Quantitative increases of extracellular vesicles in prolonged cold storage of platelets increases the potential to enhance fibrin clot formation.

BACKGROUND: Platelet derived extracellular vesicles (EVs) display a pro-coagulant phenotype and are generated throughout platelet concentrate (PC) storage. Cold storage (CS) of PCs is thought to provide a superior haemostatic advantage over room temperature (RT) storage and could prolong the storage time. However, the effect of storage conditions on EV generation and PC function is unknown. We investigated EV production under CS and RT conditions and assessed whether these EVs exhibited a more pro-coagulant phenotype in model experiments. MATERIALS AND METHODS: Buffy-coat-derived PCs in a platelet additive solution (PAS) to plasma ratio of approximately 65:35 were stored at RT (22 ± 2°C) or CS (4 ± 2°C) for a prolonged storage duration of 20 days. Impedance aggregometry assessed platelet function. EVs were isolated throughout storage and quantified using nanoparticle tracking analysis. EVs were applied to a coagulation assay to assess the impact on fibrin clot formation and lysis. RESULTS: CS produced significantly larger EVs from day 4 onwards. EV concentration was significantly increased in CS compared to RT from day 15. EVs, regardless of storage, significantly reduced time to clot formation and maximum optical density measured compared to the no EV control. Clot formation was proportionate to the number of EV applied but was not statistically different across storage conditions when corrected for EV number. CONCLUSION: EVs in CS and RT units showed similar clot formation capacity. However, the higher number of larger EVs generated in CS compared to RT suggests PC units derived from CS conditions may overall exhibit a haemostatically superior capacity compared to RT storage.

Survey of New Zealand consumer attitudes to consumption of meat and meat alternatives.

This study examined consumers' consumption, motivations, and concerns regarding meat and meat alternatives by means of an online survey of 1061 New Zealand consumers and review of literature. Outcomes of the survey indicate New Zealanders are overwhelmingly omnivorous (93%), regard taste as the most important factor in their meat purchasing decision followed by price and freshness and consider environmental impact and social responsibility of less importance. Those surveyed indicated willingness to pay 17-24% more for food safety and sustainability related meat attributes. About half of respondents lowered their meat consumption the previous year, mainly red and processed meats, due to lack of affordability and health concerns. Although those surveyed showed high awareness about meat alternatives, their consumption level of the products was very low and more prevalent for female, younger and more educated individuals. Overall, the outlook for meat consumption and meat industry in New Zealand is positive and is likely to remain so for the foreseeable future.

International development of a patient-centered core outcome set for assessing health-related quality of life in metastatic breast cancer patients.

PURPOSE: For patients living with metastatic breast cancer (MBC), achieving best possible health-related quality of life, along with maximizing survival, is vital. Yet, we have no systemic way to determine if we achieve these goals. A Core Outcome Set (COS) that allows standardized measurement of outcomes important to patients, but also promotes discussing these outcomes during clinical encounters, is long overdue. METHODS: An international expert group (EG) of patient advocates, researchers, medical specialists, nurse specialists, and pharmaceutical industry representatives (n = 17) reviewed a list of relevant outcomes retrieved from the literature. A broader group (n = 141: patients/patient advocates (n = 45), health care professionals/researchers (n = 64), pharmaceutical industry representatives (n = 28), and health authority representatives (n = 4)) participated in a modified Delphi procedure, scoring the relevance of outcomes in two survey rounds. The EG finalized the COS in a consensus meeting. RESULTS: The final MBC COS includes 101 variables about: (1) health-related quality of life (HRQoL, n = 26) and adverse events (n = 24); (2) baseline patient characteristics (n = 9); and (3) clinical variables (n = 42). Many outcome that cover aspects of HRQoL relevant to MBC patients are included, e.g. daily functioning (including ability to work), psychosocial/emotional functioning, sexual functioning, and relationship with the medical team. CONCLUSION: The COS developed in this study contains important administrative data, clinical records, and clinician-reported measures that captures the impact of cancer. The COS is important for standardization of clinical research and implementation in daily practice and has received accreditation by the International Consortium for Health Outcomes Measurement (ICHOM).

