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6 Supplementary Tables from Gene Expression of Parathyroid Tumors

Parathyroid tumors are heterogeneous, and diagnosis is often difficult using histologic and clinical features.We have undertaken expression profiling of 53 hereditary and sporadic parathyroid tumors to better define the molecular genetics of parathyroid tumors. A class discovery approach identified three distinct groups: (1) predominantly hyperplasia cluster, (2) HRPT2/carcinoma cluster consisting of sporadic carcinomas and benign and malignant tumors from Hyperparathyroidism-Jaw Tumor Syndrome patients, and (3) adenoma cluster consisting mainly of primary adenoma and MEN 1 tumors. Gene sets able to distinguish between the groups were identified and may serve as diagnostic biomarkers. We demonstrated, by both gene and protein expression, that Histone 1 Family 2, amyloid β precursor protein, and E-cadherin are useful markers for parathyroid carcinoma and suggest that the presence of a HRPT2 mutation, whether germ-line or somatic, strongly influences the expression pattern of these 3 genes. Cluster 2, characterized by HRPT2 mutations, was the most striking, suggesting that parathyroid tumors with somatic HRPT2 mutation or tumors developing on a background of germ-line HRPT2 mutation follow pathways distinct from those involved in mutant MEN 1-related parathyroid tumors. Furthermore, our findings likely preclude an adenoma to carcinoma progression model for parathyroid tumorigenesis outside of the presence of either a germ-line or somatic HRPT2 mutation. These findings provide insights into the molecular pathways involved in parathyroid tumorigenesis and will contribute to a better understanding, diagnosis, and treatment of parathyroid tumors.

Background Hospital mortality, readmission and length of stay (LOS) are commonly used measures for quality of care. We aimed to disentangle the correlations between these interrelated measures and propose a new way of combining them to evaluate the quality of hospital care. Methods We analyzed administrative data from the Global Comparators Project from 26 hospitals on patients discharged between 2007 and 2012. We correlated standardized and risk-adjusted hospital outcomes on mortality, readmission and long LOS. We constructed a composite measure with 5 levels, based on literature review and expert advice, from survival without readmission and normal LOS (best) to mortality (worst outcome). This composite measure was analyzed using ordinal regression, to obtain a standardized outcome measure to compare hospitals. Results Overall, we observed a 3.1% mortality rate, 7.8% readmission rate (in survivors) and 20.8% long LOS rate among 4,327,105 admissions. Mortality and LOS were correlated at the patient and the hospital level. A patient in the upper quartile LOS had higher odds of mortality (odds ratio = 1.45, 95% confidence interval 1.43–1.47) than those in the lowest quartile. Hospitals with a high standardized mortality had higher proportions of long LOS (r = 0.79, p

In de zomer 2008 adviseerde het Engelse National Institute on Clinical Excellence (nice) om een viertal medicijnen voor patienten met terminal nierkanker niet te verstrekken en vergoeden. Die middelen hadden weliswaar een bescheiden levensverlengend effect, maar hun prijs was zo hoog dat ze onvoldoende kosteneffectief werden geacht: ze overschreden in ruime mate de binnen de National Health Service (nhs) gebruikelijke maximale kosten-effectiviteitsverhouding (zie kader). In de Engelse media stak een storm van verontwaardiging op.

Background. Intraoperative identification of parathyroid adenomas can be challenging. We hypothesized that low-doses methyl- ene blue (MB) and near-infrared fluorescence (NIRF) imaging could be used to identify parathyroid adenomas intraoperatively. Methods. MB was injected intravenously after exploration at a dose of 0.5 mg/kg into 12 patients who underwent parathyroid surgery. NIRF imaging was performed using the Mini-FLARE imaging system. Results. In 10 of 12 patients, histology confirmed a parathyroid ade- noma. In 9 of these patients, NIRF could clearly identify the parathyroid adenoma during surgery. Seven of these 9 patients had a positive preoperative 99m Tc-sestamibi single photon emission CT (SPECT) scan. Importantly, in 2 patients, parathyroid adenomas could be identified only using NIRF. Conclusion. This is the first study to show that low-dose MB can be used as NIRF tracer for identification of parathyroid adenomas, and suggests a correlation with preoperative 99m Tc-sestamibi SPECT scan- ning. V C 2013 Wiley Periodicals, Inc. Head Neck 36: 853-858, 2014

Research objective: Reliable and unambiguously defined performance indicators are fundamental to objective and comparable measurements of hospitals' quality of care. In two separate case studies (intensive care and breast cancer care), we investigated if differences in definition interpretation of performance indicators affected the indicator scores. Design: Information about possible definition interpretations was obtained by a short telephone survey and a Web survey. We quantified the interpretation differences using a patient-level dataset from a national clinical registry (Case I) and a hospital's local database (Case II). In Case II, there was additional textual information available about the patients' status, which was reviewed to get more insight into the origin of the differences. Participants: For Case I, we investigated 15 596 admissions of 33 intensive care units in 2009. Case II consisted of 144 admitted patients with a breast tumour surgically treated in one hospital in 2009. Results: In both cases, hospitals reported different interpretations of the indicators, which lead to significant differences in the indicator values. Case II revealed that these differences could be explained by patient-related factors such as severe comorbidity and patients' individual preference in surgery date. Conclusions: With this article, we hope to increase the awareness on pitfalls regarding the indicator definitions and the quality of the underlying data. To enable objective and comparable measurements of hospitals' quality of care, organizations that request performance information should formalize the indicators they use, including standardization of all data elements of which the indicator is composed (procedures, diagnoses).

AIMS: We propose a summarizing measure for outcome indicators, representing the proportion of patients for whom all desired short-term outcomes of care (a 'textbook outcome') is realized. The aim of this study was to investigate hospital variation in the proportion of patients with a 'textbook outcome' after colon cancer resections in the Netherlands. METHODS: Patients who underwent a colon cancer resection in 2010 in the Netherlands were included in the Dutch Surgical Colorectal Audit. A textbook outcome was defined as hospital survival, radical resection, no reintervention, no ostomy, no adverse outcome and a hospital stay < 14 days. We calculated the number of hospitals with a significantly higher (positive outlier) or lower (negative outlier) Observed/Expected (O/E) textbook outcome than average. As quality measures may be more discriminative in a low-risk population, analyses were repeated for low-risk patients only. RESULTS: A total of 5582 patients, treated in 82 hospitals were included. Average textbook outcome was 49% (range 26-71%). Eight hospitals were identified as negative outliers. In these hospitals a 'textbook outcome' was realized in 35% vs. 52% in average hospitals (p < 0.01). In a sub-analysis for low-risk patients, only one additional negative outlier was identified. CONCLUSIONS: The textbook outcome, representing the proportion of patients with a perfect hospitalization, gives a simple comprehensive summary of hospital performance, while preventing indicator driven practice. Therewith the 'textbook outcome' is meaningful for patients, providers, insurance companies and healthcare inspectorate.

