Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): a large-scale, observational cohort study.

BACKGROUND: Analysis of circulating tumour DNA could stratify cancer risk in symptomatic patients. We aimed to evaluate the performance of a methylation-based multicancer early detection (MCED) diagnostic test in symptomatic patients referred from primary care. METHODS: We did a multicentre, prospective, observational study at National Health Service (NHS) hospital sites in England and Wales. Participants aged 18 or older referred with non-specific symptoms or symptoms potentially due to gynaecological, lung, or upper or lower gastrointestinal cancers were included and gave a blood sample when they attended for urgent investigation. Participants were excluded if they had a history of or had received treatment for an invasive or haematological malignancy diagnosed within the preceding 3 years, were taking cytotoxic or demethylating agents that might interfere with the test, or had participated in another study of a GRAIL MCED test. Patients were followed until diagnostic resolution or up to 9 months. Cell-free DNA was isolated and the MCED test performed blinded to the clinical outcome. MCED predictions were compared with the diagnosis obtained by standard care to establish the primary outcomes of overall positive and negative predictive value, sensitivity, and specificity. Outcomes were assessed in participants with a valid MCED test result and diagnostic resolution. SYMPLIFY is registered with ISRCTN (ISRCTN10226380) and has completed follow-up at all sites. FINDINGS: 6238 participants were recruited between July 7 and Nov 30, 2021, across 44 hospital sites. 387 were excluded due to staff being unable to draw blood, sample errors, participant withdrawal, or identification of ineligibility after enrolment. Of 5851 clinically evaluable participants, 376 had no MCED test result and 14 had no information as to final diagnosis, resulting in 5461 included in the final cohort for analysis with an evaluable MCED test result and diagnostic outcome (368 [6·7%] with a cancer diagnosis and 5093 [93·3%] without a cancer diagnosis). The median age of participants was 61·9 years (IQR 53·4-73·0), 3609 (66·1%) were female and 1852 (33·9%) were male. The MCED test detected a cancer signal in 323 cases, in whom 244 cancer was diagnosed, yielding a positive predictive value of 75·5% (95% CI 70·5-80·1), negative predictive value of 97·6% (97·1-98·0), sensitivity of 66·3% (61·2-71·1), and specificity of 98·4% (98·1-98·8). Sensitivity increased with increasing age and cancer stage, from 24·2% (95% CI 16·0-34·1) in stage I to 95·3% (88·5-98·7) in stage IV. For cases in which a cancer signal was detected among patients with cancer, the MCED test's prediction of the site of origin was accurate in 85·2% (95% CI 79·8-89·3) of cases. Sensitivity 80·4% (95% CI 66·1-90·6) and negative predictive value 99·1% (98·2-99·6) were highest for patients with symptoms mandating investigation for upper gastrointestinal cancer. INTERPRETATION: This first large-scale prospective evaluation of an MCED diagnostic test in a symptomatic population demonstrates the feasibility of using an MCED test to assist clinicians with decisions regarding urgency and route of referral from primary care. Our data provide the basis for a prospective, interventional study in patients presenting to primary care with non-specific signs and symptoms. FUNDING: GRAIL Bio UK.

Effective delivery of Complex Innovative Design (CID) cancer trials-A consensus statement.

The traditional cancer drug development pathway is increasingly being superseded by trials that address multiple clinical questions. These are collectively termed Complex Innovative Design (CID) trials. CID trials not only assess the safety and toxicity of novel anticancer medicines but also their efficacy in biomarker-selected patients, specific cancer cohorts or in combination with other agents. They can be adapted to include new cohorts and test additional agents within a single protocol. Whilst CID trials can speed up the traditional route to drug licencing, they can be challenging to design, conduct and interpret. The Experimental Cancer Medicine Centres (ECMC) network, funded by the National Institute for Health Research (NIHR), Cancer Research UK (CRUK) and the Health Boards of Wales, Northern Ireland and Scotland, formed a working group with relevant stakeholders from clinical trials units, the pharmaceutical industry, funding bodies, regulators and patients to identify the main challenges of CID trials. The working group generated ten consensus recommendations. These aim to improve the conduct, quality and acceptability of oncology CID trials in clinical research and, importantly, to expedite the process by which effective treatments can reach cancer patients.