Exploring Ductility in Dental Ceramics.

Two damage regimes-"brittle" and "ductile"-have been identified in the literature on ceramic grinding, machining, grit blasting, and wear. In the brittle regime, the damage mechanism is essentially crack formation, while in the ductile region, it is quasiplasticity. Onset of the brittle mode poses the greater threat to strength, so it becomes important to understand the mechanics of ductile-brittle thresholds in these materials. Controlled microcontact tests with a sharp indenter are employed to establish such thresholds for a suite of contemporary computer-aided design/computer-aided manufacturing dental ceramics. Plots of flexural strength S versus indentation load P show a steep decline beyond the threshold, consistent with well-established contact mechanics relations. Threshold dimensions occur on a scale of order 1 µm and contact load of order 1 N, values pertinent to practical grit finishing protocols. The ductile side of ceramic shaping is accessed by reducing grit sizes, applied loads, and depths of cut below critical levels. It is advocated that critical conditions for ductile shaping may be most readily quantified on analogous S(P) plots, but with appropriate machining variable (grit size, depths of cut, infeed rate) replacing load P. Working in the ductile region offers the promise of compelling time and cost economies in prosthesis fabrication and preparation.

Priority recommendations for the implementation of patient-reported outcomes in clinical cancer care: a Delphi study.

PURPOSE: The aim of this study was to develop priority recommendations for the service level implementation of patient-reported outcomes (PROs) into clinical cancer care. METHODS: Development of draft guidance statements was informed by a literature review, the Knowledge to Action (KTA) implementation framework, and discussion with PRO experts and cancer survivors. A two-round modified Delphi survey with key stakeholders including cancer survivors, clinical and research experts, and Information Technology specialists was undertaken. Round 1 rated the importance of the statements and round 2 ranked statements in order of priority. RESULTS: Round 1 was completed by 70 participants with round 2 completed by 45 participants. Forty-seven statements were rated in round 2. In round 1, the highest agreement items (>90% agreement) included those that focused on the formation of strong stakeholder partnerships, ensuring ongoing communication within these partnerships, and the use of PROs for improvement and guidance in clinical care. Items ranked as the highest priorities in round 2 included assessment of current staff capabilities and service requirements, mapping of workflows and processes to enable collection, and using collected PROs to guide improved health outcomes. CONCLUSIONS: This stakeholder consultation process has identified key priorities in PRO implementation into clinical cancer care that include clinical relevance, stakeholder engagement, communication, and integration within the existing processes and capabilities. IMPLICATION FOR CANCER SURVIVORS: Routine adoption of PRO collection by clinical cancer services requires multiple implementation steps; of highest priority is strong engagement and communication with key stakeholders including cancer survivors.

Stabilisation of AO OTA 31-A unstable proximal femoral fractures: Does the choice of intramedullary nail affect the incidence of post-operative complications? A systematic literature review and meta-analysis.

OBJECTIVE: To determine if there was a difference in the risk of post-operative complications associated with the use of different intramedullary (IM) devices in the treatment of unstable AO OTA 31-A trochanteric fractures. DESIGN: Systematic literature review and meta-analysis. METHODS: A systematic literature review was carried out in January 2022 in the Embase, MEDLINE and Cochrane databases. Studies comparing INTERTAN™ to other intramedullary nails for the treatment of AO OTA 31-A trochanteric fractures were selected for inclusion. After data extraction, meta-analyses were carried out on postoperative outcomes, with specific focus placed on unstable fracture patterns. RESULTS: Twenty-three studies were suitable for inclusion, of which seventeen reported on outcomes in unstable fractures. INTERTAN reduced the risk of revision/reoperation by 64% (RR 0.36, 95% CI 0.25 to 0.54, p <0.0001), implant failures by 62% (RR 0.38, 95% CI 0.25 to 0.57, p<0.0001) and hip and thigh pain by 50% (RR 0.50, 95% CI 0.35 to 0.71, p=0.0001) in unstable fractures. No differences were noted between IM nail designs for infection rates, healing time, non-union rates, femoral shortening, or Harris Hip Score. CONCLUSIONS: The INTERTAN IM nail may reduce incidence of implant-related complications, hip and thigh pain, and the need for revision/reoperation without compromising clinical and functional outcomes.