OBJECTIVE:: To investigate the safety of laparoscopic colorectal cancer resections in a nationwide population-based study. BACKGROUND:: Although laparoscopic techniques are increasingly used in colorectal cancer surgery, little is known on results outside trials. With the fast introduction of laparoscopic resection (LR), questions were raised about safety. METHODS:: Of all patients who underwent an elective colorectal cancer resection in 2010 in the Netherlands, 93% were included in the Dutch Surgical Colorectal Audit. Short-term outcome after LR, open resection (OR), and converted LR were compared in a generalized linear mixed model. We further explored hospital differences in LR and conversion rates. RESULTS:: A total of 7350 patients, treated in 90 hospitals, were included. LR rate was 41% with a conversion rate of 15%. After adjustment for differences in case-mix, LR was associated with a lower risk of mortality (odds ratio 0.63, P < 0.01), major morbidity (odds ratio 0.72, P < 0.01), any complications (odds ratio 0.74, P < 0.01), hospital stay more than 14 days (odds ratio 0.71, P < 0.01), and irradical resections (odds ratio 0.68, P < 0.01), compared to OR. Outcome after conversion was similar to OR (P > 0.05). A large variation in LR and conversion rates among hospitals was found; however, the difference in outcome associated with operative techniques was not influenced by hospital of treatment. CONCLUSIONS:: Use of laparoscopic techniques in colorectal cancer surgery in the Netherlands is safe and results are better in short-term outcome than open surgery, irrespective of the hospital of treatment. Outcome after conversion was similar to OR.

How do healthcare consumers perceive the use of medical data for scientific research, within the framework of protection of their personal data?Survey among 731 members of the Healthcare Consumer Panel of the Netherlands Institute for Health Services Research (NIVEL).A written and online questionnaire was used, consisting of general questions and 4 cases per respondent. The questions concerned the degree of trust respondents have in the use of previously registered data for different kinds of healthcare research, and their willingness to make data available under various conditions without being asked for explicit consent.Respondents showed a high degree of trust in scientific researchers and physicians concerning the re-use of medical data for research. A majority agreed that it is not necessary to be explicitly asked for consent for this kind of research, providing they are informed: one-third found their autonomy in being able to decide to be more important than scientific progress; three-quarters found explicit permission unnecessary as long as the data is well-protected and only used for scientific research.Data protection in research should be proportional to the risks of misuse and the benefits of the use of the data for research. A large majority of healthcare users trust the researchers, and the existing codes of conduct protect data sufficiently. Therefore, we see no need for stricter requirements for the use of health data, which would unnecessarily limit healthcare research. We do consider greater transparency about the research process to be necessary, in order to maintain a proper balance between personal-data protection and the need to emphasise the necessity for learning in the healthcare system.

Background Quality indicators are increasingly used to measure the quality of care and compare quality across hospitals. In the Netherlands over the past few years numerous hospital quality indicators have been developed and reported. Dutch indicators are mainly based on expert consensus and face validity and little is known about their construct validity. Therefore, we aim to study the construct validity of a set of national hospital quality indicators for hip replacements. Methods We used the scores of 100 Dutch hospitals on national hospital quality indicators looking at care delivered over a two year period. We assessed construct validity by relating structure, process and outcome indicators using chi-square statistics, bootstrapped Spearman correlations, and independent sample t-tests. We studied indicators that are expected to associate as they measure the same clinical construct. Result Among the 28 hypothesized correlations, three associations were significant in the direction hypothesized. Hospitals with low scores on wound infections had high scores on scheduling postoperative appointments (p-value = 0.001) and high scores on not transfusing homologous blood (correlation coefficient = -0.28; p-value = 0.05). Hospitals with high scores on scheduling complication meetings, also had high scores on providing thrombosis prophylaxis (correlation coefficient = 0.21; p-value = 0.04). Conclusion Despite the face validity of hospital quality indicators for hip replacement, construct validity seems to be limited. Although the individual indicators might be valid and actionable, drawing overall conclusions based on the whole indicator set should be done carefully, as construct validity could not be established. The factors that may explain the lack of construct validity are poor data quality, no adjustment for case-mix and statistical uncertainty.

Background Identification of diseased and normal parathyroid glands during parathyroid surgery can be challenging. The aim of this study was to assess whether near-infrared (NIR) fluorescence imaging using administration of a low-dose Methylene Blue (MB) at the start of the operation could provide optical guidance during parathyroid surgery and assist in the detection of parathyroid adenomas. Methods Patients diagnosed with primary hyperparathyroidism planned for parathyroidectomy were included. Patients received 0.5 mg/kg MB intravenously directly after start of anesthesia. During the operation, NIR fluorescence imaging was performed to identify parathyroid adenomas. Imaging results were compared with a previous published feasibility study in which 12 patients received MB after intraoperative identification of the adenoma. Results A total of 13 patients were included in the current study. In 10 of 12 patients with a histologically proven adenoma, the adenoma was fluorescent. Mean signal to background ratio was 3.1 ± 2.8. Mean diameter of the resected lesions was 17 ± 9 mm (range 5–28 mm). Adenomas could be identified up to 145 minutes after administration, which was the longest timespan until resection. Interestingly, in 3 patients, a total of 6 normal parathyroid glands (median diameter 2.5 mm) with a signal to background ratio of 1.8 ± 0.4 were identified using NIR fluorescence imaging. Conclusion Early administration of low-dose MB provided guidance during parathyroidectomy by identifying both parathyroid adenomas and normal parathyroid glands. In patients in whom difficult identification of the parathyroid adenoma is expected or when normal glands have to be identified, the administration of MB may improve surgical outcome.

IntroductionLocalization studies are mandatory prior to revision surgery in patients with persistent hyperparathyroidism in order to improve surgical outcome and reduce the risk of lengthy explorations. However, in this case, noninvasive localization studies are reported to have a poor sensitivity. The aim of our study is to determine the accuracy of selective venous sampling (SVS) for parathyroid hormone (PTH) in localizing residual hyperactive parathyroid glands in patients with persistent or recurrent hyperparathyroidism.Patients and methodsWe retrospectively evaluated the localizing accuracy of 20 PTH SVS performed prior to revision surgery in 18 patients with persistent or recurrent primary hyperparathyroidism (n=11) or autonomous (tertiary) hyperparathyroidism (n=7). Tc99m-methoxy-isobutyle-isonitrile (MIBI)-single photon emission computed tomography (SPECT) was also performed in all patients prior to revision surgery. Operative and pathological data were obtained from hospital records.ResultsThe SVS was able to accurately localize 15 of the 20 pathological glands removed at revision surgery, representing a sensitivity of 75%. This sensitivity is significantly higher than that of Tc99m-MIBI-SPECT, which was only 30% (P=0.012).ConclusionOur findings demonstrate that SVS is a valuable localization study in patients with persistent or recurrent hyperparathyroidism, with a sensitivity significantly higher than that of Tc99m-MIBI-SPECT. Our data suggest that SVS represents a useful addition to the preoperative workup of these patients prior to revision surgery.

