Phase Ia/b Study of Giredestrant ± Palbociclib and ± Luteinizing Hormone-Releasing Hormone Agonists in Estrogen Receptor-Positive, HER2-Negative, Locally Advanced/Metastatic Breast Cancer.

PURPOSE: Giredestrant is an investigational next-generation, oral, selective estrogen receptor antagonist and degrader for the treatment of estrogen receptor-positive (ER+) breast cancer. We present the primary analysis results of the phase Ia/b GO39932 study (NCT03332797). PATIENTS AND METHODS: Patients with ER+, HER2-negative locally advanced/metastatic breast cancer previously treated with endocrine therapy received single-agent giredestrant (10, 30, 90, or 250 mg), or giredestrant (100 mg) ± palbociclib 125 mg ± luteinizing hormone-releasing hormone (LHRH) agonist. Detailed cardiovascular assessment was conducted with giredestrant 100 mg. Endpoints included safety (primary), pharmacokinetics, pharmacodynamics, and efficacy. RESULTS: As of January 28, 2021, with 175 patients enrolled, no dose-limiting toxicity was observed, and the MTD was not reached. Adverse events (AE) related to giredestrant occurred in 64.9% and 59.4% of patients in the single-agent ± LHRH agonist and giredestrant + palbociclib ± LHRH agonist cohorts, respectively (giredestrant-only-related grade 3/4 AEs were reported in 4.5% of patients across the single-agent cohorts and 3.1% of those with giredestrant + palbociclib). Dose-dependent asymptomatic bradycardia was observed, but no clinically significant changes in cardiac-related outcomes: heart rate, blood pressure, or exercise duration. Clinical benefit was observed in all cohorts (48.6% of patients in the single-agent cohort and 81.3% in the giredestrant + palbociclib ± LHRH agonist cohort), with no clear dose relationship, including in patients with ESR1-mutated tumors. CONCLUSIONS: Giredestrant was well tolerated and clinically active in patients who progressed on prior endocrine therapy. Results warrant further evaluation of giredestrant in randomized trials in early- and late-stage ER+ breast cancer.

Concentration QTc analysis of giredestrant: Overcoming QT/heart rate confounding in the presence of drug-induced heart rate changes.

Concentration-QTc (C-QTc) analysis has become a common approach for evaluating proarrhythmic risk and delayed cardiac repolarization of oncology drug candidates. Significant heart rate (HR) change has been associated with certain classes of oncology drugs and can result in over- or underestimation of the true QT prolongation risk. Because oncology early clinical trials typically lack a placebo control arm or time-matched, treatment-free baseline electrocardiogram collection, significant HR change brings additional challenges to C-QTc analysis in the oncology setting. In this work, a spline-based correction method (QTcSPL) was explored to mitigate the impact of HR changes in giredestrant C-QTc analysis. Giredestrant is a selective estrogen receptor degrader being developed for the treatment of patients with estrogen receptor-positive (ER+) breast cancer. A dose-related HR decrease has been observed in patients under giredestrant treatment, with significant reductions (>10 bpm) observed at supratherapeutic doses. The QTcSPL method demonstrated superior functionality to reduce the correlation between QTc and HR as compared with the Fridericia correction (QTcF). The effect of giredestrant exposure on QTc was evaluated at the clinical dose of 30 mg and supratherapeutic dose of 100 mg based on a prespecified linear mixed effect model. The upper 90% confidence interval of ΔQTcSPL and ΔQTcF were below the 10 ms at both clinical and supratherapeutic exposures, suggesting giredestrant has a low risk of QT prolongation at clinically relevant concentrations. This work demonstrated the use case of QTcSPL to address HR confounding challenges in the context of oncology drug development for the first time.

American Academy of Ophthalmology Recommendations on Screening for Endogenous Candida Endophthalmitis.

The American Academy of Ophthalmology evaluated the practice of routine screening for intraocular infection from Candida septicemia. In the United States, ophthalmologists are consulted in the hospital to screen for intraocular infection routinely for patients with Candida bloodstream infections. This practice was established in the era before the use of systemic antifungal medication and the establishment of definitions of ocular disease with candidemia. A recent systematic review found a rate of less than 1% of routinely screened patients with endophthalmitis from Candida septicemia. Other studies found higher rates of endophthalmitis but had limitations in terms of inaccuracies in ocular disease classification, lack of vitreous biopsies, selection biases, and lack of longer-term visual outcomes. Some studies attributed ocular findings to Candida infections, rather than other comorbidities. Studies also have not demonstrated differences in medical management that are modified for eye disease treatment; therefore, therapy should be dictated by the underlying Candida infection, rather than be tailored on the basis of ocular findings. In summary, the Academy does not recommend a routine ophthalmologic consultation after laboratory findings of systemic Candida septicemia, which appears to be a low-value practice. An ophthalmologic consultation is a reasonable practice for a patient with signs or symptoms suggestive of ocular infection regardless of Candida septicemia.

