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Background Recent studies of cortical pathology in secondary progressive multiple sclerosis have shown that a more severe clinical course and the presence of extended subpial grey matter lesions with significant neuronal/glial loss and microglial activation are associated with meningeal inflammation, including the presence of lymphoid-like structures in the subarachnoid space in a proportion of cases. Methods To investigate the molecular consequences of pro-inflammatory and cytotoxic molecules diffusing from the meninges into the underlying grey matter, we carried out gene expression profiling analysis of the motor cortex from 20 post-mortem multiple sclerosis brains with and without substantial meningeal inflammation and 10 non-neurological controls. Results Gene expression profiling of grey matter lesions and normal appearing grey matter not only confirmed the substantial pathological cell changes, which were greatest in multiple sclerosis cases with increased meningeal inflammation, but also demonstrated the upregulation of multiple genes/pathways associated with the inflammatory response. In particular, genes involved in tumour necrosis factor (TNF) signalling were significantly deregulated in MS cases compared with controls. Increased meningeal inflammation was found to be associated with a shift in the balance of TNF signalling away from TNFR1/TNFR2 and NFkB-mediated anti-apoptotic pathways towards TNFR1- and RIPK3-mediated pro-apoptotic/pro-necroptotic signalling in the grey matter, which was confirmed by RT-PCR analysis. TNFR1 was found expressed preferentially on neurons and oligodendrocytes in MS cortical grey matter, whereas TNFR2 was predominantly expressed by astrocytes and microglia. Conclusions We suggest that the inflammatory milieu generated in the subarachnoid space of the multiple sclerosis meninges by infiltrating immune cells leads to increased demyelinating and neurodegenerative pathology in the underlying grey matter due to changes in the balance of TNF signalling.

Ianalumab plus ibrutinib for CLL A phase 1b, dose-escalation and expansion trial of ianalumab plus ibrutinib in patients with chronic lymphocytic leukaemia who did not achieve a complete response with ibrutinib was done by Kerry Anne Rogers (The Ohio State University College of Medicine, Columbus, OH, USA) and colleagues. Three patients achieved a best overall response of partial response; the overall response rate was 12% and disease control rate was 71%. Cheryl Reeves Petosemtamab in head and neck squamous cell cancer Ezra E W Cohen (Moores Cancer Center, San Diego, CA, USA) presented the expansion part of a phase 1–2 study in 49 patients with head and neck squamous cell carcinoma treated with the recommended phase 2 dose of intravenous petosemtamab (1500 mg every 2 weeks). Salmonella-IL2 in pancreatic cancer Daniel A Saltzman (Jewish General Hospital and McGill University, Montreal, QC, Canada) presented the results of a non-randomised, phase 2, two-arm study in patients with stage IV metastatic pancreatic cancer. 20 patients received Salmonella-IL2 (an attenuated strain of orally administered Salmonella that carries the human gene for IL-2, which colonises the tumour microenvironment and locally releases IL-2; 109 colony-forming units after ingestion of a gastric acid neutralising agent followed by 200 mL of an isotonic crystalloid fluid every 2 weeks) plus FOLFIRINOX.

Entinostat plus exemestane for hormone receptor-positive, HER2-negative breast cancer Entinostat, a class I selective histone deacetylase inhibitor, in combination with the aromatase inhibitor exemestane offers clinical benefit to women with hormone receptor-positive, HER2-negative breast cancer, according to Binghe Xu (Cancer Hospital Chinese Academy of Medical Sciences, Beijing, China). EMERALD phase 3 trial Men and postmenopausal women with hormone receptor-positive, HER2-negative advanced metastatic breast cancer received either elacestrant (400 mg orally daily) or investigator's choice of fulvestrant or an aromatase inhibitor in the multicentre, randomised, open-label, phase 3 EMERALD trial. PADA-1 crossover trial The multicentre, randomised, open-label, phase 3 PADA-1 trial evaluated the clinical benefit of a switch from aromatase inhibitor–palbociclib to from aromatase inhibitor–palbociclib to fulvestrant–palbociclib for patients with hormone receptor-positive, HER2-negative metastatic breast cancer with no previous therapy and no aromatase inhibitor resistance, at the onset of a ESR1 mutation detected in blood.

The results showed a significant improvement in the pathological complete response (co-primary endpoint) in patients with resectable NSCLC treated with neoadjuvant nivolumab (360 mg; n=179) plus platinum-doublet chemotherapy every 3 weeks (24·0%) versus chemotherapy alone (n=179; 2·2%; odds ratio 13·94, 99% CI 3·49–55·75; p<0·0001). Lipika Goyal (Massachusetts General Hospital Cancer Center, Boston, MA, USA) showed that this study met the primary endpoint with an objective response rate of 41·7% (43/103; 95% CI 32·1–51·9) for patients with intrahepatic cholangiocarcinoma with FGFR2 fusions or rearrangements. Dabrafenib plus trametinib in high and low grade glioma Vivek Subbiah (MD Anderson Cancer Center, Houston, TX, USA) presented the results from a non-randomised, open-label, phase 2 study of oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) in adult patients with BRAFV600E mutation-positive high-grade or low-grade glioma.

Projections by the International Agency for Research on Cancer predict a substantial increase in cancer incidence and mortality in the region over the next two decades. Sustained international attention and coordinated intervention is urgently required to improve the living conditions and overall health outcomes for this marginalised population. Barriers to effective health care need to be overcome to ensure effective cancer diagnosis and treatment, ultimately leading to improved health outcomes regardless of geographical location.