ObjectiveAdrenal cortical carcinoma (ACC) is an aggressive tumour with a high mortality. We describe six patients living 12–28 years despite recurrent and/or metastatic ACC.PatientsThe first patient presented in 1979 with an ACC of 8 cm. After resection, she developed seven recurrences for which she was treated with resection and/or mitotane (o,p′-DDD) treatment. The patient is still alive 28 years after diagnosis. The second patient presented with an ACC of 9 cm. After resection, the patient developed liver metastases, which were treated witho,p′-DDD. The patient is still alive 25 years after diagnosis. The third patient presented with an ACC of 12 cm. The tumour was resected followed byo,p′-DDD treatment. She had a local recurrence that was completely resected. She is still alive 18 years after diagnosis. The fourth patient presented with an ACC of 14 cm. After resection, adjuvanto,p′-DDD was started. Subsequently, the patient developed two recurrences, which were resected. He is still alive 17 years after the initial diagnosis. The fifth patient presented with an ACC of 10 cm. After diagnosis, she developed lung metastasis, which were treated witho,p′-DDD and chemotherapy. The patient is still alive with slowly progressive disease 12 years after diagnosis. The sixth patient presented with an ACC of 7 cm. After resection, she developed four recurrences, which were resected. The patient is still alive 28 years after diagnosis.ConclusionSome patients can have an extremely long survival of ACC, despite recurrent disease and metastases. The mainstay of therapy in our patients was repeated surgery ando,p′-DDD.

This paper focuses on the ethics of constructing and using a specific evidence-based decision aid that aims to contribute to clinical shared decision-making processes. Results of this integrated empirical ethics study demonstrate how both the production and presentation of scientific information in an evidence-based decision-support contain implicit presuppositions and values, which pre-structure the moral environment of the shared decision-making process. As a consequence, the evidencebased decision support did not only support the decision-making process; it also transformed it in a morally significant way. This phenomenon undermines the assumption within much of the literature on patient autonomy and shared decision-making implying that information disclosure is a conditional requirement before patient autonomy and shared decision-making even starts. The central point of this paper is that decision aids and evidence-based medicine are not value-free and that patient autonomy and shared decision-making are already influenced during the production and presentation of scientific information, Consequences for both the development of decision-aids and the practice of shared decision-making are discussed.

To assess the impact of variables related to setting, study design and definition on adverse outcome occurrence and mortality in hospitalized patients.Pubmed and Embase.Articles in English from 1980 onwards, in non-selected patients or surgical patients only.Data were extracted independently by two authors using a predefined form. Included study methodology variables were general variables such as setting, patient variables like age, study variables like number of reviewers and definition and the resulting adverse outcome occurrence and mortality.Eleven studies reporting on 76 617 non-selected patients and 18 studies representing 136 292 surgical patients were included. Adverse outcomes were estimated to occur in 16% (12-19%) of non-selected patients and in 18% (14-22%) of surgical patients, taking into account the heterogeneity between studies. The study methodology variables were not statistically significant in explaining variation in adverse outcome occurrence, but the individual studies, when used as a random effect variable, were significant. Conversely, the study variable was not significant to explain variation in mortality rates, whereas the study methodology variables were: having more than one reviewer increased mortality by 30-80%, older study populations resulted in higher mortality and including a cause in the definition halved the mortality rate.Study methodology variables do not explain differences in adverse outcome occurrence between studies. Other inter-study differences are more important. However, study methodology is an important predictor for mortality differences and should be taken into account when interpreting differences between studies.

Item does not contain fulltext BACKGROUND: Surgery is still the only curative treatment for medullary thyroid cancer (MTC). We evaluated clinical outcome in patients with locoregional MTC with regard to adequacy of treatment following ATA guidelines and number of sessions to first intended curative surgery in different hospitals. METHODS: We reviewed all records of MTC patients (n = 184) treated between 1980 and 2010 in two tertiary referral centers in the Netherlands. Symptomatic MTC (palpable tumor or suspicious lymphadenopathy) patients without distant metastasis were included (n = 86). Patients were compared with regard to adequacy of surgery according to ATA recommendations, tumor characteristics, number of local cancer reoperations, biochemical cure, clinical disease-free survival (DFS), overall survival (OS), and complications. RESULTS: Adherence to ATA guidelines resulted in fewer cancer-related reoperations (0.24 vs. 0.60; P = 0.027) and more biochemical cure (40.9 vs. 20 %; P = 0.038). Surgery according to ATA-guidelines on patients treated in referral centers was significantly more often adequate (59.2 vs. 26.7 %; P = 0.026). Tumor size and LN+ were the most important predictors for clinical recurrence [relative risk (RR) 4.1 (size > 40 mm) 4.1 (LN+) and death (RR 4.2 (size > 40 mm) 8.1 (LN+)]. CONCLUSIONS: ATA-compliant surgery resulted in fewer local reoperations and more biochemical cure. Patients in referral centers more often underwent adequate surgery according to ATA-guidelines. Size and LN+ were the most important predictors for DFS and OS.

Summary Objective Lithium has been reported to increase radioactive iodine (RaI) doses in benign thyroid disease and in differentiated thyroid carcinoma (DTC). It is not known whether lithium influences the outcome of RaI therapy in DTC. We therefore studied the clinical effects of RaI without and with lithium carbonate in patients with proven metastatic DTC. Controversy also exists on the mechanism by which lithium increases RaI dose in DTC. We performed an in vitro study specifically aimed at examining the effects of lithium on the sodium iodide symporter (NIS). Design In a clinical study, 12 patients were selected with metastases of DTC who had received previous RaI therapy without lithium (control) that had not influenced tumour progression, despite RaI accumulation in metastases. The patients received 1200 mg lithium carbonate/day followed by 6000 MBq RaI. Outcome parameters were RaI uptake, serum thyroglobulin (Tg) levels and radiological dimensions of metastases compared between RaI with lithium and control. In an in vitro study, iodide uptake was studied in the benign rat thyroid cell line FRTL-5, in the polarized non-thyroid MDCK cell line, stably transfected with human sodium iodide symporter (hNIS) to study the effects of lithium on NIS in a non-thyroid background, and the human follicular thyroid carcinoma cell line FTC133-hNIS to study lithium effects in a background of DTC. Lithium chloride (LiCl) was added in concentrations up to 2 mm for 0–48 h. Both steady-state iodide uptake (30 min) and initial rate (2 min) were studied using a specific activity of 100 mCi/mmol I, the latter experiment to determine lithium effects on substrate dependency. Iodide efflux studies were performed as well. Results Despite an increased uptake of RaI in seven patients, no beneficial effect of RaI with lithium was observed on the clinical course as assessed by serum Tg measurements and radiographically. In the in vitro studies, no effects of LiCl on iodide uptake or efflux were observed. Conclusions The addition of lithium to RaI did not have any beneficial effects on the clinical course in 12 patients with metastatic DTC. No beneficial effects of lithium on iodide uptake were observed in vitro. Therefore, the clinical value of lithium in DTC remains subject to debate.

