Abstract Background The recently developed MDACC nomogram purports to predict the risk of bone-only metastasis in women with early breast carcinoma based on five clinical and pathological characteristics. We set out to externally validate and assess its robustness using a tertiary breast cancer centre database. Methods All consecutive women treated for early breast cancer in our centre between January 1989 and December 2013 and who had all the nomogram variables documented were eligible for analysis. Results We identified 1255 eligible women for external validation analysis. The median follow-up was 54 months (range: 1–312) and time to initial metastasis 20 months (range: 1–80). The correspondence between the actual bone-only metastasis and the nomogram predictions implied poor calibration of the nomogram in the validation cohort, be it in the whole cohort or when stratified by breast cancer subtype. Conclusion This external validation study of the MDACC nomogram showed limitations in its generalizability to a new and independent European patient population.

The purpose of this clinical practice update expert review is to define the key principles in the diagnosis and management of low-grade dysplasia (LGD) in Barrett’s esophagus patients. The best practices outlined in this review are based on relevant publications, including systematic reviews and expert opinion (when applicable). Practice Advice 1: The extent of Barrett’s esophagus should be defined using a standardized grading system documenting the circumferential and maximal extent of the columnar lined esophagus (Prague classification) with a clear description of landmarks and visible lesions (nodularity, ulceration) when present. Practice Advice 2: Given the significant interobserver variability among pathologists, the diagnosis of Barrett’s esophagus with LGD should be confirmed by an expert gastrointestinal pathologist (defined as a pathologist with a special interest in Barrett’s esophagus–related neoplasia who is recognized as an expert in this field by his/her peers). Practice Advice 3: Expert pathologists should report audits of their diagnosed cases of LGD, such as the frequency of LGD diagnosed among surveillance patients and/or the difference in incidence of neoplastic progression among patients diagnosed with LGD vs nondysplastic Barrett’s esophagus. Practice Advice 4: Patients in whom the diagnosis of LGD is downgraded to nondysplastic Barrett’s esophagus should be managed as nondysplastic Barrett’s esophagus. Practice Advice 5: In Barrett’s esophagus patients with confirmed LGD (based on expert gastrointestinal pathology review), repeat upper endoscopy using high-definition/high-resolution white-light endoscopy should be performed under maximal acid suppression (twice daily dosing of proton pump inhibitor therapy) in 8–12 weeks. Practice Advice 6: Under ideal circumstances, surveillance biopsies should not be performed in the presence of active inflammation (erosive esophagitis, Los Angeles grade C and D). Pathologists should be informed if biopsies are obtained in the setting of erosive esophagitis and if pathology findings suggest LGD, or if no biopsies are obtained, surveillance biopsies should be repeated after the anti-reflux regimen has been further intensified. Practice Advice 7: Surveillance biopsies should be performed in a four-quadrant fashion every 1–2 cm with target biopsies obtained from visible lesions taken first. Practice Advice 8: Patients with a confirmed histologic diagnosis of LGD should be referred to an endoscopist with expertise in managing Barrett’s esophagus–related neoplasia practicing at centers equipped with high-definition endoscopy and capable of performing endoscopic resection and ablation. Practice Advice 9: Endoscopic resection should be performed in Barrett’s esophagus patients with LGD with endoscopically visible abnormalities (no matter how subtle) in order to accurately assess the grade of dysplasia. Practice Advice 10: In patients with confirmed Barrett’s esophagus with LGD by expert GI pathology review that persists on a second endoscopy, despite intensification of acid-suppressive therapy, risks and benefits of management options of endoscopic eradication therapy (specifically adverse events associated with endoscopic resection and ablation), and ongoing surveillance should be discussed and documented. Practice Advice 11: Endoscopic eradication therapy should be considered in patients with confirmed and persistent LGD with the goal of achieving complete eradication of intestinal metaplasia. Practice Advice 12: Patients with LGD undergoing surveillance rather than endoscopic eradication therapy should undergo surveillance every 6 months times 2, then annually unless there is reversion to nondysplastic Barrett’s esophagus. Biopsies should be obtained in 4-quadrants every 1–2 cm and of any visible lesions. Practice Advice 13: In patients with Barrett’s esophagus–related LGD undergoing ablative therapy, radiofrequency ablation should be used. Practice Advice 14: Patients completing endoscopic eradication therapy should be enrolled in an endoscopic surveillance program. Patients who have achieved complete eradication of intestinal metaplasia should undergo surveillance every year for 2 years and then every 3 years thereafter to detect recurrent intestinal metaplasia and dysplasia. Patients who have not achieved complete eradication of intestinal metaplasia should undergo surveillance every 6 months for 1 year after the last endoscopy, then annually for 2 years, then every 3 years thereafter. Practice Advice 15: Following endoscopic eradication therapy, the biopsy protocol of obtaining biopsies in 4 quadrants every 2 cm throughout the length of the original Barrett’s esophagus segment and any visible columnar mucosa is suggested. Practice Advice 16: Endoscopists performing endoscopic eradication therapy should report audits of their rates of complete eradication of dysplasia and intestinal metaplasia and adverse events in clinical practice.