Doublecortin (DCX) is widely regarded as a marker of immature and migrating neurons during development. While DCX expression persists in adults, particularly in the temporal lobe and neurogenic regions, it is unknown how seizures influence its expression. The aim of the present study was to explore the distribution and characteristics of DCX-expressing cells in surgical and postmortem samples from 40 adult and paediatric patients, with epilepsy and with or without hippocampal sclerosis (HS), compared to post mortem controls. The hippocampus (pes and body), parahippocampal gyrus, amygdala, temporal pole and temporal cortex were examined with DCX immunohistochemistry using four commercially-available DCX antibodies, labelled cells were quantified in different regions of interest as well as their co-expression with cell type specific markers (CD68, Iba1, GFAP, GFAP∂, nestin, SOX2, CD34, OLIG2, PDGFRβ, NeuN) and cell cycle marker (MCM2). Histological findings were compared with clinical data, as well as gene expression data obtained from the temporal cortex of 83 temporal lobe epilepsy cases with HS. DCX immunohistochemistry identified immature (Nestin − /NeuN − ) neurons in layer II of the temporal neocortex in patients with and without epilepsy. Their number declined significantly with age but was not associated with the presence of hippocampal sclerosis, seizure semiology or memory dysfunction. DCX + cells were prominent in the paralaminar nuclei and periamygdalar cortex and these declined with age but were not significantly associated with epilepsy history. DCX expressing cells with ramified processes were prominent in all regions, particularly in the hippocampal subgranular zone, where significantly increased numbers were observed in epilepsy samples compared to controls. DCX ramified cells co-expressed Iba1, CD68 and PDGFRβ, and less frequently MCM2, OLIG2 and SOX2, but no co-localization was observed with CD34, nestin or GFAP/GFAP ∂. Gene expression data from neocortical samples in patients with TLE and HS supported ongoing DCX expression in adults. We conclude that DCX identifies a range of morphological cell types in temporal lobe epilepsy, including immature populations, glial and microglial cell types. Their clinical relevance and biological function requires further study but we show some evidence for alteration with age and in epilepsy.

In 2011, inspired by the people she met during her travels, and the specific challenges faced by people in low-income and middle-income countries (LMICs), such as inadequate health-care infrastructure, poor access to screening and treatment, and the lack of education and support, amongst several other factors that severely influence cancer care and outcomes—factors that people in high-income settings often take for granted—Carolyn founded Global Focus on Cancer (GFC). GFC implements patient-centred programmes driven by local organisations, helping them connect with global cancer resources and integrate them into national health strategies. Since its inception, GFC has fostered partnerships among doctors, hospitals, cancer organisations, local support networks, advocacy groups, non-governmental organisations, and US companies, building international alliances and advocating for supportive policies at many levels. GFC, along with Taylor as its Founder and Executive Director, has a universal vision of a future in which all people have access to health services that are coordinated around their needs, respects their preferences, and provide safe, timely, and affordable care.

BIONIKK trial in kidney cancer Assessment of molecular groups based on distinct gene signatures can guide therapy in first-line treatment of metastatic clear cell renal cell carcinoma, according to data from the phase 2 BIONIKK trial presented by Yann Vano (Université de Paris, Paris, France). KEYNOTE-590 trial results The international, double-blind, KEYNOTE-590 trial, presented by Ken Kato (National Cancer Centre Hospital, Tokyo, Japan) showed that pembrolizumab and chemotherapy improves survival outcomes in untreated patients with locally advanced, unresectable, or metastatic adenocarcinoma or oesophageal squamous cell carcinoma compared with chemotherapy alone. 749 patients were randomly assigned (1:1) to pembrolizumab (200 mg every 3 weeks) plus chemotherapy (cisplatin 80 mg/m2 on day 1 every 3 weeks plus fluorouracil 800 mg/m2 on days 1–5 every 3 weeks) or chemotherapy alone. Ipatasertib for prostate cancer In the phase 3 IPATential150 trial, Johann de Bono (Institute of Cancer Research and Royal Marsden Hospital, London, UK) and colleagues investigated the addition of ipatesertib to standard treatment for metastatic castration-resistant prostate cancer. 1101 patients were randomly assigned (1:1) to receive either ipatesertib (400 mg/day) or placebo, combined with abiraterone (1000 mg/day) and prednisone (5 mg twice daily).

The field of Cardiology has seen increased information concerning cardiac-related genetic conditions, primarily regarding structural and rhythm cardiac anomalies, and inherited cardiac disease. Genetic counselors as the logical purveyors of this genetic information can be a valuable resource to cardiologists in interpreting this information for patients and their families. This study surveyed genetic counselors that see patients for cardiology-related referrals about their practices and the conditions they see, as well as medical examiners concerning their frequency of use of genetic tests, for post-mortem diagnosis in cases of sudden cardiac death and their opinions of the utility of post-mortem genetic testing to benefit surviving family members. Prospective survey participants were genetic counselors and medical examiners; 211 genetic counselors and 52 medical examiners completed an online survey. The survey results suggest that genetic counselors are seeing an increase in cardiology-related referrals, and while the proportion of genetic counselors engaged in cardiology teams is small, those who are feel that they are valued members of the team. A majority of medical examiners surveyed reported they have either recommended cases for genetic testing or feel that genetic testing could be useful in establishing a diagnosis in unexplained deaths. Overall, respondents reported that genetics may influence the field of cardiology in a numbers of way in the future, primarily in the areas of increasing genotype-phenotype correlations, early detection of previously diagnosed conditions, and advances in treatments and management.