide new possibilities for functional studies of lipid metabolism.