Abstract In 2010, EUSOMA published a position paper, describing a set of benchmark quality indicators (QIs) that could be adopted by breast centres to allow standardised auditing and quality assurance and to establish an agreed minimum standard of care. Towards the end of 2014, EUSOMA decided to update the paper on QIs to consider and incorporate new scientific knowledge in the field. Several new QIs have been included to address the need for improved follow-up care of patients following primary treatments. With regard to the management of elderly patients, considering the complexity, the expert group decided that, for some specific quality indicators, if centres fail to meet the minimum standard, older patients will be excluded from analysis, provided that reasons for non-adherence to the QI are specified in the clinical chart and are identified at the review of the clinical records. In this way, high standards are promoted, but centres are able to identify and account for the effect of non-standard treatment in the elderly. In the paper, there is no QI for outcome measurements, such as relapse rate or overall survival. However, it is hoped that this will be developed in time as the databases mature and user experience increases. All breast centres are required to record outcome data as accurately and comprehensively as possible to allow this to occur. In the paper, different initiatives undertaken at international and national level to audit quality of care through a set of QIs have been mentioned.

Background & Aims A system is needed to determine the risk of patients with Barrett’s esophagus for progression to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). We developed and validated a model to determine of progression to HGD or EAC in patients with BE, based on demographic data and endoscopic and histologic findings at the time of index endoscopy. Methods We performed a longitudinal study of patients with BE at 5 centers in United States and 1 center in Netherlands enrolled in the Barrett’s Esophagus Study database from 1985 through 2014. Patients were excluded from the analysis if they had less than 1 year of follow-up, were diagnosed with HGD or EAC within the past year, were missing baseline histologic data, or had no intestinal metaplasia. Seventy percent of the patients were used to derive the model and 30% were used for the validation study. The primary outcome was development of HGD or EAC during the follow-up period (median, 5.9 years). Survival analysis was performed using the Kaplan-Meier method. We assigned a specific number of points to each BE risk factor, and point totals (scores) were used to create categories of low, intermediate, and high risk. We used Cox regression to compute hazard ratios and 95% confidence intervals to determine associations between risk of progression and scores. Results Of 4584 patients in the database, 2697 were included in our analysis (84.1% men; 87.6% Caucasian; mean age, 55.4 ± 20.1 years; mean body mass index, 27.9 ± 5.5 kg/m2; mean length of BE, 3.7 ± 3.2 cm). During the follow-up period, 154 patients (5.7%) developed HGD or EAC, with an annual rate of progression of 0.95%. Male sex, smoking, length of BE, and baseline-confirmed low-grade dysplasia were significantly associated with progression. Scores assigned identified patients with BE that progressed to HGD or EAC with a c-statistic of 0.76 (95% confidence interval, 0.72–0.80; P < .001). The calibration slope was 0.9966 (P = .99), determined from the validation cohort. Conclusions We developed a scoring system (Progression in Barrett’s Esophagus score) based on male sex, smoking, length of BE, and baseline low-grade dysplasia that identified patients with BE at low, intermediate, and high risk for HGD or EAC. This scoring system might be used in management of patients.

Background & Aims Conventional transarterial chemoembolization (cTACE) is used to treat patients with hepatocellular carcinoma (HCC). Radioembolization is a minimally invasive procedure that involves implantation of radioactive micron-sized particles loaded with yttrium-90 (Y90) inside the blood vessels that supply a tumor. We performed a randomized, phase 2 study to compare the effects of cTACE and Y90 radioembolization in patients with HCC. Methods From October 2009 through October 2015, we reviewed patients with HCC of all Barcelona Clinic Liver Cancer (BCLC) stages for eligibility. Of these, 179 patients with BCLC stages A or B met our enrollment criteria and were candidates for cTACE or Y90 therapy. Patients were assigned randomly to groups that received Y90 therapy (n = 24; 50% Child–Pugh A) or cTACE (n = 21; 71% Child–Pugh A). The primary outcome was time to progression (TTP), evaluated by intention-to-treat analysis. Secondary outcomes included safety, rate of response (based on tumor size and necrosis criteria), and Kaplan–Meier survival time. We performed inverse probability of censoring weighting and competing risk analyses. Results Patients in the Y90 radioembolization group had significant longer median TTP (>26 mo) than patients in the cTACE group (6.8 mo; P = .0012) (hazard ratio, 0.122; 95% confidence interval [CI], 0.027–0.557; P = .007). This was confirmed by competing risk and inverse probability of censoring weighting analyses accounting for transplantation or death. A significantly greater proportion of patients in the cTACE group developed diarrhea (21%) than in the Y90 group (0%; P = .031) or hypoalbuminemia (58% in the cTACE group vs 4% in the Y90 group; P < .001). Similar proportions of patients in each group had a response to therapy, marked by necrosis (74% in the cTACE group vs 87% in the Y90 group) (P = .433). The median survival time, censored to liver transplantation, was 17.7 months for the cTACE group (95% CI, 8.3–not calculable) vs 18.6 months for the Y90 group (95% CI, 7.4–32.5) (P = .99). Conclusions In a randomized phase 2 study of patients with HCC of BCLC stages A or B, we found Y90 radioembolization to provide significantly longer TTP than cTACE. Y90 radioembolization provides better tumor control and could reduce drop-out from transplant waitlists. ClinicalTrials.gov no. NCT00956930.