Phase I Basket Study of Taselisib, an Isoform-Selective PI3K Inhibitor, in Patients with PIK3CA-Mutant Cancers.

PURPOSE: Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), which encodes the p110α catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in PIK3CA helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with PIK3CA-mutant cancers with the isoform-specific PI3K inhibitor taselisib. PATIENTS AND METHODS: Patients were enrolled on the basis of local PIK3CA mutation testing into one of 11 histology-specific cohorts and treated with taselisib at 6 or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed. RESULTS: A total of 166 patients with PIK3CA-mutant cancers were enrolled. The confirmed response rate was 9%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10%), and other cancers, plus in tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront (TP53 and PTEN) and postprogression through reactivation of the PI3K pathway (PTEN, STK11, and PIK3R1). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index. CONCLUSIONS: Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target PIK3CA-mutant tumors.

A phase Ib, open-label, dose-escalation study of the safety and pharmacology of taselisib (GDC-0032) in combination with either docetaxel or paclitaxel in patients with HER2-negative, locally advanced, or metastatic breast cancer.

PURPOSE: This open-label, phase Ib, dose-escalation, and dose-expansion study (NCT01862081) evaluated taselisib with a taxane in locally advanced or metastatic breast cancer (BC) and/or non-small cell lung cancer (NSCLC). METHODS: Patients received taselisib (2-6 mg tablet or 3-6 mg capsule) plus docetaxel or paclitaxel. Primary endpoints were safety, dose-limiting toxicities, maximum tolerated dose, and identification of a recommended phase II dose. Secondary endpoints included pharmacokinetics and antitumor activity assessment. RESULTS: Eighty patients (BC: 72; NSCLC: 7; BC/NSCLC: 1) were enrolled (docetaxel-receiving arms: 21; paclitaxel-receiving arms: 59). Grade ≥ 3 adverse events (AEs), serious AEs, and AEs leading to death were reported in 90.5%, 42.9%, and 14.3% of patients, respectively (docetaxel-receiving arms), and 78.9%, 40.4%, and 3.5% of patients, respectively (paclitaxel-receiving arms). Eight patients experienced dose-limiting toxicities. The maximum tolerated dose was exceeded with 3 mg taselisib (capsule) for 21 consecutive days plus 75 mg/m2 docetaxel and not exceeded with 6 mg taselisib (tablet) for 5 days on/2 days off plus 80 mg/m2 paclitaxel. Objective response rates and clinical benefit rates were 35.0% and 45.0%, respectively (docetaxel-receiving arms), and 20.4% and 27.8%, respectively (paclitaxel-receiving arms). Exposure for paclitaxel or docetaxel plus taselisib was consistent with the single agents. CONCLUSIONS: Taselisib in combination with a taxane has a challenging safety profile. Despite evidence of antitumor activity, the benefit-risk profile was deemed not advantageous. Further development is not planned.

Long-term mortality after screening for colorectal cancer.

BACKGROUND: In randomized trials, fecal occult-blood testing reduces mortality from colorectal cancer. However, the duration of the benefit is unknown, as are the effects specific to age and sex. METHODS: In the Minnesota Colon Cancer Control Study, 46,551 participants, 50 to 80 years of age, were randomly assigned to usual care (control) or to annual or biennial screening with fecal occult-blood testing. Screening was performed from 1976 through 1982 and from 1986 through 1992. We used the National Death Index to obtain updated information on the vital status of participants and to determine causes of death through 2008. RESULTS: Through 30 years of follow-up, 33,020 participants (70.9%) died. A total of 732 deaths were attributed to colorectal cancer: 200 of the 11,072 deaths (1.8%) in the annual-screening group, 237 of the 11,004 deaths (2.2%) in the biennial-screening group, and 295 of the 10,944 deaths (2.7%) in the control group. Screening reduced colorectal-cancer mortality (relative risk with annual screening, 0.68; 95% confidence interval [CI], 0.56 to 0.82; relative risk with biennial screening, 0.78; 95% CI, 0.65 to 0.93) through 30 years of follow-up. No reduction was observed in all-cause mortality (relative risk with annual screening, 1.00; 95% CI, 0.99 to 1.01; relative risk with biennial screening, 0.99; 95% CI, 0.98 to 1.01). The reduction in colorectal-cancer mortality was larger for men than for women in the biennial-screening group (P=0.04 for interaction). CONCLUSIONS: The effect of screening with fecal occult-blood testing on colorectal-cancer mortality persists after 30 years but does not influence all-cause mortality. The sustained reduction in colorectal-cancer mortality supports the effect of polypectomy. (Funded by the Veterans Affairs Merit Review Award Program and others.).

Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths.

BACKGROUND: In the National Polyp Study (NPS), colorectal cancer was prevented by colonoscopic removal of adenomatous polyps. We evaluated the long-term effect of colonoscopic polypectomy in a study on mortality from colorectal cancer. METHODS: We included in this analysis all patients prospectively referred for initial colonoscopy (between 1980 and 1990) at NPS clinical centers who had polyps (adenomas and nonadenomas). The National Death Index was used to identify deaths and to determine the cause of death; follow-up time was as long as 23 years. Mortality from colorectal cancer among patients with adenomas removed was compared with the expected incidence-based mortality from colorectal cancer in the general population, as estimated from the Surveillance Epidemiology and End Results (SEER) Program, and with the observed mortality from colorectal cancer among patients with nonadenomatous polyps (internal control group). RESULTS: Among 2602 patients who had adenomas removed during participation in the study, after a median of 15.8 years, 1246 patients had died from any cause and 12 had died from colorectal cancer. Given an estimated 25.4 expected deaths from colorectal cancer in the general population, the standardized incidence-based mortality ratio was 0.47 (95% confidence interval [CI], 0.26 to 0.80) with colonoscopic polypectomy, suggesting a 53% reduction in mortality. Mortality from colorectal cancer was similar among patients with adenomas and those with nonadenomatous polyps during the first 10 years after polypectomy (relative risk, 1.2; 95% CI, 0.1 to 10.6). CONCLUSIONS: These findings support the hypothesis that colonoscopic removal of adenomatous polyps prevents death from colorectal cancer. (Funded by the National Cancer Institute and others.).

Tonsillectomy: a cost-effective option for childhood sore throat? Further analysis of a randomized controlled trial.

OBJECTIVE: To compare the estimated cost-effectiveness of childhood (adeno)tonsillectomy vs medical therapy for recurrent sore throats from the intention-to-treat (ITT) analysis of a randomized controlled trial (RCT) with that modeled on the recorded timing of surgical interventions as observed in all participants irrespective of their original group allocation. STUDY DESIGN: A pragmatic RCT (trial) with a parallel nonrandomized patient preference group (cohort) of (adeno)tonsillectomy vs medical therapy. SETTING: Five secondary care UK otolaryngology departments. SUBJECTS AND METHODS: Eligible children, aged 4 to 15 years, were enrolled to the trial (268) or cohort (461) groups. Outcomes included sore throat diaries, quality of life, and general practice consultations. The RCT protocol ITT analysis was compared with an as-treated analysis incorporating the cohort group, modeled to reflect the timing of tonsillectomy and the differential switch rates among the original groups. RESULTS: In the RCT ITT analysis, tonsillectomy saved 3.5 sore throats, whereas the as-treated model suggested an average reduction of more than 8 sore throats in 2 years for surgery within 10 weeks of consultation, falling to only 3.5 twelve months later due to the spontaneous improvement in the medical therapy group. CONCLUSION: In eligible UK school-age children, tonsillectomy can save up to 8 sore throats at a reasonable cost, if performed promptly. Further prospective data collection, accounting for baseline and per-trial preferences and choice, is urgently needed.

Capability and dependency in the Newcastle 85+ cohort study. Projections of future care needs.