This study was designed to describe the consequences of diagnosis and treatment of rectal cancer for paid and unpaid labor over time and to identify sociodemographic-related factors, treatment-related factors, and quality of life-related factors associated with paid and unpaid labor. Data were assessed prospectively in two samples of patients with primary rectal cancer, participating in a multicenter clinical trial, who were randomized to receive surgery with or without 5 × 5-Gy preoperative radiotherapy. For paid labor, 292 patients who indicated paid labor before treatment filled out quality of life questionnaires, which included questions on paid labor at 3, 6, 12, 18, and 24 months after surgery. For unpaid labor, another sample of 92 patients also filled out the Health and Labor questionnaire, which included questions on unpaid labor, before treatment, and at 3 and 12 months after treatment. From 3 to 18 months after surgery, paid labor resumption increased from 19 to 63 percent (P < 0.001). At 24 months after surgery, paid labor resumption was 61 percent. In a multivariate analysis, age older than 55 years (P ≤ 0.001), lower education level (P ≤ 0.003), shorter time since surgery (P < 0.001), preoperative radiotherapy (P = 0.02), lower valuation of overall health (P < 0.01), more physical symptom distress (P < 0.001), and more limitations in daily activities (P < 0.001) were all associated with less or later resumption of paid labor. The average amount of unpaid labor increased from 17.3 hours per week at 3 months to 21 hours per week at 12 months after surgery. In a multivariate analysis, only shorter time since surgery (P = 0.03) and male gender (P < 0.001) were related to less unpaid labor. Diagnosis and treatment of rectal cancer affect paid and unpaid labor. The impact on paid labor is most pronounced. Multiple other sociodemographic and quality of life-related variables also were associated with paid labor. Patient information and decision making on preoperative radiotherapy should include the effects on paid labor, and interventions focused on promoting paid labor participation in patients with rectal cancer should be tailored to the specific characteristics and needs of those patients.

Objective: To assess the effectiveness of routine reporting to identify surgical adverse outcomes in comparison with retrospective medical record review. Design: Independent assessment of two methods applied to one sample. Surgeons and surgical residents routinely reported all adverse outcomes for patients in their care during admission. A trained research assistant, blinded to the surgeons’ reporting data, retrospectively reviewed the medical records of selected patients and registered all adverse outcomes identified from paper or electronic patient records. Setting: Dutch university hospital. Study sample: A 5% sample of patients (N = 150) discharged in 2002 was taken; oversampling of patients undergoing reoperations, sick patients (ASA ⩾3), and those undergoing technically complex surgery was done to increase the yield of adverse outcomes. Main outcome measures: The number of adverse outcomes identified by each method was compared with the total number identified by either method. This was done both for all adverse outcomes and for serious adverse outcomes. Results: Routine reporting identified fewer adverse outcomes than medical record review (62.5% v 78.2%). Complete agreement was achieved in only 40.7% of adverse outcomes. Routine reporting identified slightly more serious adverse outcomes (84.8% v 79.5% of the total), but this difference was not statistically significant. Extrapolating these results to the total number of admissions in 2002, routine reporting underestimated the annual adverse outcome incidence by 1.8% (increasing from 14.5% to 16.3%) and the incidence of serious adverse outcomes by 0.3% (increasing from 6.9% to 7.2%). Conclusions: Neither method identified all adverse outcomes. Routine reporting underestimated the incidence of minor events but was as accurate as record review in identifying serious adverse outcomes.

Purpose: To test the "false-reassurance hypothesis," which suggests that women who receive an uninformative BRCA1/2 test result may incorrectly conclude that they no longer have an elevated risk, with possible harmful consequences for adherence to breast surveillance guidelines. Methods: A prospective questionnaire design was used to compare 183 women with an uninformative BRCA test result (94 affected and 89 unaffected) with 41 proven BRCA mutation-carriers and 49 true negatives before and after BRCA1/2 test disclosure. Results: After DNA-test disclosure, test applicants differed from each other with regard to their perception of the likelihood of carrying a deleterious gene (P < 0.0001). The BRCA mutation carriers reported the highest perceived likelihood and the true negatives reported the lowest. Compared to the predisclosure measures, women who received an uninformative DNA test result reported a lower perceived risk after disclosure (P < 0.0001), suggesting a relatively high level of reassurance because of the test result. However, after DNA-test disclosure, only 12 women concluded that the risk of carrying a mutation was nonexistent, and perceived likelihood was significantly associated with the pedigree-based risk assessment (P = 0.0001). Moreover, despite the significant decrease in perceived likelihood for uninformative women, intention to obtain mammograms did not change (P = 0.71); it remained at the same almost optimal level as for BRCA mutation carriers. Conclusion: No support was found for the suggestion that the nature of uninformative test results is often misunderstood. Moreover, an uninformative test result did not affect the positive mammography intentions of both affected and unaffected women.

Parathyroid tumors are heterogeneous, and diagnosis is often difficult using histologic and clinical features. We have undertaken expression profiling of 53 hereditary and sporadic parathyroid tumors to better define the molecular genetics of parathyroid tumors. A class discovery approach identified three distinct groups: (1) predominantly hyperplasia cluster, (2) HRPT2/carcinoma cluster consisting of sporadic carcinomas and benign and malignant tumors from Hyperparathyroidism-Jaw Tumor Syndrome patients, and (3) adenoma cluster consisting mainly of primary adenoma and MEN 1 tumors. Gene sets able to distinguish between the groups were identified and may serve as diagnostic biomarkers. We demonstrated, by both gene and protein expression, that Histone 1 Family 2, amyloid β precursor protein, and E-cadherin are useful markers for parathyroid carcinoma and suggest that the presence of a HRPT2 mutation, whether germ-line or somatic, strongly influences the expression pattern of these 3 genes. Cluster 2, characterized by HRPT2 mutations, was the most striking, suggesting that parathyroid tumors with somatic HRPT2 mutation or tumors developing on a background of germ-line HRPT2 mutation follow pathways distinct from those involved in mutant MEN 1-related parathyroid tumors. Furthermore, our findings likely preclude an adenoma to carcinoma progression model for parathyroid tumorigenesis outside of the presence of either a germ-line or somatic HRPT2 mutation. These findings provide insights into the molecular pathways involved in parathyroid tumorigenesis and will contribute to a better understanding, diagnosis, and treatment of parathyroid tumors.

Purpose To review the effectiveness of routine visits and routine tests in detecting isolated locoregional recurrences in asymptomatic patients after treatment for early-stage invasive breast cancer. Methods Systematic review and meta-analysis. The proportion of isolated locoregional recurrences diagnosed during routine visits or routine tests in asymptomatic patients was compared with the proportion of isolated locoregional recurrences in symptomatic patients. Results Twelve studies that involved a total of 5,045 patients and 378 isolated locoregional recurrences were identified. Pooling data showed an overall estimate of 40% of isolated locoregional recurrences diagnosed during routine visits or routine tests in asymptomatic patients (95% CI, 35 to 45). Of these, 47% (95% CI, 39 to 54) were diagnosed after mastectomy, and 36% (95% CI, 28 to 43) were diagnosed after breast-conserving therapy (relative risk, 1.327; 95% CI, 1.014 to 1.738). Apart from differences in therapy, we have not been able to discern subgroups of patients for whom results were different. Conclusion Approximately 40% of isolated locoregional recurrences are diagnosed during routine visits and routine tests in asymptomatic patients treated for early-stage invasive breast cancer. We could not assess whether these were detected by either physical examination or other tests, nor if the detection of asymptomatic isolated recurrences had any influence on potential for cure or quality of life. As the overall quality of the included studies and the overall incidence of isolated locoregional recurrences are low, this systematic review highlights the need for prospective comparative studies on cost-effective strategies for the follow-up of patients after a diagnosis of breast cancer.

