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Background: Colonoscopy has become a preferred colorectal cancer (CRC) screening modality. Little is known about why patients who are referred for colonoscopy do not complete the recommended procedures. Prior adherence studies have evaluated colonoscopy only in combination with flexible sigmoidoscopy, failed to differentiate between screening and diagnostic procedures, and have examined cancellations/no‐shows, but not nonscheduling, as mechanisms of nonadherence. Methods: Sociodemographic predictors of screening completion were assessed in a retrospective cohort of 647 patients referred for colonoscopy at a major university hospital. Then, using a qualitative study design, a convenience sample of patients who never completed screening after referral (n=52) was interviewed by telephone, and comparisons in reported reasons for nonadherence were made by gender. Results: Half of all patients referred for colonoscopy failed to complete the procedure, overwhelmingly because of nonscheduling. In multivariable analysis, female sex, younger age, and insurance type predicted poorer adherence. Patient‐reported barriers to screening completion included cognitive‐emotional factors (e.g., lack of perceived risk for CRC, fear of pain, and concerns about modesty and the bowel preparation), logistic obstacles (e.g., cost, other health problems, and competing demands), and health system barriers (e.g., scheduling challenges, long waiting times). Women reported more concerns about modesty and other aspects of the procedure than men. Only 40% of patients were aware of alternative screening options. Conclusions: Adherence to screening colonoscopy referrals is sub‐optimal and may be improved by better communication with patients, counseling to help resolve logistic barriers, and improvements in colonoscopy referral and scheduling mechanisms.

Patient knowledge about lower endoscopy might have beneficial effects on satisfaction outcomes, pre-procedure anxiety, and adherence, although this is poorly understood. Methods Searching the national and international literature, we reviewed 20 years of observational studies and randomized trials that examine possible relationships between educating patients about lower endoscopy and clinical outcomes. Twenty-three publications were included but their heterogeneity precluded meta-analyses. Standard and modified informed consent procedures and enhanced educational interventions were associated most often with levels of patient knowledge, satisfaction, anxiety, and adherence. Regardless of the approach, a large proportion of patients have poor comprehension of lower endoscopy’s risks, benefits, and alternatives; patient satisfaction with information and procedures manifests ceiling effects; only a subset of patients have clinically significant pre-procedure anxiety; and providing written information and reminders may improve procedure adherence. Future work should focus on strategies for improving patient knowledge in the setting of initial screening colonoscopy within open access systems. Patient knowledge of lower endoscopy is often inadequate even though greater knowledge might be associated with better clinical outcomes for certain patient subgroups. Professional societies have an important role to play in endorsing educational strategies and in clarifying and assessing the adequacy of patient knowledge.

BACKGROUND: Colonoscopy has become a preferred colorectal cancer (CRC) screening modality. Little is known about why patients who are referred for colonoscopy do not complete the recommended procedures. Prior adherence studies have evaluated colonoscopy only in combination with flexible sigmoidoscopy, failed to differentiate between screening and diagnostic procedures, and have examined cancellations/no-shows, but not nonscheduling, as mechanisms of nonadherence. METHODS: Sociodemographic predictors of screening completion were assessed in a retrospective cohort of 647 patients referred for colonoscopy at a major university hospital. Then, using a qualitative study design, a convenience sample of patients who never completed screening after referral (n=52) was interviewed by telephone, and comparisons in reported reasons for nonadherence were made by gender. RESULTS: Half of all patients referred for colonoscopy failed to complete the procedure, overwhelmingly because of nonscheduling. In multivariable analysis, female sex, younger age, and insurance type predicted poorer adherence. Patient-reported barriers to screening completion included cognitive-emotional factors (e.g., lack of perceived risk for CRC, fear of pain, and concerns about modesty and the bowel preparation), logistic obstacles (e.g., cost, other health problems, and competing demands), and health system barriers (e.g., scheduling challenges, long waiting times). Women reported more concerns about modesty and other aspects of the procedure than men. Only 40% of patients were aware of alternative screening options. CONCLUSIONS: Adherence to screening colonoscopy referrals is suboptimal and may be improved by better communication with patients, counseling to help resolve logistic barriers, and improvements in colonoscopy referral and scheduling mechanisms.[PUBLICATION ABSTRACT]