BACKGROUND: Little is known of the capabilities of the oldest old, the fastest growing age group in the population. We aimed to estimate capability and dependency in a cohort of 85 year olds and to project future demand for care. METHODS: Structured interviews at age 85 with 841 people born in 1921 and living in Newcastle and North Tyneside, UK who were permanently registered with participating general practices. Measures of capability included were self-reported activities of daily living (ADL), timed up and go test (TUG), standardised mini-mental state examination (SMMSE), and assessment of urinary continence in order to classify interval-need dependency. To project future demand for care the proportion needing 24-hour care was applied to the 2008 England and Wales population projections of those aged 80 years and over by gender. RESULTS: Of participants, 62% (522/841) were women, 77% (651/841) lived in standard housing, 13% (106/841) in sheltered housing and 10% (84/841) in a care home. Overall, 20% (165/841) reported no difficulty with any of the ADLs. Men were more capable in performing ADLs and more independent than women. TUG validated self-reported ADLs. When classified by 'interval of need' 41% (332/810) were independent, 39% (317/810) required help less often than daily, 12% (94/810) required help at regular times of the day and 8% (67/810) required 24-hour care. Of care-home residents, 94% (77/82) required daily help or 24-hour care. Future need for 24-hour care for people aged 80 years or over in England and Wales is projected to increase by 82% from 2010 to 2030 with a demand for 630,000 care-home places by 2030. CONCLUSIONS: This analysis highlights the diversity of capability and levels of dependency in this cohort. A remarkably high proportion remain independent, particularly men. However a significant proportion of this population require 24-hour care at home or in care homes. Projections for the next 20 years suggest substantial increases in the number requiring 24-hour care due to population ageing and a proportionate increase in demand for care-home places unless innovative health and social care interventions are found.

Fecal occult blood test in patients on low-dose aspirin, warfarin, clopidogrel, or non-steroidal anti-inflammatory drugs.

AIM: To determine the effect of anticoagulants and antiplatelet medications on the positive-predictive-value of fecal occult blood test (FOBT). METHODS: All patients who underwent a colonoscopy at our institution from 1995 to 2006 for a positive FOBT were identified. Medical records were searched, and patients were stratified into five groups selected a priori: low-dose aspirin, NSAIDs, warfarin, clopidogrel, or controls. The positive-predictive-value of FOBT for advanced colonic neoplasia was computed for each group. RESULTS: During the study period, 1,126 patients underwent colonoscopy for a positive FOBT and met entry criteria. The average age of study participants was 69 years and most were men. The positive-predictive-value of FOBT for advanced colon neoplasia was significantly higher in the control group (30.5%) when compared to those on low-dose aspirin (20.5%; p = 0.003), NSAIDs (19.7%; p = 0.003), clopidogrel (7.3%; p = 0.002), or warfarin (20%; p = 0.05). The positive-predictive-value of FOBT was significantly lower for those on clopidogrel than those on low-dose aspirin (p = 0.04) and NSAIDs (p = 0.05), but not warfarin (p = 0.08). The positive-predictive-value for FOBT was similar for those on aspirin, NSAIDs, and warfarin. There was a linear trend between the number of number of positive FOBT cards and prevalence of advanced colon neoplasia (p = 0.01). CONCLUSION: Anticoagulants and antiplatelet medications lower the positive-predictive-value of FOBT for advance colonic neoplasia and should be stopped if clinically feasible prior to stool collection.

Is BRAF mutation associated with interval colorectal cancers?

INTRODUCTION: Colon cancers diagnosed in the interval after a complete colonoscopy may occur due to limitations of colonoscopy or due to rapid tumor growth. The aim of this study was to compare the association of BRAF V600E mutation in interval versus non-interval colorectal cancers and to determine the relationship between BRAF mutation and 5-year survival. METHODS: We searched our institution's cancer registry for interval cancers, defined as colon cancers that developed within 5 years of a complete colonoscopy. These were frequency matched to patients with non-interval cancers. Archived cancer specimens were tested for BRAF V600E mutation and MSI. RESULTS: There were 63 interval and 131 non-interval cancers. BRAF mutation was present in 28% of interval cancers compared to 19% of non-interval cancers (P = 0.18). In a multivariable logistic regression model, proximal location (OR 1.85; 95% CI 1.01-3.8) and MSI (OR 2.7; 95% 1.1-6.8) were independently associated with interval cancers while BRAF mutation was not (OR 0.93; 95% CI 0.36-2.38). BRAF mutation portended a poor 5-year survival, particularly among microsatellite stable cancers. CONCLUSIONS: BRAF mutation is not associated with interval cancers but is a marker of poor prognosis, particularly in microsatellite stable cancers.

Childhood tonsillectomy: who is referred and what treatment choices are made? Baseline findings from the North of England and Scotland Study of Tonsillectomy and Adenotonsillectomy in Children (NESSTAC).