Effective communication of treatment risks is important to enable patients to make informed decisions. This study aimed to determine the effects of different risk formats on participants' evaluation and interpretation of risk information and on their treatment choice. Participants (N=44) were recruited among patients who had undergone surgery for an abdominal aneurysm and were asked to evaluate treatment risks (surgery or an observation policy) of two hypothetical cases presented in one of three risk formats (numbers, vertical bars or icons). Risk information presented in vertical bars was evaluated as the most difficult to comprehend, and the perceived threat of this information was evaluated as higher than that of the other risk formats. Risk information presented as icons was evaluated as more helpful for making a decision, but resulted in a lower percentage of participants choosing for surgery than when risks were presented in the other formats. In conclusion, this study showed that different risk formats have different effects on participants' evaluation of the information and on their choice. Doctors should therefore be careful in choosing the format in which they present treatment risks.

Objective. The primary aim of ultrasound follow-up after aorto-iliac prosthetic reconstruction is to correct false aneurysms before rupture occurs. We investigated whether follow-up improves the life expectancy of patients and sought to identify the most cost-effective follow-up strategy. Design of the Study. A Monte Carlo Markov decision model was constructed. The occurrence of false aneurysms was modelled as a time-dependent process for each anastomotic site, based on published series. Using this model, the impact of various follow-up strategies was investigated for three types of prostheses, aorto-distal tube, aorto-bi-iliac, and aorto-bi-femoral prostheses. Main outcome measures were discounted quality adjusted life years (dQALYs), discounted costs, and (discounted) cost-effectiveness (CE) ratios. Results. Follow-up of patients with aorto-distal tube and aorto-bifemoral prostheses did not result in an improvement life expectancy and was not cost-effective, QALYs 7.53 and 7.62 years, respectively. The results for aorto-distal tube and aorto-bifemoral prostheses were not sensitive to any variation in the model parameters. In the base case analysis, the life expectancy of patients with aorto-bi-iliac prostheses was 7.50 QALYs (95% confidence interval 7.46–7.54) whether or not they underwent routine follow-up. However, patients aged 54 years or younger gained 0.11 QALYs with annual follow-up (p

The purposes of this study were 1) to investigate the feasibility of using providers' administrative systems for the assessment of healthcare utilization in economic evaluations performed alongside multicenter studies, 2) to assess the convergent validity of patients' and providers' reports of care, and 3) to investigate whether differences between providers' and patients' reports are related to age, gender, health, recall period, and volumes of care.Data were obtained as part of a cost-utility analysis alongside a multicenter clinical trial in patients with rectal cancer. For a sample of 179 patients from 49 hospitals, data on hospitalizations, outpatient visits, medications, and care products during the first year after treatment were obtained from the patients by questionnaire or diary. For all patients, hospitals were contacted for information on hospitalizations and outpatient visits. For a subsample of 94 patients, 86 pharmacists and 10 suppliers of stoma care products were contacted for information on medications and care products.Response by providers of care was high, ranging from 84% to 100%. With respect to hospital days and outpatient visits, we found no significant differences between patients' and providers' reports. For medications and care products, agreement was lower, with providers reporting up to 2 times more product types and costs than patients. Providers failed to report 20% to 25% of all products, whereas patients failed to report 50% to 60% of all products.Patients' reports seem as valid as providers' reports for hospital days and outpatient visits. For medications and care products, we recommend the use of reports from providers of care, whenever feasible, because they much less underestimate volumes and costs than patients.

Summary objective To investigate to what extent thyroid remnant ablation and withdrawal from thyroxine are required to achieve sufficient accuracy of serum thyroglobulin (Tg) measurements as an indicator of tumour recurrence in the follow-up of patients with differentiated thyroid carcinoma. design and methods We conducted a meta-analysis of the literature from 1975 to 2003 on serum Tg measurements in the follow-up of differentiated thyroid carcinoma. In a computer-based search, we initially found 915 articles that were finally narrowed down to 120. These 120 papers were subjected to strict in/and exclusion criteria, leaving 46 articles (totalling 9094 patients). Data from these articles were extracted in a structured fashion and were grouped according to initial therapy, TSH status, Tg assay method and definition of a ‘gold standard’. Original 2 × 2 tables were pooled by summary receiver operating characteristic curve analysis (sROCa), best estimates of sensitivity and specificity being obtained by the combination of sROCa and Mantel–Haenszel odds ratios. results Despite considerable differences between series in laboratory and clinical methodology, we consistently found higher specificity for Tg measurements after thyroid remnant ablation than after surgery alone. Highest pooled sensitivity 0·961 ± 0·013 (SE) was found for immunometric assay (IMA) after thyroid remnant ablation and thyroid hormone withdrawal, at a specificity of 0·947 ± 0·007. Pooled sensitivity decreased significantly if ablated patients were tested while on thyroid hormone (0·778 ± 0·023, at a specificity of 0·977 ± 0·005). Significantly decreased pooled specificity was found in patients who did not undergo remnant ablation (sensitivity 0·972 ± 0·023, at a specificity of 0·759 ± 0·028). If recombinant human TSH (rhTSH) stimulation was used as a substitute for thyroxine withdrawal, sensitivity remained high (0·925 ± 0·018) while specificity decreased to 0·880 ± 0·013. In all analyses, specificity of Tg would decrease when unspecified activity in the thyroid region at scintigraphy was considered benign, whereas sensitivity decreased when such activity was considered malignant. conclusion This study confirms that the best accuracy of Tg-guided follow-up in patients treated for differentiated thyroid carcinoma is obtained if treatment includes remnant ablation, and Tg testing is performed while off thyroxine.

Purpose To compare the societal costs and the (quality-adjusted) life expectancy of patients with rectal cancer undergoing total mesorectal excision (TME) with or without short-term preoperative radiotherapy (5 × 5 Gy). Patients and Methods We used a Markov model to project the clinical and economic outcomes of preoperative radiotherapy. Data on local recurrence rates, quality of life, and costs were obtained from the patients of a multicenter randomized clinical trial. In this trial, 1,861 patients with resectable rectal cancer from 108 hospitals were randomly assigned for TME surgery with or without preoperative radiotherapy. Outcome measures of the model were life expectancy, quality-adjusted life expectancy, lifetime costs per patient, and the incremental cost-effectiveness ratio. Results The base case model estimates that the loss of quality of life due to preoperative radiotherapy is outweighed by the gain in life expectancy. Life expectancy increases by 0.67 years; quality-adjusted life expectancy, by 0.39 years; and costs, by $9,800 per patient. The corresponding cost-effectiveness ratio is $25,100 per quality-adjusted life year. Sensitivity analyses indicate that the cost-effectiveness ratio remains acceptable under a wide range of assumptions. Conclusion Assuming that the reduced local recurrence rate does lead to a survival advantage, the cost-utility analysis estimates that the improved survival outweighs the impaired quality of life and the increased costs. We conclude that short-term preoperative radiotherapy in patients with rectal cancer undergoing TME is both effective and cost-effective.

