Spatial profiling of gastric cancer patient-matched primary and locoregional metastases reveals principles of tumour dissemination.

OBJECTIVE: Endoscopic mucosal biopsies of primary gastric cancers (GCs) are used to guide diagnosis, biomarker testing and treatment. Spatial intratumoural heterogeneity (ITH) may influence biopsy-derived information. We aimed to study ITH of primary GCs and matched lymph node metastasis (LNmet). DESIGN: GC resection samples were annotated to identify primary tumour superficial (PTsup), primary tumour deep (PTdeep) and LNmet subregions. For each subregion, we determined (1) transcriptomic profiles (NanoString 'PanCancer Progression Panel', 770 genes); (2) next-generation sequencing (NGS, 225 gastrointestinal cancer-related genes); (3) DNA copy number profiles by multiplex ligation-dependent probe amplification (MLPA, 16 genes); and (4) histomorphological phenotypes. RESULTS: NanoString profiling of 64 GCs revealed no differences between PTsup1 and PTsup2, while 43% of genes were differentially expressed between PTsup versus PTdeep and 38% in PTsup versus LNmet. Only 16% of genes were differently expressed between PTdeep and LNmet. Several genes with therapeutic potential (eg IGF1, PIK3CD and TGFB1) were overexpressed in LNmet and PTdeep compared with PTsup. NGS data revealed orthogonal support of NanoString results with 40% mutations present in PTdeep and/or LNmet, but not in PTsup. Conversely, only 6% of mutations were present in PTsup and were absent in PTdeep and LNmet. MLPA demonstrated significant ITH between subregions and progressive genomic changes from PTsup to PTdeep/LNmet. CONCLUSION: In GC, regional lymph node metastases are likely to originate from deeper subregions of the primary tumour. Future clinical trials of novel targeted therapies must consider assessment of deeper subregions of the primary tumour and/or metastases as several therapeutically relevant genes are only mutated, overexpressed or amplified in these regions

Adaptor Template Oligo-Mediated Sequencing (ATOM-Seq) is a new ultra-sensitive UMI-based NGS library preparation technology for use with cfDNA and cfRNA

Liquid biopsy testing utilising Next Generation Sequencing (NGS) is rapidly moving towards clinical adoption for personalised oncology. However, before NGS can fulfil its potential any novel testing approach must identify ways of reducing errors, allowing separation of true low-frequency mutations from procedural artefacts, and be designed to improve upon current technologies. Popular NGS technologies typically utilise two DNA capture approaches; PCR and ligation, which have known limitations and seem to have reached a development plateau with only small, stepwise improvements being made. To maximise the ultimate utility of liquid biopsy testing we have developed a highly versatile approach to NGS: Adaptor Template Oligo Mediated Sequencing (ATOM-Seq). ATOM-Seq's strengths and versatility avoid the major limitations of both PCR- and ligation-based approaches. This technology is ligation free, simple, efficient, flexible, and streamlined, and it offers novel advantages that make it perfectly suited for use on highly challenging clinical material. Using reference and clinical materials, we demonstrate detection of known SNVs down to allele frequencies of 0.1% using as little as 20–25 ng of cfDNA, as well as the ability to detect fusions from RNA. We illustrate ATOM-Seq’s suitability for clinical testing by showing high concordance rates between paired cfDNA and FFPE clinical samples

Effect of self-monitoring of blood pressure on blood pressure control in pregnant individuals with chronic or gestational hypertension: the BUMP 2 randomized clinical trial

Importance: inadequate management of elevated blood pressure is a significant contributing factor to maternal deaths. The role of blood pressure self-monitoring in pregnancy in improving clinical outcomes for the pregnant individual and infant is unclear. Objective: To evaluate the effect of blood pressure self-monitoring, compared with usual care alone, on blood pressure control and other related maternal and infant outcomes, in individuals with pregnancy hypertension. Design, setting, and participants: unblinded, randomized clinical trial that recruited between November 2018 and September 2019 in 15 hospital maternity units in England. Individuals with chronic hypertension (enrolled up to 37 weeks' gestation) or with gestational hypertension (enrolled between 20 and 37 weeks' gestation). Final follow-up was in May 2020. Interventions: Participants were randomized to either blood pressure self-monitoring using a validated monitor and a secure telemonitoring system in addition to usual care (n = 430) or to usual care alone (n = 420). Usual care comprised blood pressure measured by health care professionals at regular antenatal clinics. Main outcomes and measures: the primary maternal outcome was the difference in mean systolic blood pressure recorded by health care professionals between randomization and birth. Results: Among 454 participants with chronic hypertension (mean age, 36 years; mean gestation at entry, 20 weeks) and 396 with gestational hypertension (mean age, 34 years; mean gestation at entry, 33 weeks) who were randomized, primary outcome data were available from 444 (97.8%) and 377 (95.2%), respectively. In the chronic hypertension cohort, there was no statistically significant difference in mean systolic blood pressure for the self-monitoring groups vs the usual care group (133.8 mm Hg vs 133.6 mm Hg, respectively; adjusted mean difference, 0.03 mm Hg [95% CI, -1.73 to 1.79]). In the gestational hypertension cohort, there was also no significant difference in mean systolic blood pressure (137.6 mm Hg compared with 137.2 mm Hg; adjusted mean difference, -0.03 mm Hg [95% CI, -2.29 to 2.24]). There were 8 serious adverse events in the self-monitoring group (4 in each cohort) and 3 in the usual care group (2 in the chronic hypertension cohort and 1 in the gestational hypertension cohort). Conclusions andrelevance: among pregnant individuals with chronic or gestational hypertension, blood pressure self-monitoring with telemonitoring, compared with usual care, did not lead to significantly improved clinic-based blood pressure control. Trial Registration: ClinicalTrials.gov Identifier: NCT03334149.</p