Exome and immune cell score analyses reveal great variation within synchronous primary colorectal cancers

BACKGROUND: Approximately 4% of colorectal cancer (CRC) patients have at least two simultaneous cancers in the colon. Due to the shared environment, these synchronous CRCs (SCRCs) provide a unique setting to study colorectal carcinogenesis. Understanding whether these tumours are genetically similar or distinct is essential when designing therapeutic approaches. METHODS: We performed exome sequencing of 47 primary cancers and corresponding normal samples from 23 patients. Additionally, we carried out a comprehensive mutational signature analysis to assess whether tumours had undergone similar mutational processes and the first immune cell score analysis (IS) of SCRC to analyse the interplay between immune cell invasion and mutation profile in both lesions of an individual. RESULTS: The tumour pairs shared only few mutations, favouring different mutations in known CRC genes and signalling pathways and displayed variation in their signature content. Two tumour pairs had discordant mismatch repair statuses. In majority of the pairs, IS varied between primaries. Differences were not explained by any clinicopathological variable or mutation burden. CONCLUSIONS: The study shows major diversity within SCRCs. Rather than rely on data from one tumour, our study highlights the need to evaluate both tumours of a synchronous pair for optimised targeted therapy.Peer reviewe

Exome-wide somatic mutation characterization of small bowel adenocarcinoma

Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003-2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify driver genes from the exome data. We also defined frequently affected cancer signalling pathways and performed the first extensive allelic imbalance (Al) analysis in SBA. Exome data analysis revealed significantly mutated genes previously linked to SBA (TP53, KRAS, APC, SMAD4, and BRAF), recently reported potential driver genes (SOX9, ATM, and ARID2), as well as novel candidate driver genes, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We also identified clear mutation hotspot patterns in ERBB2 and BRAF. No BRAF V600E mutations were observed. Additionally, we present a comprehensive mutation signature analysis of SBA, highlighting established signatures 1A, 6, and 17, as well as U2 which is a previously unvalidated signature. Finally, comparison of the three small bowel segments revealed differences in tumor characteristics. This comprehensive work unveils the mutational landscape and most frequently affected genes and pathways in SBA, providing potential therapeutic targets, and novel and more thorough insights into the genetic background of this tumor type.Peer reviewe

Using high-flow nasal cannulas for infants with bronchiolitis admitted to paediatric wards is safe and feasible

Abstract Aim: Using a high‐flow nasal cannula (HFNC) for infant bronchiolitis is increasingly common, but insufficiently studied. In this retrospective study, we examined the outcomes of HFNC and compared infants who did and did not respond to this oxygen delivery method. Methods: This 2012–2015 study of six Finnish hospitals focused on 88 infants under 12 months who received HFNC: 53 on paediatric wards and 35 in paediatric intensive care units (PICUs). We reviewed patient files for underlying factors, clinical parameters and HFNC treatment. The treatment failed if the patient was transferred to another respiratory support. Results: We found HFNC treatment was successful in 76 (86%) infants, including all 53 on the paediatric wards and 23/35 PICU patients. The responders’ heart rates were significantly lower, and their oxygen saturation was significantly higher at 60 minutes after HFNC treatment started and then stayed relatively constant. Their respiratory rate was only significantly lower after 360 minutes. In non‐responders, the respiratory rate initially decreased but was higher at 180 and 360 minutes after the start of HFNC. Conclusion: We found preliminary evidence that oxygen support needs and heart rate were useful early predictors of HFNC therapy success in infants hospitalised with bronchiolitis, but respiratory rate was not

Overview of AI events in SBA.

<p>Frequency of gains and losses in 106 SBA samples.</p

Mutational landscape of the most significant genes in MSS SBAs.

<p>The figure includes the 25 highest-ranking genes in MSS tumors (n = 91) according to OncodriveFML, ranked by the <i>P</i>-value (right, red line at <i>P</i> = 0.05). Of these, <i>TP53</i>, <i>KRAS</i>, <i>APC</i>, <i>SOX9</i>, <i>SMAD4</i>, <i>BRAF</i>, and <i>ACVR2A</i> were significant also after correction for multiple testing. Different colors distinguish between the different types of mutations (in the middle). “Double hit” refers to two truncating mutations. The percentage of mutated tumors by gene are shown on the left. The upper bars represent the total number of both synonymous and non-synonymous mutations per tumor.</p

Clinicopathologic features of the patient cohort.

<p>Clinicopathologic features of the patient cohort.</p

Mutation pattern in ERBB receptor family.

<p>Mutations in <i>ERBB2</i> (ENST00000269571) grouped into four hotspots (top). Samples (n = 29) with a mutated member of ERBB receptor family are presented in columns (below). In addition to a hotspot mutation, some samples displayed simultaneously a non-hotspot mutation in the same gene, thus all mutations are not shown in the figure. Recep_L = Receptor L domain; Furin-like = Furin-like cysteine rich region; GF_recep = Growth factor receptor domain; Pkinase_Tyr = Protein tyrosine kinase.</p

Mutations in <i>BRAF</i> (ENST00000288602).

<p>In total, 12 mutations were identified in 11 tumors (MSS n = 10, MSI n = 1). RBD = Raf-like Ras-binding domain; C1_1 = C1 domain; Pkinase_Tyr = Protein tyrosine kinase.</p

Signature contexts.

<p>The 15 MSI tumors displayed signature 6. There were three signatures (1A, 17, and U2) that could be extracted from the 91 MSS tumors.</p

Video-assisted surgery : suggestions for failure prevention in laparoscopic cholecystectomy

Background: Surgery differs from other medical specialties in its execution. It is often complex and includes considerable individual variations. Observing problems in operating theatres (OT) allows for the identification of system failures which should be defined for learning purposes to increase patient safety and enhance general safety culture within hospital organizations. This study evaluates a common video-assisted surgical procedure, laparoscopic cholecystectomy (LC) through failure analysis. The profile of the LC procedure and failure sources is presented. Methods: Data consisted video-observations and interviews concerning twelve LC operations performed at a day surgery unit. All operations were teaching sessions. Qualitative analysis was undertaken. Through task analysis, specialist interviews and failure identification a failure profile of LC was produced. Results: Twenty failure types were identified, failures were for example: remote attention towards ergonomics; novice’s skill failures; inadequate supervision and unnecessary risk taking caused by tight operating schedules. The results showed that the importance of working principles should be emphasized. The failure profile of LC revealed three phases featuring multiple failures: dissecting the peritoneal covering; identifying, sealing and cutting the cystic duct and cystic artery; detaching the gallbladder from the hepatic bed and inspecting the hepatic bed. Conclusions: This study offers information for hospital organizations about the current state of surgical work and surgical skills learning. This information could be exploited in the development of system defences: error prevention mechanisms through investing in the redesign of work tasks and working methods; as well as reinforcing education and training for enhancing patient safety in OT.peerReviewe