Purpose To document the clinical nature and prognosis of locally recurrent rectal cancer after total mesorectal excision (TME) with or without 5 × 5 Gy preoperative radiotherapy (PRT) and to identify patient-, disease-, and treatment-related factors associated with differences in prognosis after local recurrence. Patients and Methods For 96 Dutch patients with a local recurrence who participated in a multicenter randomized clinical trial, data on treatments and follow-up were gathered from surgeons and radiation and medical oncologists. Twenty-three patients (24%) had previously been treated with PRT plus TME, and 73 patients (76%) had been treated with TME alone. Eighty-one patients (84%) were followed until death; median follow-up time of the alive patients after local recurrence was 21 months (range, 5 to 48 months). Results Survival after local recurrence in the PRT + TME group was significantly shorter than in the TME group (median survival, 6.1 v 15.9 months; hazard ratio for death, 2.1; P = .008). Patients with a local recurrence in the PRT + TME group had distant metastases more often (74% v 40%; P = .004), underwent surgical resection of local recurrence less often (17% v 35%; P = .11), and received radiotherapy for local recurrence at a total dose ≥ 45 Gy less often (4% v 42%; P = .001) than patients without PRT. In a multivariate analysis, the difference in survival after local recurrence between randomization groups was no longer statistically significant (hazard ratio for death of PRT, 1.53; P = .16). Conclusion The clinical nature and prognosis of patients with locally recurrent rectal cancer has changed since the introduction of PRT. The majority of patients who present with a local recurrence after previous PRT have simultaneous distant metastases, and median survival has decreased to 6 months.

Ethicists differ considerably in their reasons for using empirical data. This paper presents a brief overview of four traditional approaches to the use of empirical data: "the prescriptive applied ethicists," "the theorists," "the critical applied ethicists," and "the particularists." The main aim of this paper is to introduce a fifth approach of more recent date (i.e. "integrated empirical ethics") and to offer some methodological directives for research in integrated empirical ethics. All five approaches are presented in a table for heuristic purposes. The table consists of eight columns: "view on distinction descriptive-prescriptive sciences," "location of moral authority," "central goal(s)," "types of normativity," "use of empirical data," "method," "interaction empirical data and moral theory," and "cooperation with descriptive sciences." Ethicists can use the table in order to identify their own approach. Reflection on these issues prior to starting research in empirical ethics should lead to harmonization of the different scientific disciplines and effective planning of the final research design. Integrated empirical ethics (IEE) refers to studies in which ethicists and descriptive scientists cooperate together continuously and intensively. Both disciplines try to integrate moral theory and empirical data in order to reach a normative conclusion with respect to a specific social practice. IEE is not wholly prescriptive or wholly descriptive since IEE assumes an interdepence between facts and values and between the empirical and the normative. The paper ends with three suggestions for consideration on some of the future challenges of integrated empirical ethics.

This paper challenges the traditional assumption that descriptive and prescriptive sciences are essentially distinct by presenting a study on the implicit normativity of the production and presentation of biomedical scientific facts within evidence-based medicine. This interdisciplinary study serves as an illustration of the potential worth of the concept of implicit normativity for bioethics in general and for integrated empirical ethics research in particular. It demonstrates how both the production and presentation of scientific information in an evidence-based decision-support contain implicit presuppositions and values, which pre-structure the moral environment of the clinical process of decision-making. As a consequence, the evidence-based decision support did not only support the clinical decision-making process; it also transformed it in a morally significant way. This phenomenon undermines the assumption within much of the literature on patient autonomy that information disclosure is a conditional requirement before patient autonomy even starts; patient autonomy is already influenced during the production and presentation of information. These results imply an increased responsibility of those who produce and present evidence-based facts(i.e. scientists in general and physicians in particular). The insights of this study not only involve a different focus on both theory and practice of patient autonomy and informed consent, but they also call for a broader scope of morality than does traditional empirical research in bioethics. The concept of implicit normativity within integrated empirical ethics research calls for a strong cooperation between bioethicists and descriptive scientists, i.e., a cooperation that goes beyond the discipline-specific epistemic values and that takes place during all phases of the research process.

Follow-up after curative treatment of patients with colorectal cancer has as its main aims the quality assessment of the treatment given, patient support, and improved outcome by the early detection and treatment of cancer recurrence. How often, and to what extent, the final aim, improved survival, is indeed realised is so far unclear. A literature search was performed to provide quantitative estimates for the main determinants of the effectiveness of the follow-up. Data were extracted from a total of 267 articles and databases, and were aggregated using modern meta-analytic methods. In order to provide one more colorectal cancer patient with long-term survival through follow-up, 360 positive follow-up tests and 11 operations for colorectal cancer recurrence are needed. In the remaining 359 tests and 10 operations, either no gains are achieved or harm is done. As the third aim of colorectal cancer follow-up, improved survival, is realised in only few patients, follow-up should focus less on diagnosis and treatment of recurrences. It should be of limited intensity and duration (3 years), and the search for preclinical cancer recurrence should primarily be performed by carcino-embryonic antigen (CEA) testing and ultrasound (US). The focus of colorectal cancer follow-up should shift from the early detection of recurrence towards quality assessment and patient support. As support that is as good or even better can be provided by a patient's general practitioner (GP) or by specialised nursing personnel, there is no need for routine follow-up to be performed by the surgeon.

Background — Doppler ultrasound (duplex) tests are commonly applied after carotid endarterectomy to detect possible recurrent stenosis. The appropriate frequency and the benefits are unknown. We investigated the costs and effects of various follow-up strategies to determine the optimal strategy after carotid endarterectomy. Methods — Using decision-analytic methods, a Monte Carlo Markov model was constructed. Probabilities and costs were obtained by systematic literature review. From empirical data regarding restenosis, a disease model was constructed to test the effect of various follow-up strategies using duplex testing and angiography. Main outcome measures were quality-adjusted life-years (QALYs), probability of stroke, and costs (for both the Dutch and the American situation). Results — The average quality-adjusted life expectancy for a 66-year-old patient was 6.31 years for the symptom-guided strategy (with duplex scanning only being performed in case of symptoms of cerebral ischemia). The mean lifetime costs for this strategy were $5 600 for the US and 4 600 Euro for the Netherlands. The cumulative probability of stroke was 13%. Yearly routine duplex tests up to 5 years after operation resulted in similar QALYs and a similar probability of stroke, but higher costs ($7 300 for the US and 5 600 Euro for The Netherlands situation). No other strategy, including routine duplex surveillance, increased QALYs. When MR instead of conventional angiography was used as confirmatory test, no improvement was observed either. Conclusions — Routine duplex surveillance does not result in an increase in quality-adjusted life expectancy, but it does increase costs. After successful carotid endarterectomy, a symptom-guided follow-up is an appropriate approach.