BACKGROUND: Tonsillectomies are frequently performed, yet variations exist in tonsillectomy rates. Clinicians use guidelines, but complex psychosocial influences on childhood tonsillectomy include anecdotal evidence of parental enthusiasm. Studies indicate that undergoing preferred treatment improves outcome. Despite the enthusiasm with which tonsillectomy is offered and sought, there is little evidence of efficacy. This resulted in a randomised controlled trial to evaluate the cost-effectiveness of (adeno)tonsillectomy in children with recurrent sore throats. OBJECTIVE: To compare characteristics of children entering the randomised trial with those recruited to a parallel, non-randomised study, to establish trends in referral and patient preferences for treatment. DESIGN: Baseline data from a randomised controlled trial with parallel non-randomised preference study, comparing surgical intervention with medical treatment in children aged 4-15 years with recurrent sore throat referred to five secondary care otolaryngology departments located in the north of England or west central Scotland. RESULTS: Centres assessed 1546 children; 21% were not eligible for tonsillectomy. Among older children (8-15 years), girls were significantly more likely to be referred to secondary care. Of 1015 eligible children, 268 (28.2%) agreed to be randomised, while 461 (45.4%) agreed to the parallel, non-randomised preference study, with a strong preference for tonsillectomy. Participants reporting that progress at school had been impeded or with more experience of persistent sore throat were more likely to seek tonsillectomy. Referred boys were more likely than girls to opt for medical treatment. Socio-economic data showed no effect. CONCLUSION: Preference for tonsillectomy reflects educational impact and recent experience, rather than age or socio-economic status.

CIMP status of interval colon cancers: another piece to the puzzle.

OBJECTIVES: Colon cancers diagnosed in the interval after a complete colonoscopy may occur due to limitations of colonoscopy or due to the development of new tumors, possibly reflecting molecular and environmental differences in tumorigenesis resulting in rapid tumor growth. In a previous study from our group, interval cancers (colon cancers diagnosed within 5 years of a complete colonoscopy) were almost four times more likely to demonstrate microsatellite instability (MSI) than non-interval cancers. In this study we extended our molecular analysis to compare the CpG island methylator phenotype (CIMP) status of interval and non-interval colorectal cancers and investigate the relationship between the CIMP and MSI pathways in the pathogenesis of interval cancers. METHODS: We searched our institution's cancer registry for interval cancers, defined as colon cancers that developed within 5 years of a complete colonoscopy. These were frequency matched in a 1:2 ratio by age and sex to patients with non-interval cancers (defined as colon cancers diagnosed on a patient's first recorded colonoscopy). Archived cancer specimens for all subjects were retrieved and tested for CIMP gene markers. The MSI status of subjects identified between 1989 and 2004 was known from our previous study. Tissue specimens of newly identified cases and controls (between 2005 and 2006) were tested for MSI. RESULTS: There were 1,323 cases of colon cancer diagnosed over the 17-year study period, of which 63 were identified as having interval cancer and matched to 131 subjects with non-interval cancer. Study subjects were almost all Caucasian men. CIMP was present in 57% of interval cancers compared to 33% of non-interval cancers (P=0.004). As shown previously, interval cancers were more likely than non-interval cancers to occur in the proximal colon (63% vs. 39%; P=0.002), and have MSI 29% vs. 11%, P=0.004). In multivariable logistic regression model, proximal location (odds ratio (OR) 1.85; 95% confidence interval (CI) 1.01-3.8), MSI (OR 2.7; 95% CI 1.1-6.8) and CIMP (OR 2.41; 95% CI 1.2-4.9) were independently associated with interval cancers. CIMP was associated with interval cancers independent of MSI status. There was no difference in 5-year survival between the two groups. CONCLUSIONS: Interval cancers are more likely to arise in the proximal colon and demonstrate CIMP, which suggests there may be differences in biology between these and non-interval CRC. Additional studies are needed to determine whether interval cancers arise as a result of missed lesions or accelerated neoplastic progression.

Variation in detection of adenomas and polyps by colonoscopy and change over time with a performance improvement program.