Abstract Purpose Determining the appropriate rate of radiotherapy (RT) utilization is important for health care planning and resource allocation. The difference between the observed and the appropriate RT rate is influenced by the choice of a criterion based benchmarking (CBB) or evidence-based estimates (EBEST) measure. Our primary objective was to determine the utilization of radiotherapy for cancers of the breast (B), cervix (C), lung (L), prostate (P) and rectum (R) in Alberta (AB) Canada and to compare the observed RT rates to estimates of need derived from the criterion based benchmarking (CBB) and evidence-based estimates (EBEST). Materials and methods All incident cases of B,C,L,P and R cancers diagnosed in AB during 2004-8 (prior to the decentralization of provincial RT capacity) were identified from the Alberta Cancer Registry. Patients receiving RT within one year (RT-1y) of diagnosis were identified and the proportion receiving RT-1y was then calculated. Factors associated with RT utilization were analysed by region. Estimates of the need for RT were derived from CBB and EBEST methods in the literature. Results A total of n = 68,164 cancer cases were identified from the ACR. RT-1y rates (95% C.I.) were B: 51.5% (50.1–52.9), C: 48.9% (43.8–54.0), L: 37.1% (35.4–38.8), P: 26.9% (25.1–28.7) and R: 39.3% (36.5–42.1). Observed rates of RT in AB were lower than estimates derived using the CBB and EBEST estimates. Shortfalls varied across cancer sites according to whether a CBB or EBEST estimate was used ranging from a low of -0.3% in cancer of the cervix to a high of 30.3% in rectal cancer. Conclusions RT shortfalls exist in the utilization of RT in AB, Canada despite centralized cancer care and a publically funded health care system. Decisions to address shortfalls need to be mindful of how model selection can impact on findings.

Abstract Aims In Italy, incidence rates of thyroid cancer (TC) are among the highest worldwide with substantial intracountry heterogeneity. The aim of the study was to examine time trends of TC incidence in Italy and to estimate the proportion of TC cases potentially attributable to overdiagnosis. Methods Data on TC cases reported to Italian cancer registries during 1998–2012 aged <85 years were included. Age-standardised incidence rates (ASR) were computed by sex, period, and histology. TC overdiagnosis was estimated by sex, period, age, and Italian region. Results In Italy between 1998–2002 and 2008–2012, TC ASR increased of 74% in women (from 16.2 to 28.2/100,000) and of 90% in men (from 5.3 to 10.1/100,000). ASR increases were nearly exclusively due to papillary TC (+91% in women, +120% in men). In both sexes, more than three-fold differences emerged between regions with highest and lowest ASR. Among TC cases diagnosed in 1998–2012 in Italy, we estimated that overdiagnosis accounted for 75% of cases in women and 63% in men and increased over the study period leading to overdiagnosis of 79% in women and 67% in men in 2008–2012. Notably, overdiagnosis was over 80% among women aged <55 years, and substantial variations were documented across Italian regions, in both genders. Conclusion(s) Incidence rates of TC are steadily increasing in Italy and largely due to overdiagnosis. These findings call for an update of thyroid gland examination practices in the asymptomatic general population, at national and regional levels.