The implementation of a decision aid for women with early-stage breast cancer considering contralateral prophylactic mastectomy: A pilot study.

OBJECTIVE: Despite little survival benefit and potential for harm, contralateral prophylactic mastectomy (CPM) rates are increasing amongst early-stage breast cancer patients at low contralateral breast cancer risk. We developed a CPM decision aid (DA) and conducted a pilot implementation. METHODS: Surgeons and oncologists recruited eligible patients considering CPM. Consenting patients received the DA, completed a questionnaire and participated in a semi-structured interview. Clinicians were interviewed at study close. RESULTS: Eleven clinicians and 31 patients participated. Three themes emerged: perceived utility and impact of the DA, disagreement regarding timing of delivery and target population, and implementation strategies. Both women and clinicians found the DA valuable, indicating it confirmed rather than changed preferences. Women (all of whom raised CPM themselves), preferred offering the DA early in treatment discussions whilst clinicians favoured targeting women who enquired about CPM. CONCLUSION: A DA about CPM is feasible and acceptable, but questions remain about the role of DAs in these types of decisions where one option has limited medical benefit. PRACTICE IMPLICATIONS: Some women have a high need to make an informed choice about CPM. Tools to support this could include a DA with a clear recommendation against CPM and an explanation why.

Telemedicine and cystic fibrosis: Do we still need face-to-face clinics?

There has been growing interest in telemedicine for cystic fibrosis over recent years based largely on convenience for patients and/or increasing the frequency of surveillance and early detection which, it is assumed, could improve treatment outcomes. During 2020, the covid-19 pandemic catalysed the pace of development of this field, as CF patients were presumed to be at high risk of infection. Most clinics adapted to digital platforms with provision of lung function monitoring and sample collection systems. Here, we present the views of multidisciplinary team members at a large paediatric CF centre on what has worked well and what requires further optimisation in the future. In response to the question posed, 'Do we still need face to face clinics?' our answer is 'Yes, but not every time, and not for everyone'.

Guiding the rational design of patient-centred drug trials in Cystic Fibrosis: A Delphi study.

BACKGROUND: Making trials more patient-centred improves recruitment and retention, patient satisfaction and makes research accessible to a more representative population. We aimed to understand the factors that influence participation and engagement in clinical trials in cystic fibrosis (CF) trials to guide the rational design and delivery of patient-centred trials. METHODS: We used a Delphi process, supported by extensive literature review and 3 workshops, to determine which factors stakeholders think exert significant influence in participation and engagement in CF trials. Panellists were recruited from across the UK and the study was administered online. RESULTS: We had representation from 19 CF centres; 28 people with CF (pwCF), 26 parents and 30 healthcare professionals (HCPs). Panels were presented with a shortlist of 104 factors and asked which they thought influence participation and engagement in CF trials. After 3 iterations, 43 statements met consensus for pwCF, 48 for the parents and 69 for the HCPs. CONCLUSIONS: We identified many targets to make trials more patient-centred. Whilst some require an overhaul of trial delivery, many are relatively easy to implement. We outline a list of 'dos and don'ts' for sponsors and research teams including: focus on good communication; recognise that lack of time is the greatest barrier to trial participation so minimise the frequency and length of visits; help participants fit trials around busy lives; remember trial participation can be a major life-event and support participants accordingly; and don't underestimate the impact of simple strategies e.g. on-site access to Wifi and cups of tea.

Cost-effectiveness of radioguided occult lesion localization using 125I seeds versus hookwire localization before breast-conserving surgery for non-palpable breast cancer.