BACKGROUND & AIMS: There has been no prospective, community-based study to track changes in adenoma detection by individual physicians over time and to determine the effectiveness of targeted educational interventions. METHODS: We prospectively collected information on 47,253 screening colonoscopies in average-risk individuals 50 years and older performed by a community-based practice in the Twin Cities of Minnesota. During a period of 3 years, 5 specific interventions were implemented; each was designed to improve adenoma detection rates. Controlling for patient-related and procedure-related factors, rates of adenoma detection and 3-year trends for individual physicians were plotted, and intraclass correlation coefficients were calculated. Generalized estimating equations were used to identify factors associated with detection of adenomas and polyps. RESULTS: At least 1 polyp and 1 adenoma were found in 36% and 22% of examinations, respectively. Adenoma detection rates by endoscopists ranged from 10%-39%. There was no significant improvement during the study period despite planned, systematic interventions. Factors associated with adenoma detection included age of the patient (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.02-1.02), male sex (OR, 1.53; 95% CI, 1.34-1.74), and adequate preparation quality (OR, 2.26; 95% CI, 1.64-3.12). CONCLUSIONS: The detection of adenomas by individual physicians during a 3-year period varied and did not appear to change between individual endoscopists, despite planned, systematic interventions. This indicates that other targeted interventions might be required to improve adenoma detection rates among experienced, community gastroenterologists.

A randomized controlled clinical trial of palliative therapies for patients with inoperable esophageal cancer.

OBJECTIVES: A dramatic rise in incidence, an aging population, and expensive palliative treatments have led to an escalating burden on clinicians managing inoperable esophageal cancer with only limited evidence of effectiveness. This study compares the clinical effectiveness and cost-effectiveness of self-expanding metal stents (SEMSs) with other palliative therapies to aid clinicians in making an evidence-based treatment choice. METHODS: We conducted a prospective, multicenter, randomized, controlled, clinical trial with 215 patients followed until death or study closure. The primary outcome measures were dysphagia, quality of life (QL) 6 weeks following treatment, and total cost of treatment. Secondary outcome measures included treatment-associated morbidity, mortality, survival, and cost-effectiveness. An intention-to-treat analysis was carried out. RESULTS: There was a significant difference in mean dysphagia grade between treatment arms 6 weeks following treatment (P=0.046), with worse swallowing reported by rigid stent-treated patients (mean dysphagia score difference=-0.49; 95% confidence interval (CI) -0.10 to -0.89, P=0.014). Global QL scores were lower at both 1 and 6 weeks following treatment for patients treated by SEMSs (mean difference QL index week 1=-0.66; 95% CI: -0.02 to -1.30, P=0.04; mean difference QL index week 6=-1.01; 95% CI -0.30 to -1.72, P=0.006). These findings were associated with higher post-procedure pain scores in the SEMS patient group (mean difference of the European Organisation for Research and Treatment of Cancer QLQ C-30 pain symptom score at week 1=11.13; 95% CI: 2.89-19.4; P=0.01). Although mean EQ-5D QL values differed between the treatments (P<0.001), this difference dissipated following generation of quality-adjusted life year values. Total costs varied between treatment arms but these findings canceled out when SEMSs were compared with non-SEMS therapies (95% CI -845.15-1,332.62). These results were robust to sensitivity analysis. There were no differences in the in-hospital mortality or early complication rates, but late complications were more frequent after rigid stenting (risk ratio=2.47; 95% CI 1.88-3.04). There was a survival advantage for non-stent-treated patients (log-rank statistic=4.21, P=0.04). CONCLUSIONS: The treatment choice for patients with inoperable esophageal cancer should be between a SEMS or a non-stent treatment after consideration has been given to both patient and tumor characteristics and clinician and patient preferences.

A pooled analysis of advanced colorectal neoplasia diagnoses after colonoscopic polypectomy.

BACKGROUND & AIMS: Limited data exist regarding the actual risk of developing advanced adenomas and cancer after polypectomy or the factors that determine risk. METHODS: We pooled individual data from 8 prospective studies comprising 9167 men and women aged 22 to 80 with previously resected colorectal adenomas to quantify their risk of developing subsequent advanced adenoma or cancer as well as identify factors associated with the development of advanced colorectal neoplasms during surveillance. RESULTS: During a median follow-up period of 47.2 months, advanced colorectal neoplasia was diagnosed in 1082 (11.8%) of the patients, 58 of whom (0.6%) had invasive cancer. Risk of a metachronous advanced adenoma was higher among patients with 5 or more baseline adenomas (24.1%; standard error, 2.2) and those with an adenoma 20 mm in size or greater (19.3%; standard error, 1.5). Risk factor patterns were similar for advanced adenomas and invasive cancer. In multivariate analyses, older age (P < .0001 for trend) and male sex (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.19-1.65) were associated significantly with an increased risk for metachronous advanced neoplasia, as were the number and size of prior adenomas (P < .0001 for trend), the presence of villous features (OR, 1.28; 95% CI, 1.07-1.52), and proximal location (OR, 1.68; 95% CI, 1.43-1.98). High-grade dysplasia was not associated independently with metachronous advanced neoplasia after adjustment for other adenoma characteristics. CONCLUSIONS: Occurrence of advanced colorectal neoplasia is common after polypectomy. Factors that are associated most strongly with risk of advanced neoplasia are patient age and the number and size of prior adenomas.