Abstract Background Resection of breast cancer liver metastases (BCLM) combined with systemic treatment is increasingly accepted but not offered as therapeutic option. New evidence of the additional value of surgery in these patients is scarce while prognoses without surgery remains poor. Patients and methods For this case matched analysis, all nationally registered patients with BCLM confined to the liver in the Netherlands (systemic group; N = 523) were selected and compared with patients who received systemic treatment and underwent hepatectomy (resection group; N = 139) at a hepatobiliary centre in France. Matching was based on age, decade when diagnosed, interval to metastases, maximum metastases size, single or multiple tumours, chemotherapy, hormonal or targeted therapy after diagnosis. Based on published guidelines, palliative systemic treatment strategies are similar in both European countries. Results Between 1983 and 2013, 3894 patients were screened for inclusion. Overall median follow-up was 80 months (95% CI 70–90 months). The median, 3- and 5-year overall survival of the whole population was 19 months, 29% and 19%, respectively. The resection and systemic group had median survival of 73 vs. 13 months (P < 0.001), respectively. Three and 5-year survival was 18% and 10% for the systemic group and 75% and 54% for the resection group, respectively. After matching, the resection group had a median overall survival of 82 months with a 3- and 5-year overall survival of 81% and 69%, respectively, compared with a median overall survival of 31 months in the systemic group with a 3- and 5-year overall survival of 32% and 24%, respectively (HR 0.28, 95% CI 0.15–0.52; P < 0.001). Conclusions For patients with BCLM, liver resection combined with systemic treatment results in improved overall survival compared to systemic treatment alone. Liver resection should be considered in selected cases.

Abstract Background Heart failure is a complex clinical syndrome that occurs at the end stage of heart disease. Despite advances in therapy for heart failure, improvement of clinical outcomes remains a challenge for physicians. The identification of treatment response early in the course of disease would be useful to improve management of these patients. The aim of this study was to identify novel biomarkers in plasma that could predict treatment response in patients with heart failure. Methods Patients with heart failure who met inclusion and exclusion criteria according to the guidelines of the European Society of Cardiology were recruited. Uptitration of angiotensin-converting enzyme inhibitors and β blockers was performed over 6 months. Patients were followed up for clinical events within the next 24 months. Plasma proteins in patients who responded to standard treatment (responders) were compared with patients who died or were re-admitted for heart failure (non-responders). Plasma samples were depleted of 14 high abundance proteins with a multiple affinity removal system column (MARS). Then plasma samples were analysed on two-dimensional liquid chromatography coupled to a tandem mass spectrometry (2D LC-ESI-MS/MS) in high definition mode (HDMSE) to identify and quantify the different expression of proteins in plasma. Finally, ELISA was used to verify candidate biomarkers. Findings Participants were 100 patients with heart failure matched for sex and age (50 responders [25 women], 50 non-responders [25 women], mean age 76·6 years [SD 8·1]). Of the non-responders, 18 died and 32 were re-admitted to hospital. 2D LC-ESI-MS/MS showed that the expression of neurotrimin (NTM) was highly upregulated, by 26·5 times (p<0·0001), in the responder group compared with the non-responder group. ELISA in the verification phase showed that the concentrations of NTM in plasma were significantly higher in the responders and lower in the non-responders (mean 4·73 log10 relative light units [SD 0·07] vs 4·70 [0·08], p=0·036). When ANOVA with Bonferroni post-hoc comparisons was used in three outcome subgroups (responders, patients re-admitted to hospital, and deaths), NTM concentrations were significantly different between death and the other groups (higher in responder vs death group, p<0·0001; higher in re-admission vs death group, p=0·001). Interpretation Our findings suggest that NTM as a novel biomarker in heart failure will not only add information to understand the pathophysiological mechanisms of heart failure better, but also might provide a more accurate prediction of treatment response to guide medical therapy. In addition, a novel therapeutic target could be identified for design of drugs to improve outcomes. Futher work is required in larger populations to confirm this biomarker. Funding European Union's Seventh Framework Programme (BIOSTAT-CHF), John and Lucille van Geest Foundation.

Abstract Background Patients with invasive residual disease after neoadjuvant chemotherapy (NACT) are considered to have chemo-resistant breast cancer. Bisphosphonates are an established treatment for bone metastases and are of potential benefit as adjuvant treatment in early breast cancer. Patients and methods Patients who had invasive tumour residuals (ypT1-4 and/or ypN+) after a minimum of four cycles of anthracycline-taxane-containing NACT were eligible for the NeoAdjuvant Trial Add-oN study. Patients were randomised within 3 years after surgery to receive zoledronate 4 mg i.v. for 5 years versus observation. Zoledronate was given every 4 weeks for the first 6 months, every 3 months for the following 2 years, and every 6 months for the last 2.5 years. Primary objective was disease-free survival. Results After a median time of 54.7 months no difference in disease-free survival was observed between the zoledronate and observation groups (hazard ratio [HR] 0.960, 95% confidence interval [CI] 0.709–1.30, log rank P = 0.789). Various subgroups were examined without identifying a treatment effect of zoledronate. Patients over 55 years of age showed a HR of 0.832 in favour of zoledronate, but the result was not significant (P = 0.480). A similar result was obtained for overall survival with a HR of 1.19 (95% CI 0.79–1.79; log rank P = 0.408). Zoledronate was well tolerated and no new toxicity signal was identified. Conclusion Postneoadjuvant treatment with zoledronate does not improve outcome in patients without pathological complete response after neoadjuvant anthracycline-taxane-based chemotherapy for early breast cancer.