BACKGROUND: The aim was to determine the cost-effectiveness of radioguided occult lesion localization using 125I-labelled seeds (125I seeds) versus hookwire localization in terms of incremental cost per reoperation avoided for women with non-palpable breast cancer undergoing breast-conserving surgery. METHODS: This study was based on a multicentre RCT with eight study sites comprising seven public hospitals and one private hospital. An Australian public health system perspective was taken. The primary effectiveness outcome for this study was reoperations avoided. Cost-effectiveness was expressed as an incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were used to explore uncertainty. The willingness to pay (additional cost of localization using 125I seeds justified by reoperation cost avoided) was set at the weighted, top-down cost of reoperation. Costs were in 2019 Australian dollars ($1 was equivalent to €0.62). RESULTS: The reoperation rate was 13.9 (95 per cent confidence interval 10.7 to 18.0) per cent for the 125I seed group and 18.9 (14.8 to 23.8) per cent for the hookwire localization group. The ICER for 125I seed versus hookwire localization was $4474 per reoperation averted. The results were most sensitive to uncertainty around the probability of reoperation. Accounting for transition probability and cost uncertainty for 125I seed localization, there was a 77 per cent probability that using 125I seeds would be cost-effective, with a willingness to pay of $7693 per reoperation averted. CONCLUSION: Radioguided occult lesion localization using 125I seeds is likely to be cost-effective, because the marginal (additional) cost compared with hookwire localization is less than the cost of reoperations avoided.

Surgical outcomes after radioactive 125I seed versus hookwire localization of non-palpable breast cancer: a multicentre randomized clinical trial.

BACKGROUND: Previous studies have suggested improved efficiency and patient outcomes with 125I seed compared with hookwire localization (HWL) in breast-conserving surgery, but high-level evidence of superior surgical outcomes is lacking. The aim of this multicentre pragmatic RCT was to compare re-excision and positive margin rates after localization using 125I seed or hookwire in women with non-palpable breast cancer. METHODS: Between September 2013 and March 2018, women with non-palpable breast cancer eligible for breast-conserving surgery were assigned randomly to preoperative localization using 125I seeds or hookwires. Randomization was stratified by lesion type (pure ductal carcinoma in situ (DCIS) or other) and study site. Primary endpoints were rates of re-excision and margin positivity. Secondary endpoints were resection volumes and weights. RESULTS: A total of 690 women were randomized at eight sites; 659 women remained after withdrawal (125I seed, 327; HWL, 332). Mean age was 60.3 years in the 125I seed group and 60.7 years in the HWL group, with no difference between the groups in preoperative lesion size (mean 13.2 mm). Lesions were pure DCIS in 25.9 per cent. The most common radiological lesion types were masses (46.9 per cent) and calcifications (28.2 per cent). The localization modality was ultrasonography in 65.5 per cent and mammography in 33.7 per cent. The re-excision rate after 125I seed localization was significantly lower than for HWL (13.9 versus 18.9 per cent respectively; P = 0.019). There were no significant differences in positive margin rates, or in specimen weights and volumes. CONCLUSION: Re-excision rates after breast-conserving surgery were significantly lower after 125I seed localization compared with HWL. Registration number: ACTRN12613000655741 (http://www.ANZCTR.org.au/).

Single-use negative-pressure wound therapy versus conventional dressings for closed surgical incisions: systematic literature review and meta-analysis.