Validation of a questionnaire to assess self-reported colorectal cancer screening status using face-to-face administration.

PURPOSE: The aim of this study was to assess the accuracy of a National Cancer Institute (NCI)-developed colorectal cancer screening questionnaire. METHODS: We conducted 36 cognitive interviews and made iterative changes to the questionnaire to improve comprehension. The revised questionnaire was administered face-to-face to 201 participants. The primary outcome was agreement between questionnaire responses and medical records for whether or not a participant was up-to-date for any colorectal cancer screening test. RESULTS: Comprehension of descriptions and questions was generally good; however, the barium enema description required several revisions. The sensitivity of the questionnaire for up-to-date screening status was 94%, specificity 63%, and concordance 88%. CONCLUSIONS: The modified questionnaire was highly sensitive for determining if a person was up-to-date for any colorectal cancer screening test, although the specificity was low. Given the difficulty of obtaining all relevant records, self-report using this questionnaire is a reasonable option for identifying people who have undergone testing.

Colorectal adenomas in a randomized folate trial: the role of baseline dietary and circulating folate levels.

The Aspirin/Folate Polyp Prevention Study is a randomized, placebo-controlled trial of aspirin use and folic acid supplementation and incidence of colorectal adenomas in individuals with a history of these lesions. The trial showed that folic acid supplementation does not prevent the occurrence of new adenomas and may increase risk. We extend these results by investigating whether the effect of folic acid treatment differed by baseline dietary and circulating folate levels. Diet and supplement use were ascertained at baseline through a food-frequency questionnaire; a blood sample was used to determine plasma and RBC folate levels. Individuals were followed for 3 years (first follow-up) and subsequently for an additional 3 to 5 years (second follow up). We used generalized linear regression to estimate risk ratios and 95% confidence limits as measures of association. There was little evidence that baseline dietary and total folate intake, and plasma and RBC folate modified the association between folic acid treatment and risk of any adenomas or advanced lesions. However, there was a protective association of the highest tertile of dietary and total intake as well as circulating folate with risk of any adenomas among those in the placebo group but no association among individuals in the folic acid group. Our findings support the idea that although moderate doses of folate may be protective compared with deficiency, at some point of sufficiency, supplementation provides no additional benefit.

Two-year progression from mild cognitive impairment to dementia: to what extent do different definitions agree?

OBJECTIVES: To determine the 2-year outcome from 16 different current classifications of mild cognitive impairment (MCI) in a population-based sample. DESIGN: Prospective cohort study: baseline and 2-year follow-up phases. SETTING: Large-scale multicenter study, United Kingdom. PARTICIPANTS: : Thirteen thousand four individuals aged 65 and older from the Medical Research Council Cognitive Function and Ageing Study. From this, a subsample of 2,640 individuals was selected and completed a more-detailed cognitive assessment. Individuals who underwent further assessment were asked to complete annual or 2-year follow-ups. MEASUREMENTS: Information on sociodemographic status, general health, cognitive impairment and functional ability were collected using a structured interview. Individuals were classified according to 16 different definitions of MCI. These were applied retrospectively. RESULTS: The dominant outcome across definitions was an impairment that was not classifiable or reversion to normality. Progression to dementia was variable and generally poor. Overall progression was highest in classifications in which impairment extended to memory and nonmemory domains. Predictability was age dependent in some but not all classifications. CONCLUSION: Current classifications of MCI have variable outcomes in population-based samples. Progression to dementia is relatively rare and is dependent on age and definition. Selection criteria developed for the clinic are based on a "high risk" approach that leads to exclusion of a large percentage of the impaired population who are neither normal nor demented and for whom no intervention options are currently available. A refined definition of this construct is urgently needed if MCI is to be used to predict dementia in population-based studies.