Abstract Background The recently developed MDACC nomogram purports to predict the risk of bone-only metastasis in women with early breast carcinoma based on five clinical and pathological characteristics. We set out to externally validate and assess its robustness using a tertiary breast cancer centre database. Methods All consecutive women treated for early breast cancer in our centre between January 1989 and December 2013 and who had all the nomogram variables documented were eligible for analysis. Results We identified 1255 eligible women for external validation analysis. The median follow-up was 54 months (range: 1–312) and time to initial metastasis 20 months (range: 1–80). The correspondence between the actual bone-only metastasis and the nomogram predictions implied poor calibration of the nomogram in the validation cohort, be it in the whole cohort or when stratified by breast cancer subtype. Conclusion This external validation study of the MDACC nomogram showed limitations in its generalizability to a new and independent European patient population.

The purpose of this clinical practice update expert review is to define the key principles in the diagnosis and management of low-grade dysplasia (LGD) in Barrett’s esophagus patients. The best practices outlined in this review are based on relevant publications, including systematic reviews and expert opinion (when applicable). Practice Advice 1: The extent of Barrett’s esophagus should be defined using a standardized grading system documenting the circumferential and maximal extent of the columnar lined esophagus (Prague classification) with a clear description of landmarks and visible lesions (nodularity, ulceration) when present. Practice Advice 2: Given the significant interobserver variability among pathologists, the diagnosis of Barrett’s esophagus with LGD should be confirmed by an expert gastrointestinal pathologist (defined as a pathologist with a special interest in Barrett’s esophagus–related neoplasia who is recognized as an expert in this field by his/her peers). Practice Advice 3: Expert pathologists should report audits of their diagnosed cases of LGD, such as the frequency of LGD diagnosed among surveillance patients and/or the difference in incidence of neoplastic progression among patients diagnosed with LGD vs nondysplastic Barrett’s esophagus. Practice Advice 4: Patients in whom the diagnosis of LGD is downgraded to nondysplastic Barrett’s esophagus should be managed as nondysplastic Barrett’s esophagus. Practice Advice 5: In Barrett’s esophagus patients with confirmed LGD (based on expert gastrointestinal pathology review), repeat upper endoscopy using high-definition/high-resolution white-light endoscopy should be performed under maximal acid suppression (twice daily dosing of proton pump inhibitor therapy) in 8–12 weeks. Practice Advice 6: Under ideal circumstances, surveillance biopsies should not be performed in the presence of active inflammation (erosive esophagitis, Los Angeles grade C and D). Pathologists should be informed if biopsies are obtained in the setting of erosive esophagitis and if pathology findings suggest LGD, or if no biopsies are obtained, surveillance biopsies should be repeated after the anti-reflux regimen has been further intensified. Practice Advice 7: Surveillance biopsies should be performed in a four-quadrant fashion every 1–2 cm with target biopsies obtained from visible lesions taken first. Practice Advice 8: Patients with a confirmed histologic diagnosis of LGD should be referred to an endoscopist with expertise in managing Barrett’s esophagus–related neoplasia practicing at centers equipped with high-definition endoscopy and capable of performing endoscopic resection and ablation. Practice Advice 9: Endoscopic resection should be performed in Barrett’s esophagus patients with LGD with endoscopically visible abnormalities (no matter how subtle) in order to accurately assess the grade of dysplasia. Practice Advice 10: In patients with confirmed Barrett’s esophagus with LGD by expert GI pathology review that persists on a second endoscopy, despite intensification of acid-suppressive therapy, risks and benefits of management options of endoscopic eradication therapy (specifically adverse events associated with endoscopic resection and ablation), and ongoing surveillance should be discussed and documented. Practice Advice 11: Endoscopic eradication therapy should be considered in patients with confirmed and persistent LGD with the goal of achieving complete eradication of intestinal metaplasia. Practice Advice 12: Patients with LGD undergoing surveillance rather than endoscopic eradication therapy should undergo surveillance every 6 months times 2, then annually unless there is reversion to nondysplastic Barrett’s esophagus. Biopsies should be obtained in 4-quadrants every 1–2 cm and of any visible lesions. Practice Advice 13: In patients with Barrett’s esophagus–related LGD undergoing ablative therapy, radiofrequency ablation should be used. Practice Advice 14: Patients completing endoscopic eradication therapy should be enrolled in an endoscopic surveillance program. Patients who have achieved complete eradication of intestinal metaplasia should undergo surveillance every year for 2 years and then every 3 years thereafter to detect recurrent intestinal metaplasia and dysplasia. Patients who have not achieved complete eradication of intestinal metaplasia should undergo surveillance every 6 months for 1 year after the last endoscopy, then annually for 2 years, then every 3 years thereafter. Practice Advice 15: Following endoscopic eradication therapy, the biopsy protocol of obtaining biopsies in 4 quadrants every 2 cm throughout the length of the original Barrett’s esophagus segment and any visible columnar mucosa is suggested. Practice Advice 16: Endoscopists performing endoscopic eradication therapy should report audits of their rates of complete eradication of dysplasia and intestinal metaplasia and adverse events in clinical practice.