BACKGROUND: Surgical-site complications (SSCs) remain a significant cause of morbidity and mortality, particularly in high-risk patients. The aim of this study was to determine whether prophylactic use of a specific single-use negative-pressure wound therapy (sNPWT) device reduced the incidence of SSCs after closed surgical incisions compared with conventional dressings. METHODS: A systematic literature review was performed using MEDLINE, Embase and the Cochrane Library to identify articles published from January 2011 to August 2018. RCTs and observational studies comparing PICO™ sNPWT with conventional dressings, with at least 10 patients in each treatment arm, were included. Meta-analyses were performed to determine odds ratios (ORs) or mean differences (MDs), as appropriate. PRISMA guidelines were followed. The primary outcome was surgical-site infection (SSI). Secondary outcomes were other SSCs and hospital efficiencies. Risk of bias was assessed. RESULTS: Of 6197 citations screened, 29 studies enrolling 5614 patients were included in the review; all studies included patients with risk factors for SSCs. sNPWT reduced the number of SSIs (OR 0.37, 95 per cent c.i. 0.28 to 0.50; number needed to treat (NNT) 20). sNPWT reduced the odds of wound dehiscence (OR 0.70, 0.53 to 0.92; NNT 26), seroma (OR 0.23, 0.11 to 0.45; NNT 13) and necrosis (OR 0.11, 0.03 to 0.39; NNT 12). Mean length of hospital stay was shorter in patients who underwent sNPWT (MD -1.75, 95 per cent c.i. -2.69 to -0.81). CONCLUSION: Use of the sNPWT device in patients with risk factors reduced the incidence of SSCs and the mean length of hospital stay.

Anharmonic Origin of the Giant Thermal Expansion of NaBr.

All phonons in a single crystal of NaBr are measured by inelastic neutron scattering at temperatures of 10, 300, and 700 K. Even at 300 K, the phonons, especially the longitudinal-optical phonons, show large shifts in frequencies and show large broadenings in energy owing to anharmonicity. Ab initio computations are first performed with the quasiharmonic approximation (QHA) in which the phonon frequencies depend only on V and on T only insofar as it alters V by thermal expansion. This QHA is an unqualified failure for predicting the temperature dependence of phonon frequencies, even 300 K, and the thermal expansion is in error by a factor of 4. Ab initio computations that include both anharmonicity and quasiharmonicity successfully predict both the temperature dependence of phonons and the large thermal expansion of NaBr. The frequencies of longitudinal-optical phonon modes decrease significantly with temperature owing to the real part of the phonon self-energy from explicit anharmonicity originating from the cubic anharmonicity of nearest-neighbor NaBr bonds. Anharmonicity is not a correction to the QHA predictions of thermal expansion and thermal phonon shifts but dominates the behavior.

Correction: External validation of risk prediction models for incident colorectal cancer using UK Biobank.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement.

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

Malnutrition associated with nutrition impact symptoms and localization of the disease: Results of a multicentric research on oncological nutrition.

BACKGROUND & AIMS: Malnutrition in cancer is an independent factor associated with negative clinical outcomes. The aim was to evaluate the prevalence and independent risk factors for malnutrition in hospitalized cancer patients using the Patient-Generated Subjective Global Assessment (PG-SGA). METHODS: We evaluated 4783 cancer patients, aged ≥20 years, in a hospital-based, multicenter, cross-sectional study. Patients were classified as well-nourished (PG-SGA Stage A), moderate/suspected malnutrition (PG-SGA Stage B), or severely malnourished (PG-SGA Stage C), and provided a score to define required nutritional interventions. Multivariate analysis was composed of the odds ratio (OR) estimated by ordinal polytomous logistic regression. RESULTS: 45.3% were classified as Stage B and 11.8% as Stage C. Moreover, 45.3% of the patients presented a need for nutritional intervention. The variables that presented the highest ORs for Stage B or Stage C were: problems with swallowing (OR 2.8, 95% confidence interval (CI) 2.2-3.4, p < 0.001), loss of appetite (OR 1.9, 95% CI 1.6-2.3, p < 0.001), vomiting (OR 1.8, 95% CI 1.5-2.3, p < 0.001), presence of more than 3 nutrition impact symptoms (OR 8.3, 95% CI 5.8-12, p < 0.001), and cancer site: lung (OR 4.6, 95% CI 3.2-6.6, p < 0.001), upper digestive cancer (OR 3.7, 95% CI 2.7-5.2, p < 0.001), and head and neck cancer (OR 3.7, 95% CI 2.7-5.2, p < 0.001). The score for Worksheet 4 on the PG-SGA had a higher association with malnutrition (OR 7.3, 95% CI 6.6-8.2, p < 0.001). CONCLUSIONS: Malnutrition is highly prevalent in cancer patients in Brazil, and is associated with nutritional impact symptoms, cancer site and age ≥65 years.