A survey of oncology healthcare professionals' knowledge and attitudes toward the use of music as a therapeutic tool in healthcare.

BACKGROUND: Music as a therapeutic tool, defined as "music care," can help manage physical and psychological symptoms in individuals with cancer. There is further need to understand interest level and the potential role of music care among health professionals working in the field of oncology. PURPOSE: To investigate knowledge of and attitudes toward the use of music as a therapeutic tool in cancer and palliative care, as well as to identify barriers associated with learning to use music in care among health professionals. METHODS: Participants (N = 204), mostly nurses working in oncology and palliative care, completed a survey to assess awareness, knowledge, and attitudes toward the use of music in healthcare practice. RESULTS: In total, 55.5% of participants reported being "somewhat or very knowledgeable" about how to apply/use music therapy for the management of symptoms or on how to make a music therapy referral or for any application of music care. Participants demonstrated a high interest level in learning how to incorporate music into practice (mean = 4.05; SD = 1.045). CONCLUSION: While there is generally high interest and perceived value among nurses in music care interventions, knowledge level about such interventions was low. The study has implications for knowledge translation and education needed to further support uptake and use of music care in nursing practice.

The Influence of Side Effect Information Framing on Nocebo Effects.

BACKGROUND: One contributing factor to the development of nocebo effects is information provided about possible side effects. However, nondisclosure of information can be problematic. PURPOSE: We assessed whether positively framed side effect information (highlighting likelihood of not experiencing side effects) can reduce nocebo effects compared to negatively framed information (highlighting likelihood of experiencing side effects). METHODS: One hundred twelve participants took part in research ostensibly assessing the influence of benzodiazepines (actually sham capsules) on anxiety. Participants were randomized to receive a sham capsule with positively or negatively framed information about four side effects, or a no-treatment control condition. Side effect expectations were assessed after information provision. Framed side effects and other unmentioned symptoms were assessed during the session and 24-hr follow-up. RESULTS: Nocebo effects occurred in symptoms presented as side effects (regardless of framing) during the study session and follow-up (ps < .003). At follow-up, there was also a nocebo effect in other unmentioned symptoms (p = .018). Positive framing reduced side effect symptoms compared with negative framing during the study session (p = .037), but this effect was no longer present at follow-up (p = .53). Side effect expectations did not differ between the framing conditions (p = .14). CONCLUSIONS: Positive framing reduced side effects short-term, but not at follow-up. Expectations did not differ between negative and positive framing. Nocebo effects appeared to generalize to other unmentioned symptoms over a 24-hr period. Further research is needed to determine whether the initial impact of positive framing can be maintained over time.

SCOT: a comparison of cost-effectiveness from a large randomised phase III trial of two durations of adjuvant Oxaliplatin combination chemotherapy for colorectal cancer.

BACKGROUND: The Short Course Oncology Therapy (SCOT) study is an international, multicentre, non-inferiority randomised controlled trial assessing the efficacy, toxicity, and cost-effectiveness of 3 months (3 M) versus the usually given 6 months (6 M) of adjuvant chemotherapy in colorectal cancer. METHODS: In total, 6088 patients with fully resected high-risk stage II or stage III colorectal cancer were randomised and followed up for 3-8 years. The within-trial cost-effectiveness analysis from a UK health-care perspective is presented using the resource use data, quality of life (EQ-5D-3L), time on treatment (ToT), disease-free survival after treatment (DFS) and overall survival (OS) data. Quality-adjusted partitioned survival analysis and Kaplan-Meier Sample Average Estimator estimated QALYs and costs. Probabilistic sensitivity and subgroup analysis was undertaken. RESULTS: The 3 M arm is less costly (-£4881; 95% CI: -£6269; -£3492) and entails (non-significant) QALY gains (0.08; 95% CI: -0.086; 0.230) due to a better significant quality of life. The net monetary benefit was significantly higher in 3 M under a wide range of monetary values of a QALY. The subgroup analysis found similar results for patients in the CAPOX regimen. However, for the FOLFOX regimen, 3 M had lower QALYs than 6 M (not statistically significant). CONCLUSIONS: Overall, 3 M dominates 6 M with no significant detrimental impact on QALYs. The results provide the economic case that a 3 M treatment strategy should be considered a new standard of care.