Most cancer-related deaths are a result of metastasis, and thus the importance of this process as a target of therapy cannot be understated. By asking ‘how can we effectively treat cancer?’, we do not capture the complexity of a disease encompassing >200 different cancer types — many consisting of multiple subtypes — with considerable intratumoural heterogeneity, which can result in variable responses to a specific therapy. Moreover, we have much less information on the pathophysiological characteristics of metastases than is available for the primary tumour. Most disseminated tumour cells that arrive in distant tissues, surrounded by unfamiliar cells and a foreign microenvironment, are likely to die; however, those that survive can generate metastatic tumours with a markedly different biology from that of the primary tumour. To treat metastasis effectively, we must inhibit fundamental metastatic processes and develop specific preclinical and clinical strategies that do not rely on primary tumour responses. To address this crucial issue, Cancer Research UK and Cancer Therapeutics CRC Australia formed a Metastasis Working Group with representatives from not-for-profit, academic, government, industry and regulatory bodies in order to develop recommendations on how to tackle the challenges associated with treating (micro)metastatic disease. Herein, we describe the challenges identified as well as the proposed approaches for discovering and developing anticancer agents designed specifically to prevent or delay the metastatic outgrowth of cancer.

The effects of extra-pleural pneumonectomy (EPP) on survival and quality of life in patients with malignant pleural mesothelioma have, to our knowledge, not been assessed in a randomised trial. We aimed to assess the clinical outcomes of patients who were randomly assigned to EPP or no EPP in the context of trimodal therapy in the Mesothelioma and Radical Surgery (MARS) feasibility study. MARS was a multicentre randomised controlled trial in 12 UK hospitals. Patients aged 18 years or older who had pathologically confirmed mesothelioma and were deemed fit enough to undergo trimodal therapy were included. In a prerandomisation registration phase, all patients underwent induction platinum-based chemotherapy followed by clinical review. After further consent, patients were randomly assigned (1:1) to EPP followed by postoperative hemithorax irradiation or to no EPP. Randomisation was done centrally with computer-generated permuted blocks stratified by surgical centre. The main endpoints were feasibility of randomly assigning 50 patients in 1 year (results detailed in another report), proportion randomised who received treatment, proportion eligible (registered) who proceeded to randomisation, perioperative mortality, and quality of life. Patients and investigators were not masked to treatment allocation. This is the principal report of the MARS study; all patients have been recruited. Analyses were by intention to treat. This trial is registered, number ISRCTN95583524. Between Oct 1, 2005, and Nov 3, 2008, 112 patients were registered and 50 were subsequently randomly assigned: 24 to EPP and 26 to no EPP. The main reasons for not proceeding to randomisation were disease progression (33 patients), inoperability (five patients), and patient choice (19 patients). EPP was completed satisfactorily in 16 of 24 patients assigned to EPP; in five patients EPP was not started and in three patients it was abandoned. Two patients in the EPP group died within 30 days and a further patient died without leaving hospital. One patient in the no EPP group died perioperatively after receiving EPP off trial in a non-MARS centre. The hazard ratio [HR] for overall survival between the EPP and no EPP groups was 1·90 (95% CI 0·92–3·93; exact p=0·082), and after adjustment for sex, histological subtype, stage, and age at randomisation the HR was 2·75 (1·21–6·26; p=0·016). Median survival was 14·4 months (5·3–18·7) for the EPP group and 19·5 months (13·4 to time not yet reached) for the no EPP group. Of the 49 randomly assigned patients who consented to quality of life assessment (EPP n=23; no EPP n=26), 12 patients in the EPP group and 19 in the no EPP group completed the quality of life questionnaires. Although median quality of life scores were lower in the EPP group than the no EPP group, no significant differences between groups were reported in the quality of life analyses. There were ten serious adverse events reported in the EPP group and two in the no EPP group. In view of the high morbidity associated with EPP in this trial and in other non-randomised studies a larger study is not feasible. These data, although limited, suggest that radical surgery in the form of EPP within trimodal therapy offers no benefit and possibly harms patients. Cancer Research UK ( CRUK/04/003), the June Hancock Mesothelioma Research Fund, and Guy's and St Thomas' NHS Foundation Trust.