Systematic review of the impact of breast-conserving surgery on cancer outcomes of multiple ipsilateral breast cancers.

BACKGROUND: The clinical effectiveness of treating ipsilateral multifocal (MF) and multicentric (MC) breast cancers using breast-conserving surgery (BCS) compared with the standard of mastectomy is uncertain. Inconsistencies relate to definitions, incidence, staging and intertumoral heterogeneity. The primary aim of this systematic review was to compare clinical outcomes after BCS versus mastectomy for MF and MC cancers, collectively defined as multiple ipsilateral breast cancers (MIBC). METHODS: Comprehensive electronic searches were undertaken to identify complete papers published in English between May 1988 and July 2015, primarily comparing clinical outcomes of BCS and mastectomy for MIBC. All study designs were included, and studies were appraised critically using the Newcastle-Ottawa Scale. The characteristics and results of identified studies were summarized. RESULTS: Twenty-four retrospective studies were included in the review: 17 comparative studies and seven case series. They included 3537 women with MIBC undergoing BCS; breast cancers were defined as MF in 2677 women, MC in 292, and reported as MIBC in 568. Six studies evaluated MIBC treated by BCS or mastectomy, with locoregional recurrence (LRR) rates of 2-23 per cent after BCS at median follow-up of 59·5 (i.q.r. 56-81) months. BCS and mastectomy showed apparently equivalent rates of LRR (risk ratio 0·94, 95 per cent c.i. 0·65 to 1·36). Thirteen studies compared BCS in women with MIBC versus those with unifocal cancers, reporting LRR rates of 2-40 per cent after BCS at a median follow-up of 64 (i.q.r. 57-73) months. One high-quality study reported 10-year actuarial LRR rates of 5·5 per cent for BCS in 300 women versus 6·5 per cent for mastectomy among 887 women. CONCLUSION: The available studies were mainly of moderate quality, historical and underpowered, with limited follow-up and biased case selection favouring BCS rather than mastectomy for low-risk patients. The evidence was inconclusive, weakening support for the St Gallen consensus and supporting a future randomized trial.

Genetic characterisation of molecular targets in carcinoma of unknown primary.

BACKGROUND: Carcinoma of unknown primary (CUP) is a metastatic epithelial malignancy in the absence of an identifiable primary tumour. Prognosis for patients with CUP is poor because treatment options are generally limited to broad spectrum chemotherapy. A shift towards personalised cancer management based on mutation profiling offers the possibility of new treatment paradigms. This study has explored whether actionable, oncogenic driver mutations are present in CUP that have potential to better inform treatment decisions. METHODS: Carcinoma of unknown primary cases (n = 21) were selected and DNA was isolated from formalin-fixed paraffin embedded sections prior to amplification and sequencing. Two distinct yet complementary targeted gene panels were used to assess variants in up to 76 known cancer-related genes for the identification of biologically relevant and actionable mutations. RESULTS: Variants were detected in 17/21 cases (81%) of which 11 (52%) were potentially actionable with drugs currently approved for use in known primary cancer types or undergoing clinical trials. The most common variants detected were in TP53 (47%), KRAS (12%), MET (12%) and MYC (12%). Differences at the molecular level were seen between common CUP histological subtypes. CUP adenocarcinomas and poorly differentiated carcinomas harboured the highest frequency of variants in genes involved in signal transduction pathways (e.g. MET, EGFR, HRAS, KRAS, and BRAF). In contrast, squamous cell carcinoma exhibited a higher frequency of variants in cell cycle control and DNA repair genes (e.g. TP53, CDKN2A and MLH1). CONCLUSION: Taken together, mutations in biologically relevant genes were detected in the vast majority of CUP tumours, of which half provided a potentially novel treatment option not generally considered in CUP.

Correction to: Incidental diagnosis of tuberous sclerosis complex by exome sequencing in three families with subclinical findings.

The published online version contain mistake in the author list. Instead of "A.M.Ilyas" it should have been "M.Ilyas ".