Selection outweighs drift at a fine scale: Lack of MHC differentiation within a family living lizard across geographically close but disconnected rocky outcrops.

The highly polymorphic genes of the major histocompatibility complex (MHC) are involved in disease resistance, mate choice and kin recognition. Therefore, they are widely used markers for investigating adaptive variation. Although selection is the key driver, gene flow and genetic drift also influence adaptive genetic variation, sometimes in opposing ways and with consequences for adaptive potential. To further understand the processes that generate MHC variation, it is helpful to compare variation at the MHC with that at neutral genetic loci. Differences in MHC and neutral genetic variation are useful for inferring the relative influence of selection, gene flow and drift on MHC variation. To date, such investigations have usually been undertaken at a broad spatial scale. Yet, evolutionary and ecological processes can occur at a fine spatial scale, particularly in small or fragmented populations. We investigated spatial patterns of MHC variation among three geographically close, naturally discrete, sampling sites of Egernia stokesii, an Australian lizard. The MHC of E. stokesii has recently been characterized, and there is evidence for historical selection on the MHC. We found E. stokesii MHC weakly differentiated among sites compared to microsatellites, suggesting selection, acting similarly at each site, has outweighed any effects of low gene flow or of genetic drift on E. stokesii MHC variation. Our findings demonstrate the strength of selection in shaping patterns of MHC variation or consistency at a fine spatial scale.

Egernia stokesii (gidgee skink) MHC I positively selected sites lack concordance with HLA peptide binding regions.

Genes of the major histocompatibility complex (MHC) play an important role in vertebrate disease resistance, kin recognition and mate choice. Mammalian MHC is the most widely characterised of all vertebrates, and attention is often given to the peptide binding regions of the MHC because they are presumed to be under stronger selection than non-peptide binding regions. For vertebrates where the MHC is less well understood, researchers commonly use the amino acid positions of the peptide binding regions of the human leukocyte antigen (HLA) to infer the peptide binding regions within the MHC sequences of their taxon of interest. However, positively selected sites within MHC have been reported to lack correspondence with the HLA in fish, frogs, birds and reptiles including squamates. Despite squamate diversity, the MHC has been characterised in few snakes and lizards. The Egernia group of scincid lizards is appropriate for investigating mechanisms generating MHC variation, as their inclusion will add a new lineage (i.e. Scincidae) to studies of selection on the MHC. We aimed to identify positively selected sites within the MHC of Egernia stokesii and then determine if these sites corresponded with the peptide binding regions of the HLA. Six positively selected sites were identified within E. stokesii MHC I, only two were homologous with the HLA. E. stokesii positively selected sites corresponded more closely to non-lizard than other lizard taxa. The characterisation of the MHC of more intermediate taxa within the squamate order is necessary to understand the evolution of the MHC across all vertebrates.

Genes and Group Membership Predict Gidgee Skink (Egernia stokesii) Reproductive Pairs.

Due to their role in mate choice, disease resistance and kin recognition, genes of the major histocompatibility complex (MHC) are good candidates for investigating genetic-based mate choice. MHC-based mate choice is context dependent and influenced by many factors including social structure. Social structure diversity makes the Egernia group of lizards suitable for comparative studies of MHC-based mate choice. We investigated mate choice in the gidgee skink (Egernia stokesii), a lizard that exhibits high levels of social group and spatial stability. Group membership was incorporated into tests of the good genes as heterozygosity and compatible genes hypotheses for adaptive (MHC) and neutral (microsatellite) genetic diversity (n = 47 individuals genotyped). Females were more likely to pair with a male with higher MHC diversity and with whom they had a lower degree of microsatellite relatedness. Males were more likely to pair with a female with higher microsatellite heterozygosity and with whom they shared a lower proportion of MHC alleles. Lizards were more likely to mate with an individual from within, rather than outside, their social group, which confirmed earlier findings for this species and indicated mate choice had already largely occurred prior to either social group formation or acceptance of an individual into an existing group. Thus, a combination of genes and group membership, rather than group membership alone, predicted mate choice in this species. This work will contribute to an enhanced understanding of squamate group formation and a deeper understanding of the evolution of sociality within all vertebrates.

Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial.

BACKGROUND: Antiangiogenic agents have established efficacy in the treatment of metastatic colorectal cancer. We investigated whether bevacizumab could improve disease-free survival in the adjuvant setting after resection of the primary tumour. METHODS: For the open-label, randomised, controlled QUASAR 2 trial, which was done at 170 hospitals in seven countries, we recruited patients aged 18 years or older with WHO performance status scores of 0 or 1 who had undergone potentially curative surgery for histologically proven stage III or high-risk stage II colorectal cancer. Patients were randomly assigned (1:1) to receive eight 3-week cycles of oral capecitabine alone (1250 mg/m2 twice daily for 14 days followed by a break for 7 days) or the same regimen of oral capecitabine plus 16 cycles of 7·5 mg/kg bevacizumab by intravenous infusion over 90 min on day 1 of each cycle. Randomisation was done by a computer-generated schedule with use of minimisation with a random element stratified by age, disease stage, tumour site, and country. The study was open label and no-one was masked to treatment assignment. The primary endpoint was 3-year disease-free survival, assessed in the intention-to-treat population. Toxic effects were assessed in patients who received at least one dose of randomised treatment. This trial is registered with the ISRCTN registry, number ISRCTN45133151. FINDINGS: Between April 25, 2005, and Oct 12, 2010, 1952 eligible patients were enrolled, of whom 1941 had assessable data (968 in the capecitabine alone group and 973 in the capecitabine and bevacizumab group). Median follow-up was 4·92 years (IQR 4·00-5·16). Disease-free survival at 3 years did not differ between the groups (75·4%, 95% CI 72·5-78·0 in the capecitabine and bevacizumab group vs 78·4%, 75·7-80·9 in the capecitabine alone group; hazard ratio 1·06, 95% CI 0·89-1·25, p=0·54). The most common grade 3-4 adverse events were hand-foot syndrome (201 [21%] of 963 in the capecitabine alone group vs 257 [27%] of 959 in the capecitabine and bevacizumab group) and diarrhoea (102 [11%] vs 104 [11%]), and, with the addition of bevacizumab, expected increases were recorded in all-grade hypertension (320 [33%] vs 75 [8%]), proteinuria (197 [21%] vs 49 [5%]), and wound healing problems (30 [3%] vs 17 [2%]). 571 serious adverse events were reported (221 with capecitabine alone and 350 with capecitabine and bevacizumab). Most of these were gastrointestinal (n=245) or cardiovascular (n=169). 23 deaths within 6 months of randomisation were classified as being related to treatment, eight in the capecitabine alone group and 15 in the capecitabine and bevacizumab group. INTERPRETATION: The addition of bevacizumab to capecitabine in the adjuvant setting for colorectal cancer yielded no benefit in the treatment of an unselected population and should not be used. FUNDING: Roche.

Randomized controlled trial of primary prevention of atopy using house dust mite allergen oral immunotherapy in early childhood.

BACKGROUND: Children born to atopic parents are at increased risk of sensitization to environmental allergens. OBJECTIVE: We sought to demonstrate proof of concept for oral immunotherapy to high-dose house dust mite (HDM) allergen in infancy in the prevention of allergen sensitization and allergic diseases. METHODS: This was a prospective, randomized, double-blind, placebo-controlled, proof-of-concept study involving 111 infants less than 1 year of age at high risk of atopy (≥ 2 first-degree relatives with allergic disease) but with negative skin prick test responses to common allergens at randomization. HDM extract (active) and appropriate placebo solution were administered orally twice daily for 12 months, and children were assessed every 3 months. Coprimary outcomes were cumulative sensitization to HDM and sensitization to any common allergen during treatment, whereas development of eczema, wheeze, and food allergy were secondary outcomes. All adverse events were recorded. RESULTS: There was a significant (P = .03) reduction in sensitization to any common allergen (16.0%; 95% CI, 1.7% to 30.4%) in the active (5 [9.4%]) compared with placebo (13 [25.5%]) treatment groups. There was no treatment effect on the coprimary outcome of HDM sensitization and the secondary outcomes of eczema, wheeze, and food allergy. The intervention was well tolerated, with no differences between active and placebo treatments in numbers or nature of adverse events. CONCLUSION: Prophylactic HDM oral immunotherapy is well tolerated in children at high heredity risk. The results met the trial's prespecified criteria for proof of concept in reducing sensitization to any allergen; however, no significant preventive effect was observed on HDM sensitization or allergy-related symptoms.

Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial.

BACKGROUND: Evidence is scarce for the effectiveness of therapies for oesophageal cancer progressing after chemotherapy, and no randomised trials have been reported. We aimed to compare gefitinib with placebo in previously treated advanced oesophageal cancer. METHODS: For this phase 3, parallel, randomised, placebo-controlled trial, eligible patients were adults with advanced oesophageal cancer or type I/II Siewert junctional tumours, histologically confirmed squamous-cell carcinoma or adenocarcinoma, who had progressed after chemotherapy, with WHO performance status 0-2, and with measurable or evaluable disease on CT scan. Participants were recruited from 48 UK centres and randomly assigned (1:1) to gefitinib (500 mg) or matching placebo by simple randomisation with no stratification factors. Patients, clinicians, and trial office staff were masked to treatment allocation. Treatment continued until disease progression, unacceptable toxicity, or patient choice. The primary outcome was overall survival, analysed by intention to treat. This trial is registered, number ISRCTN29580179. FINDINGS: Between March 30, 2009, and Nov 18, 2011, 450 patients were randomly assigned to treatment groups (one patient withdrew consent; 224 patients allocated gefitinib and 225 allocated placebo included in analyses). Overall survival did not differ between groups (median 3·73 months, 95% CI 3·23-4·50, for gefitinib vs 3·67 months, 95% CI 2·97-4·37, for placebo; hazard ratio [HR] 0·90, 95% CI 0·74-1·09, p=0·29). Among the prespecified patient-reported outcomes (110 patients on gefitinib and 121 on placebo completed both baseline and 4 week questionnaires and were included in analyses), odynophagia was significantly better in the gefitinib group (adjusted mean difference -8·61, 95% CI -14·49 to -2·73; n=227; p=0·004), whereas the other outcomes were not significantly improved compared with placebo: global quality of life (2·69, 95% CI -2·33 to 7·72, n=231, p=0·293), dysphagia (-3·18, 95% CI -8·36 to 2·00, n=231, p=0·228), and eating (-4·11, 95% CI -9·96 to 1·75, n=229, p=0·168). Median progression-free survival was marginally longer with gefitinib than it was with placebo (1·57 months, 95% CI 1·23-1·90 in the gefitinib group vs 1·17 months, 95% CI 1·07-1·37 in the placebo group; HR 0·80, 95% CI 0·66-0·96, p=0·020). The most common toxicities were diarrhoea (36 [16%] of 224 patients on gefitinib vs six [3%] of 225 on placebo) and skin toxicity (46 [21%] vs two [1%]), both mostly grade 2. The commonest grade 3-4 toxicities were fatigue (24 [11%] vs 13 [6%] patients) and diarrhoea (13 [6%] vs two [1%]). Serious adverse events were reported in 109 (49%) of 224 patients assigned to gefitinib and 101 (45%) of 225 on placebo. 54 (24%) of patients in the gefitinib group achieved disease control at 8 weeks, as did 35 (16%) of patients on placebo (p=0·023). INTERPRETATION: The use of gefitinib as a second-line treatment in oesophageal cancer in unselected patients does not improve overall survival, but has palliative benefits in a subgroup of these difficult-to-treat patients with short life expectancy. Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients. FUNDING: Cancer Research UK.

Time From Colorectal Cancer Surgery to Adjuvant Chemotherapy: Post Hoc Analysis of the SCOT Randomized Clinical Trial.