Introduction Hospital mortality, readmission and length of stay (LOS) are commonly used measures for quality of care, given availability in administrative data. However, these measures are interrelated. For example, a short LOS due to patient9s death should be interpreted differently than short LOS in survivors. And patients who died cannot be readmitted. In this study we aim to disentangle the relationship between mortality, readmission and LOS and propose a way to jointly report the three figures to facilitate insight and evaluation of quality of care. Methods Data from the Global Comparators Project were used, in which 22 hospitals from 5 countries have reconciliated the different coding systems of their administrative admission data to obtain risk-adjusted hospital outcomes. Patients discharged between 2007–2011 were included. Three outcomes were considered: mortality, readmission, and prolonged LOS (>75 percentile). We analyzed all patients, stroke patients and colorectal patients as we expected these conditions to vary in short-term mortality and readmission/long LOS. We assessed the correlations between the three standardized outcomes: mortality versus readmission (survivors), mortality versus long LOS, readmission (survivors) versus long LOS (survivors) and long LOS (deaths) versus long LOS (survivors). Second we constructed a composite measure with 5 levels: survivors no readmission normal LOS (best), survivors no readmission long LOS, survivors readmission normal LOS, survivors readmission long LOS, deaths (worst). This composite measure was analyzed using ordinal regression, to obtain a single standardized rate to compare hospitals. Results A total of 4,134,359 admissions were included in the analysis, with 76,517 for stroke and 31,736 for colorectal patients. The overall mortality rate was 3.1%, the readmission rate (in survivors) was 7.4% and 20.5% of the admissions had a long LOS (for stroke: 13.9%, 7.1% and 23.0%; for colorectal: 5.0%, 10.4% and 45.7%). The median number of admission per hospital was 170,497 (range 9,294 to 430,731). Standardized (risk-adjusted) outcome rates varied largely between hospitals: 55–140 (mortality), 58–116 (readmission), 50–165 (long LOS). No correlation was found between standardized mortality and readmission rates, and between readmission and long LOS rates (survivors). However, standardized mortality and long LOS rates were positively correlated (r=0.73, p=0.0001), indicating longer hospital stay in patients who died. Long LOS (survivors) was highly correlated with long LOS (deaths) (r=0.74 p The figure shows the variation in the composite outcome measure, consistent with a variation in standardized rates between 43 and 171 (for stroke: 34–162; for colorectal: 33–1.9). This composite measure correlated well with all individual measures, except readmission (r=0.06 p=0.79) caused by the smaller variation between hospitals in readmission rates, therefore weighted less. Discussion The three outcome measures were highly related. Disentangling the interrelations in outcomes facilitates insight so that hospitals get better directions for quality improvement. We propose to summarize the three outcomes into a single composite measure. The variation between hospitals in this composite measure is larger than for the individual measures, indicating a more accurate (detailed) representation of quality of care. Declaration of competing interests None.

Objectives - The purpose of this study is to demonstrate to what extent an evidence based decision model can improve physicians' decisions and whether a selective use of the decision model is feasible. Methods - Four experienced vascular surgeons were asked to make a treatment decision for 137 "paper patient" cases with asymptomatic abdominal aneurysms. Their decisions were compared with the optimal treatment as calculated by a computerised evidence based decision analytical model. Results - Surgeons agreed with the model's advice based on life expectancy in 81% of the cases, and decided to operate in only 12% of the cases for which there was no agreement. Surgeons' decisions differed from the decision model's calculated optimal treatment, in particular for older patients with aneurysms of intermediate size and with many risk factors, and for younger patients with small aneurysms and few risk factors. Not all these decisions, however, were reported to be more difficult. Conclusion - Use of a decision analytical model might lead to more appropriate decisions and a better quality of care. Selective use of the decision tool for difficult decisions only would be more efficient but is not yet feasible because reported decision difficulty is not strongly related to disagreement with the decision tool.

When making decisions about adjuvant chemotherapy for early-stage breast cancer, costs and benefits of treatment should be carefully weighed. In this process, patients' preferences are of major importance. The objectives of the present study were: (1) to determine the minimum benefits that patients need to find chemotherapy acceptable, and (2) to explore potential preference determinants, namely: positive experience of the treatment, reconciliation with the treatment decision, and demographic variables. Preferences were elicited from patients scheduled for adjuvant chemotherapy (chemotherapy group: n = 38) before (T 1), during (T 2), and 1 month after chemotherapy (T 3), and were compared to responses from patients not scheduled for chemotherapy (no-chemotherapy group: n = 38). The patients were asked, for a hypothetical situation, to indicate the minimum benefit (in terms of improved 5-year disease-free survival) to find adjuvant chemotherapy acceptable. In the chemotherapy group, the median benefit was 1% at all 3 measurement points. In the no-chemotherapy group the attitude towards chemotherapy became more negative over time, although not statistically significantly so (T 1: 12%, T 2: 15%, T 3: 15%;P = 0.10). At all measurement points, the patients in the chemotherapy group indicated that they would accept chemotherapy for significantly (P< 0.01) less benefit than the patients in the no-chemotherapy group. Of the demographic variables, age was related to preferences, but only at T 2 and only in the no-chemotherapy group. The more positive attitude towards chemotherapy and the stability of preferences in the chemotherapy group indicated that reconciliation with the treatment decision was a more important determinant of patients' preferences than positive experience of the treatment. © 2001 Cancer Research Campaign http://www.bjcancer.com

Colorectal cancer is an important cause of death in the Western world, with a propensity of cancer recurrence even after resection with curative intent. Active follow-up has been advocated as a means to detect cancer recurrence at an earlier stage and thereby improve the survival of colorectal cancer patients. The present study assesses published evidence on the effectiveness of follow-up. Articles were obtained from a 20-year Medline search and from cross-references between articles. Articles were included, scored for quality, and extracted by explicit criteria. Regression analysis and chi-squared analysis was performed to assess (1) whether detection of recurrence at earlier asymptomatic disease stage leads to better post-treatment prognosis, and (2) whether active follow-up does improve overall (quality adjusted) survival, as compared to symptom-guided care only. The relationship between disease stage of recurrence (symptoms, number and size) and survival was analysed from 42 articles, 10 of which provided adequate data. Absence of symptoms and small number of recurrence were significantly related to better survival, smaller size insignificantly so. The potential of active follow-up seemed related to a marginally better outcome, larger gains being found in lower quality studies. Available data do suggest that survival gains vary between 0.5 and 2%, 1% seeming to be a best estimate of overall survival gain. Neither the notion that earlier detection of recurrences does significantly improve outcome, nor the hope that active follow-up provides a statistically and clinically significant gain in (quality adjusted) survival, are so far supported by adequate evidence. Colorectal cancer follow-up still fails to meet the criteria for evidence based medicine.