Tamoxifen preserves bone in postmenopausal women, but non-steroidal aromatase inhibitors accelerate bone loss and increase fracture risk. We aimed to study the effect on bone health in a subgroup of women included in the Intergroup Exemestane Study (IES), a large randomised trial that compared the switch to the steroidal aromatase inhibitor exemestane with continuation of tamoxifen in the adjuvant treatment of postmenopausal breast cancer. Results were analysed from 206 evaluable patients from the IES, in which postmenopausal women with histologically confirmed and completely resected unilateral breast cancer (that was oestrogen-receptor positive or of unknown status), who were disease-free after 2–3 years of treatment with tamoxifen were randomised to continue oral tamoxifen 20 mg/day or switch to oral exemestane 25 mg/day to complete a total of 5 years of adjuvant endocrine therapy. The primary endpoint was change in bone-mineral density (BMD) assessed by dual energy X-ray absorptiometry. Changes in biochemical markers of bone turnover were also analysed in this substudy, and the incidence of fractures in the entire study reported. The IES is registered on the Current Controlled Trials website http://www.controlled-trials.com/ISRCTN11883920. Within 6 months of switching to exemestane, BMD was lowered by 0·051 g/cm 3 (2·7%; 95% CI 2·0–3·4; p<0·0001) at the lumbar spine and 0·025 g/cm 3 (1·4%; 0·8–1·9; p<0·0001) at the hip compared with baseline. BMD decreases were only 1·0% (0·4–1·7; p=0·002) and 0·8% (0·3–1·4; p=0·003) in year 2 at the lumbar spine and hip, respectively. No patient with BMD in the normal range at trial entry developed osteoporosis. Bone resorption and formation markers increased at all time points in women receiving exemestane (p<0·001). With a median follow-up in all IES participants (n=4274) of 58 months, 162 (7%) and 115 (5%) patients in the exemestane and tamoxifen groups, respectively, had fractures (odds ratio 1·45 [1·13–1·87]; p=0·003). These results indicate that the increase in survival shown previously with the IES switch strategy is achieved at the expense of some detriment to skeletal health, so the risk-benefit ratio to women needs to be individually assessed.

Bipolar disorder (BD) has high clinical heterogeneity, frequent psychiatric comorbidities, and elevated suicide risk. To determine genetic differences between common clinical sub-phenotypes of BD, we performed a systematic polygenic risk score (PRS) analysis using multiple PRSs from a range of psychiatric, personality, and lifestyle traits to dissect differences in BD sub-phenotypes in two BD cohorts: the Mayo Clinic BD Biobank ( N  = 968) and Genetic Association Information Network ( N  = 1001). Participants were assessed for history of psychosis, early-onset BD, rapid cycling (defined as four or more episodes in a year), and suicide attempts using questionnaires and the Structured Clinical Interview for DSM-IV. In a combined sample of 1969 bipolar cases (45.5% male), those with psychosis had higher PRS for SCZ (OR = 1.3 per S.D.; p  = 3e-5) but lower PRSs for anhedonia (OR = 0.87; p  = 0.003) and BMI (OR = 0.87; p  = 0.003). Rapid cycling cases had higher PRS for ADHD (OR = 1.23; p  = 7e-5) and MDD (OR = 1.23; p  = 4e-5) and lower BD PRS (OR = 0.8; p  = 0.004). Cases with a suicide attempt had higher PRS for MDD (OR = 1.26; p  = 1e-6) and anhedonia (OR = 1.22; p  = 2e-5) as well as lower PRS for educational attainment (OR = 0.87; p  = 0.003). The observed novel PRS associations with sub-phenotypes align with clinical observations such as rapid cycling BD patients having a greater lifetime prevalence of ADHD. Our findings confirm that genetic heterogeneity contributes to clinical heterogeneity of BD and consideration of genetic contribution to psychopathologic components of psychiatric disorders may improve genetic prediction of complex psychiatric disorders.

Several social determinants of health (SDoH) have been associated with the onset of major depressive disorder (MDD). However, prior studies largely focused on individual SDoH and thus less is known about the relative importance (RI) of SDoH variables, especially in older adults. Given that risk factors for MDD may differ across the lifespan, we aimed to identify the SDoH that was most strongly related to newly diagnosed MDD in a cohort of older adults. We used self-reported health-related survey data from 41 174 older adults (50-89 years, median age = 67 years) who participated in the Mayo Clinic Biobank, and linked ICD codes for MDD in the participants' electronic health records. Participants with a history of clinically documented or self-reported MDD prior to survey completion were excluded from analysis ( = 10 938, 27%). We used Cox proportional hazards models with a gradient boosting machine approach to quantify the RI of 30 pre-selected SDoH variables on the risk of future MDD diagnosis. Following biobank enrollment, 2073 older participants were diagnosed with MDD during the follow-up period (median duration = 6.7 years). The most influential SDoH was perceived level of social activity (RI = 0.17). Lower level of social activity was associated with a higher risk of MDD [hazard ratio = 2.27 (95% CI 2.00-2.50) for highest lowest level]. Across a range of SDoH variables, perceived level of social activity is most strongly related to MDD in older adults. Monitoring changes in the level of social activity may help identify older adults at an increased risk of MDD.