Importance: The timing of adjuvant chemotherapy after surgery for colorectal cancer and its association with long-term outcomes have been investigated in national cohort studies, with no consensus on the optimal time from surgery to adjuvant chemotherapy. Objective: To analyze the association between the timing of adjuvant chemotherapy after surgery for colorectal cancer and disease-free survival. Design, Setting, and Participants: This is a post hoc analysis of the phase 3 SCOT randomized clinical trial, from 244 centers in 6 countries, investigating the noninferiority of 3 vs 6 months of adjuvant chemotherapy. Patients with high-risk stage II or stage III nonmetastatic colorectal cancer who underwent curative-intended surgery were randomized to either 3 or 6 months of adjuvant chemotherapy consisting of fluoropyrimidine and oxaliplatin regimens. Those with complete information on the date of surgery, treatment type, and long-term follow-up were investigated for the primary and secondary end points. Data were analyzed from May 2022 to February 2024. Intervention: In the post hoc analysis, patients were grouped according to the start of adjuvant chemotherapy being less than 6 weeks vs greater than 6 weeks after surgery. Main Outcomes and Measures: The primary end point was disease-free survival. The secondary end points were adverse events in the total treatment period or the first cycle of adjuvant chemotherapy. Results: A total of 5719 patients (2251 [39.4%] female; mean [SD] age, 63.4 [9.3] years) were included in the primary analysis after data curation; among them, 914 were in the early-start group and 4805 were in the late-start group. Median (IQR) follow-up was 72.0 (47.3-88.1) months, with a median (IQR) of 56 (41-66) days from surgery to chemotherapy. Five-year disease-free survival was 78.0% (95% CI, 75.3%-80.8%) in the early-start group and 73.2% (95% CI, 72.0%-74.5%) in the late-start group. In an adjusted Cox regression analysis, the start of adjuvant chemotherapy greater than 6 weeks after surgery was associated with worse disease-free survival (hazard ratio, 1.24; 95% CI, 1.06-1.46; P = .01). In adjusted logistic regression models, there was no association with adverse events in the total treatment period (odds ratio, 0.82; 95% CI, 0.65-1.04; P = .09) or adverse events in the first cycle of treatment (odds ratio, 0.77; 95% CI, 0.56-1.09; P = .13). Conclusions and Relevance: In this international population of patients with high-risk stage II and stage III colorectal cancer, starting adjuvant chemotherapy more than 6 weeks after surgery was associated with worse disease-free survival, with no difference in adverse events between the groups. Trial Registration: isrctn.org Identifier: ISRCTN59757862.

The influence of video-based social modelling on the nocebo effect.

OBJECTIVE: Seeing someone else experience side effects (i.e., social modelling) can increase negative expectations and subsequent nocebo effects. In face-to-face contexts, this effect appears stronger in female participants. Less is known about the influence of gender on negative expectations and nocebo effects generated via video-based social modelling. METHODS: One hundred and seven undergraduate participants recruited from a participant pool at an Australian university took part in a study ostensibly investigating the influence of beta-blocker medications (actually a sham treatment) on physiological and psychological aspects of anxiety. Participants were randomly assigned to either a no-treatment control group, a standard treatment group, or a video modelling group, in which participants viewed video-recorded confederates (one male, one female) report experiencing four side effects (two each) after taking the study treatment. Symptoms were assessed 15-min following pill ingestion, and at follow-up 24 h later. RESULTS: Video modelling of side effects, compared to standard treatment, interacted with gender and was associated with increased reporting of modelled symptoms in female compared to male participants, p = .01, ηp2=0.06. Video modelling also increased negative expectations in female compared to male participants, p = .03, ηp2=0.07, and expectations mediated the influence of modelling on modelled symptoms in female participants. CONCLUSIONS: Social modelling of side effects via video increased negative expectations, and nocebo symptoms, to a greater extent in female participants. These findings suggest that males and females are differentially impacted by video-based side effect modelling. Results have implications for social modelling of side effects via social media and patient-support websites.

Post-inflammatory Hyperpigmentation in an African American Female: An Atypical Presentation and Treatment Dilemma.

We present the case of a 32-year-old African American female with a known history of primary Sjogren's syndrome, multiple vitamin deficiencies, and prior facial cellulitis who presented with diffuse facial post-inflammatory hyperpigmentation following a motor vehicle accident. Following glucocorticoid treatment, only select hyperpigmented areas associated with inflammation, infection, or trauma improved, which thereby posed a clinical challenge to improve the patient's appearance and condition. Such results may warrant the consideration of adjunctive topical therapies to lighten the remaining areas of hyperpigmentation.