Abstract In 2010, EUSOMA published a position paper, describing a set of benchmark quality indicators (QIs) that could be adopted by breast centres to allow standardised auditing and quality assurance and to establish an agreed minimum standard of care. Towards the end of 2014, EUSOMA decided to update the paper on QIs to consider and incorporate new scientific knowledge in the field. Several new QIs have been included to address the need for improved follow-up care of patients following primary treatments. With regard to the management of elderly patients, considering the complexity, the expert group decided that, for some specific quality indicators, if centres fail to meet the minimum standard, older patients will be excluded from analysis, provided that reasons for non-adherence to the QI are specified in the clinical chart and are identified at the review of the clinical records. In this way, high standards are promoted, but centres are able to identify and account for the effect of non-standard treatment in the elderly. In the paper, there is no QI for outcome measurements, such as relapse rate or overall survival. However, it is hoped that this will be developed in time as the databases mature and user experience increases. All breast centres are required to record outcome data as accurately and comprehensively as possible to allow this to occur. In the paper, different initiatives undertaken at international and national level to audit quality of care through a set of QIs have been mentioned.

Background & Aims A system is needed to determine the risk of patients with Barrett’s esophagus for progression to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). We developed and validated a model to determine of progression to HGD or EAC in patients with BE, based on demographic data and endoscopic and histologic findings at the time of index endoscopy. Methods We performed a longitudinal study of patients with BE at 5 centers in United States and 1 center in Netherlands enrolled in the Barrett’s Esophagus Study database from 1985 through 2014. Patients were excluded from the analysis if they had less than 1 year of follow-up, were diagnosed with HGD or EAC within the past year, were missing baseline histologic data, or had no intestinal metaplasia. Seventy percent of the patients were used to derive the model and 30% were used for the validation study. The primary outcome was development of HGD or EAC during the follow-up period (median, 5.9 years). Survival analysis was performed using the Kaplan-Meier method. We assigned a specific number of points to each BE risk factor, and point totals (scores) were used to create categories of low, intermediate, and high risk. We used Cox regression to compute hazard ratios and 95% confidence intervals to determine associations between risk of progression and scores. Results Of 4584 patients in the database, 2697 were included in our analysis (84.1% men; 87.6% Caucasian; mean age, 55.4 ± 20.1 years; mean body mass index, 27.9 ± 5.5 kg/m2; mean length of BE, 3.7 ± 3.2 cm). During the follow-up period, 154 patients (5.7%) developed HGD or EAC, with an annual rate of progression of 0.95%. Male sex, smoking, length of BE, and baseline-confirmed low-grade dysplasia were significantly associated with progression. Scores assigned identified patients with BE that progressed to HGD or EAC with a c-statistic of 0.76 (95% confidence interval, 0.72–0.80; P < .001). The calibration slope was 0.9966 (P = .99), determined from the validation cohort. Conclusions We developed a scoring system (Progression in Barrett’s Esophagus score) based on male sex, smoking, length of BE, and baseline low-grade dysplasia that identified patients with BE at low, intermediate, and high risk for HGD or EAC. This scoring system might be used in management of patients.

Background & Aims Conventional transarterial chemoembolization (cTACE) is used to treat patients with hepatocellular carcinoma (HCC). Radioembolization is a minimally invasive procedure that involves implantation of radioactive micron-sized particles loaded with yttrium-90 (Y90) inside the blood vessels that supply a tumor. We performed a randomized, phase 2 study to compare the effects of cTACE and Y90 radioembolization in patients with HCC. Methods From October 2009 through October 2015, we reviewed patients with HCC of all Barcelona Clinic Liver Cancer (BCLC) stages for eligibility. Of these, 179 patients with BCLC stages A or B met our enrollment criteria and were candidates for cTACE or Y90 therapy. Patients were assigned randomly to groups that received Y90 therapy (n = 24; 50% Child–Pugh A) or cTACE (n = 21; 71% Child–Pugh A). The primary outcome was time to progression (TTP), evaluated by intention-to-treat analysis. Secondary outcomes included safety, rate of response (based on tumor size and necrosis criteria), and Kaplan–Meier survival time. We performed inverse probability of censoring weighting and competing risk analyses. Results Patients in the Y90 radioembolization group had significant longer median TTP (>26 mo) than patients in the cTACE group (6.8 mo; P = .0012) (hazard ratio, 0.122; 95% confidence interval [CI], 0.027–0.557; P = .007). This was confirmed by competing risk and inverse probability of censoring weighting analyses accounting for transplantation or death. A significantly greater proportion of patients in the cTACE group developed diarrhea (21%) than in the Y90 group (0%; P = .031) or hypoalbuminemia (58% in the cTACE group vs 4% in the Y90 group; P < .001). Similar proportions of patients in each group had a response to therapy, marked by necrosis (74% in the cTACE group vs 87% in the Y90 group) (P = .433). The median survival time, censored to liver transplantation, was 17.7 months for the cTACE group (95% CI, 8.3–not calculable) vs 18.6 months for the Y90 group (95% CI, 7.4–32.5) (P = .99). Conclusions In a randomized phase 2 study of patients with HCC of BCLC stages A or B, we found Y90 radioembolization to provide significantly longer TTP than cTACE. Y90 radioembolization provides better tumor control and could reduce drop-out from transplant waitlists. ClinicalTrials.gov no. NCT00956930.