SCOT: Tumor Sidedness and the Influence of Adjuvant Chemotherapy Duration on Disease Free Survival (DFS).

AIM: Patients with loco-regional right-sided colorectal tumors have a worse overall survival (OS). Here we investigate the difference in disease free survival (DFS) between colorectal patients with right and left sided tumors in the SCOT study. METHODS: The SCOT study showed 3-months of oxaliplatin-containing adjuvant chemotherapy (OxFp) is non-inferior to 6-months for patients with stage III and high-risk stage II colorectal cancer. We divided the cohort into patients with left and right sided tumors, and evaluated the effect on DFS and the principle 3 versus 6-months analysis. RESULTS: 6088 patients with Stage III/high risk Stage II colorectal cancers were randomized between 27th March 2008 and 29th November 2013 from 244 centers internationally. In February 2017 (3-years FU) information on sidedness was available for 3309 patients (1238 R-sided, 2071 L-sided). Patients with right-sided tumors had a significantly worse DFS (3-year DFS right: 73.3% (se = 1.3%), left: 80.2% (se = 0.9%) HR 1.423 (95% CI 1.237-1.637; P < .0001). Adjusting for T and N-stage reduced the HR to 1.230 (95% CI 1.066-1.420, P = .005). The data did not suggest that sidedness affected the impact of chemotherapy duration on 3-year DFS (R: HR 1.024 [0.831-1.261], L: HR 0.944 [0.783-1.139]). Test for heterogeneity, P = .571. Further sub-set analysis was limited due to cohort size. CONCLUSIONS: This is the first study to show that unselected patients with right-sided tumors had a worse DFS compared to left-sided tumors. Tumor sidedness did not impact upon the 3-months versus 6-months comparison in SCOT.

EnROL: a multicentre randomised trial of conventional versus laparoscopic surgery for colorectal cancer within an enhanced recovery programme.

BACKGROUND: During the last two decades the use of laparoscopic resection and a multimodal approach known as an enhanced recovery programme, have been major changes in colorectal perioperative care. Clinical outcome improves using laparoscopic surgery to resect colorectal cancer but until recently no multicentre trial evidence had been reported regarding whether the benefits of laparoscopy still exist when open surgery is optimized within an enhanced recovery programme. The EnROL trial (Enhanced Recovery Open versus Laparoscopic) examines the hypothesis that laparoscopic surgery within an enhanced recovery programme will provide superior postoperative outcomes when compared to conventional open resection of colorectal cancer within the same programme. METHODS/DESIGN: EnROL is a phase III, multicentre, randomised trial of laparoscopic versus open resection of colon and rectal cancer with blinding of patients and outcome observers to the treatment allocation for the first 7 days post-operatively, or until discharge if earlier. 202 patients will be recruited at approximately 12 UK hospitals and randomised using minimization at a central computer system in a 1:1 ratio. Recruiting surgeons will previously have performed >100 laparoscopic colorectal resections and >50 open total mesorectal excisions to minimize conversion. Eligible patients are those suitable for elective resection using either technique. Excluded patients include: those with acute intestinal obstruction and patients in whom conversion from laparoscopic to open procedure is likely. The primary outcome is physical fatigue as measured by the physical fatigue domain of the multidimensional fatigue inventory 20 (MFI-20) with secondary outcomes including postoperative hospital stay; complications; reoperation and readmission; quality of life indicators; cosmetic assessments; standardized performance indicators; health economic analysis; the other four domains of the MFI-20. Pathological assessment of surgical quality will also be undertaken and compliance with the enhanced recovery programme will be recorded for all patients. DISCUSSION: Should this trial demonstrate that laparoscopic surgery confers a significant clinical and/or health economic benefit this will further support the transition to this type of surgery, with implications for the training of surgeons and resource allocation. TRIAL REGISTRATION: ISRCTN48516968.

Long-Term Hearing Results of Endoskeletal Ossicular Reconstruction in Chronic Ears Using Titanium Prostheses Having a Helical Coil: Part 1-Kraus K-Helix Crown, Incus to Stapes.