Abstract Purpose Determining the appropriate rate of radiotherapy (RT) utilization is important for health care planning and resource allocation. The difference between the observed and the appropriate RT rate is influenced by the choice of a criterion based benchmarking (CBB) or evidence-based estimates (EBEST) measure. Our primary objective was to determine the utilization of radiotherapy for cancers of the breast (B), cervix (C), lung (L), prostate (P) and rectum (R) in Alberta (AB) Canada and to compare the observed RT rates to estimates of need derived from the criterion based benchmarking (CBB) and evidence-based estimates (EBEST). Materials and methods All incident cases of B,C,L,P and R cancers diagnosed in AB during 2004-8 (prior to the decentralization of provincial RT capacity) were identified from the Alberta Cancer Registry. Patients receiving RT within one year (RT-1y) of diagnosis were identified and the proportion receiving RT-1y was then calculated. Factors associated with RT utilization were analysed by region. Estimates of the need for RT were derived from CBB and EBEST methods in the literature. Results A total of n = 68,164 cancer cases were identified from the ACR. RT-1y rates (95% C.I.) were B: 51.5% (50.1–52.9), C: 48.9% (43.8–54.0), L: 37.1% (35.4–38.8), P: 26.9% (25.1–28.7) and R: 39.3% (36.5–42.1). Observed rates of RT in AB were lower than estimates derived using the CBB and EBEST estimates. Shortfalls varied across cancer sites according to whether a CBB or EBEST estimate was used ranging from a low of -0.3% in cancer of the cervix to a high of 30.3% in rectal cancer. Conclusions RT shortfalls exist in the utilization of RT in AB, Canada despite centralized cancer care and a publically funded health care system. Decisions to address shortfalls need to be mindful of how model selection can impact on findings.

Abstract Aims In Italy, incidence rates of thyroid cancer (TC) are among the highest worldwide with substantial intracountry heterogeneity. The aim of the study was to examine time trends of TC incidence in Italy and to estimate the proportion of TC cases potentially attributable to overdiagnosis. Methods Data on TC cases reported to Italian cancer registries during 1998–2012 aged <85 years were included. Age-standardised incidence rates (ASR) were computed by sex, period, and histology. TC overdiagnosis was estimated by sex, period, age, and Italian region. Results In Italy between 1998–2002 and 2008–2012, TC ASR increased of 74% in women (from 16.2 to 28.2/100,000) and of 90% in men (from 5.3 to 10.1/100,000). ASR increases were nearly exclusively due to papillary TC (+91% in women, +120% in men). In both sexes, more than three-fold differences emerged between regions with highest and lowest ASR. Among TC cases diagnosed in 1998–2012 in Italy, we estimated that overdiagnosis accounted for 75% of cases in women and 63% in men and increased over the study period leading to overdiagnosis of 79% in women and 67% in men in 2008–2012. Notably, overdiagnosis was over 80% among women aged <55 years, and substantial variations were documented across Italian regions, in both genders. Conclusion(s) Incidence rates of TC are steadily increasing in Italy and largely due to overdiagnosis. These findings call for an update of thyroid gland examination practices in the asymptomatic general population, at national and regional levels.