OBJECTIVES: 1) To assess long-term hearing results after endoskeletal ossicular chain reconstruction (eOCR) using the titanium Kraus K-Helix Crown prosthesis, implanted incus to stapes, with glass-ionomer cement (GIC) in chronic ears and 2) to determine safety of the prosthesis and cement. STUDY DESIGN: Prospective, nonrandomized, sequential, single center, single surgeon. SETTING: Private practice, ambulatory surgical center. PATIENTS: N = 15 males (42%) and 21 females (58%). Mean age was 40.4 years (range, 6-81 years); 38 ears (22 right ears [58%] and 16 left ears [42%]). INTERVENTIONS: eOCR in chronic ears. Comprehensive preoperative and postoperative hearing measurements were performed for up to 9 years. MAIN OUTCOME MEASURES: Postoperative hearing results at 1 year showed statistically significant improvement as compared with preoperative hearing. Long-term hearing results remained stable and showed no statistically significant change over 9 years. RESULTS: Estimated mean pure-tone air conduction average improved by 14.5 dB (95% confidence interval = 10.3-18.7). Estimated mean speech reception thresholds improved by 15.5 dB (10.8-20.2). Word recognition scores improved by -2.2% (-5.3 to 1.0). The estimated mean postoperative air-bone gap was 10.5 dB (7.2-13.8). The estimated mean calculated air-bone gap was 11.3 dB (8.0-14.5). The estimated mean change in high-tone bone conduction (HTBC) average was +3.5 dB (0.9-6.0). Two prostheses extruded (5%). No patients experienced any unanticipated serious adverse effects or events. CONCLUSION: eOCR using the K-Helix Crown prosthesis, incus to stapes, and GIC can significantly improve hearing at 1 year and maintain stable hearing over 9 years. Both prosthesis and cement are safe.

The Expanding Scope, Inclusivity, and Integration of Music in Healthcare: Recent Developments, Research Illustration, and Future Direction.

This paper is in three sections. Section One presents a historical overview of international initiatives that have expanded the role of music in healthcare, from the initial formalization of music therapy to its more research-based rehabilitation focus to recent decades that have seen an increasing role for professional and community musicians, paraprofessional music services, music-oriented service organizations, and a very large increase in medical funding for music effects. "Music Care" is a particular and comprehensive concept promoted by the Room 217 Foundation in Canada, featuring an inclusive and integrated approach to optimizing the use of music in healthcare settings. It is part of an expanding landscape of global practices and policies where music is used to address specific issues of care. Section Two is provided as an illustration of the growing scope of the concept of using music in healthcare. It reports on a multi-year project that engaged 24 long-term care homes in conducting individualized action research projects using the fundamental approach of "Music Care", empowering all caregivers, formal and informal, musicians and non-musicians, to use music to improve quality of life and care. Section Two presents only high-level results of the study focused on using music care to reduce resident isolation and loneliness. Section Three draws on the results from the study reported in Section Two to inform the potential and path to the future of music optimization in any healthcare setting.

Violent Video Games and the P300: No Evidence to Support the Neural Desensitization Hypothesis.

It has been proposed that exposure to violent video games (VVGs) resulted in alterations of social behaviors such as increased aggression. The most damaging reported effect of playing VVGs is neural desensitization to violent stimuli and this is a major concern given the reported number of players and time spent playing major video game titles. The aim of this study was to investigate the existence of neural desensitization that was reported at the P300 component of event-related potentials (ERPs) in response to violent stimuli. Eighty-seven participants were recruited and placed into one of two conditions based on their video gaming behavior (violent games players and nonplayers). ERPs were recorded from participants who passively viewed violent and neutral images selected from the International Affective Picture System (IAPS). The participants then played a VVG, postplaying ERPs were recorded while viewing the neutral and violent IAPS images. The mean amplitudes of the P300 were analyzed with respect to condition, time, and content. There was a significant effect of image but not of VVG player and nonplayer. The results were interpreted as evidence against the neural desensitization hypothesis. The findings of this study are consistent with imaging research and the implications for the reported negative effects of playing VVGs are discussed.