Abstract Background Resection of breast cancer liver metastases (BCLM) combined with systemic treatment is increasingly accepted but not offered as therapeutic option. New evidence of the additional value of surgery in these patients is scarce while prognoses without surgery remains poor. Patients and methods For this case matched analysis, all nationally registered patients with BCLM confined to the liver in the Netherlands (systemic group; N = 523) were selected and compared with patients who received systemic treatment and underwent hepatectomy (resection group; N = 139) at a hepatobiliary centre in France. Matching was based on age, decade when diagnosed, interval to metastases, maximum metastases size, single or multiple tumours, chemotherapy, hormonal or targeted therapy after diagnosis. Based on published guidelines, palliative systemic treatment strategies are similar in both European countries. Results Between 1983 and 2013, 3894 patients were screened for inclusion. Overall median follow-up was 80 months (95% CI 70–90 months). The median, 3- and 5-year overall survival of the whole population was 19 months, 29% and 19%, respectively. The resection and systemic group had median survival of 73 vs. 13 months (P < 0.001), respectively. Three and 5-year survival was 18% and 10% for the systemic group and 75% and 54% for the resection group, respectively. After matching, the resection group had a median overall survival of 82 months with a 3- and 5-year overall survival of 81% and 69%, respectively, compared with a median overall survival of 31 months in the systemic group with a 3- and 5-year overall survival of 32% and 24%, respectively (HR 0.28, 95% CI 0.15–0.52; P < 0.001). Conclusions For patients with BCLM, liver resection combined with systemic treatment results in improved overall survival compared to systemic treatment alone. Liver resection should be considered in selected cases.

Abstract Background Heart failure is a complex clinical syndrome that occurs at the end stage of heart disease. Despite advances in therapy for heart failure, improvement of clinical outcomes remains a challenge for physicians. The identification of treatment response early in the course of disease would be useful to improve management of these patients. The aim of this study was to identify novel biomarkers in plasma that could predict treatment response in patients with heart failure. Methods Patients with heart failure who met inclusion and exclusion criteria according to the guidelines of the European Society of Cardiology were recruited. Uptitration of angiotensin-converting enzyme inhibitors and β blockers was performed over 6 months. Patients were followed up for clinical events within the next 24 months. Plasma proteins in patients who responded to standard treatment (responders) were compared with patients who died or were re-admitted for heart failure (non-responders). Plasma samples were depleted of 14 high abundance proteins with a multiple affinity removal system column (MARS). Then plasma samples were analysed on two-dimensional liquid chromatography coupled to a tandem mass spectrometry (2D LC-ESI-MS/MS) in high definition mode (HDMSE) to identify and quantify the different expression of proteins in plasma. Finally, ELISA was used to verify candidate biomarkers. Findings Participants were 100 patients with heart failure matched for sex and age (50 responders [25 women], 50 non-responders [25 women], mean age 76·6 years [SD 8·1]). Of the non-responders, 18 died and 32 were re-admitted to hospital. 2D LC-ESI-MS/MS showed that the expression of neurotrimin (NTM) was highly upregulated, by 26·5 times (p<0·0001), in the responder group compared with the non-responder group. ELISA in the verification phase showed that the concentrations of NTM in plasma were significantly higher in the responders and lower in the non-responders (mean 4·73 log10 relative light units [SD 0·07] vs 4·70 [0·08], p=0·036). When ANOVA with Bonferroni post-hoc comparisons was used in three outcome subgroups (responders, patients re-admitted to hospital, and deaths), NTM concentrations were significantly different between death and the other groups (higher in responder vs death group, p<0·0001; higher in re-admission vs death group, p=0·001). Interpretation Our findings suggest that NTM as a novel biomarker in heart failure will not only add information to understand the pathophysiological mechanisms of heart failure better, but also might provide a more accurate prediction of treatment response to guide medical therapy. In addition, a novel therapeutic target could be identified for design of drugs to improve outcomes. Futher work is required in larger populations to confirm this biomarker. Funding European Union's Seventh Framework Programme (BIOSTAT-CHF), John and Lucille van Geest Foundation.

Abstract Background Patients with invasive residual disease after neoadjuvant chemotherapy (NACT) are considered to have chemo-resistant breast cancer. Bisphosphonates are an established treatment for bone metastases and are of potential benefit as adjuvant treatment in early breast cancer. Patients and methods Patients who had invasive tumour residuals (ypT1-4 and/or ypN+) after a minimum of four cycles of anthracycline-taxane-containing NACT were eligible for the NeoAdjuvant Trial Add-oN study. Patients were randomised within 3 years after surgery to receive zoledronate 4 mg i.v. for 5 years versus observation. Zoledronate was given every 4 weeks for the first 6 months, every 3 months for the following 2 years, and every 6 months for the last 2.5 years. Primary objective was disease-free survival. Results After a median time of 54.7 months no difference in disease-free survival was observed between the zoledronate and observation groups (hazard ratio [HR] 0.960, 95% confidence interval [CI] 0.709–1.30, log rank P = 0.789). Various subgroups were examined without identifying a treatment effect of zoledronate. Patients over 55 years of age showed a HR of 0.832 in favour of zoledronate, but the result was not significant (P = 0.480). A similar result was obtained for overall survival with a HR of 1.19 (95% CI 0.79–1.79; log rank P = 0.408). Zoledronate was well tolerated and no new toxicity signal was identified. Conclusion Postneoadjuvant treatment with zoledronate does not improve outcome in patients without pathological complete response after neoadjuvant anthracycline-taxane-based chemotherapy for early breast cancer.