Summary BACKGROUND The preferred treatment of Cushing's disease (CD) nowadays is transsphenoidal pituitary surgery (TPS). Prior to TPS, patients at the Leiden University Medical Centre were treated by unilateral adrenalectomy followed by external pituitary irradiation (UAPI). We report on long-term results of both UAPl and TPS and compare remission, relapse rates, and complications. PATIENTS AND METHODS A retrospective Study was carried out on 130 patients with CD. Patients with pituitary macroadenoma were excluded. Eighty-six and 44 patients underwent UAPl and TPS, respectively. Of these patients, 85 and 41 were evaluable for long-term results. RESULTS Remission following UAPl and TPS was identical at 64% (54/85 and 27/41). Cumulative relapse was also comparable - 17% (9/54) and 22% (6/27), respectively, - for UAPl and TPS, although the mean follow-up periods were different - 21.4 years and 8.5 years, respectively. Cumulative disease-free survival curves after UAPl and TPS are identical until 5 years of follow-up, but diverge thereafter indicating more sustained remissions following UAPl (P=0.17, Wilcoxon statistic). Pituitary dysfunction following UAPl (36%) and pituitary surgery (55%) likewise did not dlffer significantly. However, pituitary dysfunction was an immediate event after TPS, whereas it developed after a mean interval of 17.8 years following UAPI. Low-dose dexamethasone testing during follow-up had no value in predicting therapeutic outcome. CONCLUSIONS The results of unilateral adrenalectomy followed by external pituitary irradiation do not Justify that this therapy is totally abandoned in favour of transsphenoidal pituitary surgery. Unilateral adrenalectorny followed by external pituitary irradiation is a valid therapeutic modality for the treatment of Cushing's disease, and could be considered as alternative to bilateral adrenalectomy and under some circumstances to transsphenoidal pituitary surgery.

Adrenal masses that are detected incidentally in the course of abdominal diagnostic imaging performed for other reasons are called incidentalomas. Incidentalomas are found in 0.3% (0.1% to 1.5%) of abdominal imaging procedures performed for other reasons and in as many as 15% of patients at autopsy. 1,8,19,44,55,128 The detection of more incidentalomas is expected as the use of abdominal imaging (e.g., ultrasound, CT, or MR imaging) increases. Once an incidentaloma has been detected, a decision concerning its management is unavoidable. An incidentaloma can involve a significant disorder affecting a patient's health, such as primary adrenocortical carcinoma, or an insignificant disorder, such as an inactive benign tumor that will neither affect a patient's health nor warrant the risks of surgery. Ignoring an adrenal incidentaloma, associated with risks and benefits, is as much a strategy as performing diagnostic tests or surgery. The fact that underlying disorders range from a harmless adenoma to potentially lethal cancer or pheochromocytoma may entice physicians and patients to test; however, the justification for such testing must ultimately lie in its potential to improve a patient's health outcome and to do so at an acceptable price. Adrenal incidentaloma has increasingly been the focus of scientific attention. Recent publications have described institutional series of adrenal incidentalomas and reviewed the management of these lesions. Some of these reports have presented algorithms for the approach to these patients. The strategies recommended by Copeland 26 and by Ross and Aron 112 are the most well known.* *References 26,39,40,49,50,70,71,83,99,112 and 124 . Because these reviews have not assessed the costs and effects of dealing with adrenal incidentalomas in explicit and quantitative terms, the relationship between advice and available evidence is not always clear. The authors performed a cost-effectiveness analysis of the possible diagnostic-therapeutic approaches to adrenal incidentalomas using data from a quantitative literature review supplemented by two Dutch patient series. The following questions were addressed: 1What is the effect of untreated adrenal incidentaloma on the (quality-adjusted) life expectancy of the patient? 2How do outcomes differ between various diagnostic-therapeutic strategies, overall and for different subgroups of patients? 3What is the clinical significance of cost-effectiveness calculations, and which guideline can be formulated on the basis of this evidence? By answering these questions, it was hoped that the authors could elucidate to what extent the approach to adrenal incidentaloma is ordained by the strength of available evidence, and to what extent this evidence leaves room for individualization or personal preference.

Objective. Many studies suggest that impaired health states are valued more positively when experienced than when hypothetical. This study investigated to what extent this discrepancy occurs and examined four possible explanations: non-corresponding description of the hypothetical health state, new understanding due to experience with the health state, valuation shift due to a new status quo, and instability of preference. Patients and methods. Fifty-five breast cancer patients evaluated their actually experienced health state, a radiotherapy scenario, and a chemotherapy control scenario before, during, and after postoperative radiotherapy. Utilities were elicited by means of a visual analog scale (VAS), a chained time tradeoff (TTO), and a chained standard gamble (SG). Results. The discrepancy was found for all methods and was statistically significant for the TTO (predicted utilities: 0.89, actual utilities: 0.92, p ≤ 0.05). During radiotherapy, significant differences (p ≤ 0.01) were found between the utilities for the radiotherapy scenario and the actual health state by means of the VAS and the SG, suggesting non-corresponding description as an explanation. The utilities of the radiotherapy scenario and the chemotherapy control scenario remained stable over time, and thus new understanding, valuation shift, and instability could be ruled out as explanations. Conclusion. Utilities obtained through hypothetical scenarios may not be valid predictors of the value judgments of actually experienced health states. The discrepancy in this study seems to have been due to differences between the situations in question (non-corresponding descriptions). Key words: stability; utility assessment; standard gamble; time tradeoff; breast cancer; chemotherapy; radiotherapy. (Med Decis Making 2000;20:62-71)

In medicine, response shift refers to a change — as a result of an event such as a therapy — in the meaning of one's self-evaluation of quality of life. Due to response shift, estimates of side effects of radiotherapy may be attenuated if patients adapt to treatment toxicities. The purpose of our study was to assess to what extent two components of response shift, scale recalibration and changes in values, occur in early-stage breast cancer patients undergoing radiotherapy and to examine what the implications would be for treatment evaluation. In the week before start of post-operative radiotherapy, 46 patients filled out a questionnaire consisting of quality of life items of the SF-36 and the Rotterdam symptom checklist (RSCL) (pretest). During radiotherapy, patients were asked to fill out the questionnaire twice: a posttest (quality of life at that moment) and a thentest (quality of life before treatment, retrospectively), supposedly using the same internal standard. Changes in values were studied by asking the patients on the two occasions to rate the importance of seven attributes representing various domains of quality of life. Patients were also asked whether their quality of life with respect to the measured aspects had changed since the pretest (subjective transition scores). Significant scale recalibration effects were observed in the areas of fatigue and overall quality of life. When the groups were divided according to their subjective transition scores, significant scale recalibration effects were found in case of worsened quality of life for fatigue and overall quality of life, and in case of improved quality of life for fatigue and psychological well-being. The mean importance ratings remained fairly stable over time, except for ‘skin reactions’, which obtained less importance at the end of radiotherapy than before. In conclusion, effects of scale recalibration were observed that would have significantly affected quality of life evaluations, in that the impact of radiotherapy on fatigue and overall quality of life would have been underestimated. Changes in internal values were observed only for ‘skin reactions’.

The objective of this study was to present the long-term results of total adrenalectomy for Cushing's disease. Forty-four patients undergoing total adrenalectomy for Cushing's disease between 1953 and 1989 at Leiden University Medical Center, The Netherlands, were studied retrospectively. Remission was achieved in 42 patients (95%), with a mean duration of 19 years. Adrenal remnants were observed in 12 patients (27%), and were without clinical consequence in the majority of patients, but caused early recurrent disease in 2 patients. Nine patients (20%) experienced Addisonian crises up to 30 years following treatment. Nelson's syndrome developed in 10 patients (23%) 7-24 years following total adrenalectomy. Prior pituitary irradiation was a protective factor against Nelson's syndrome as it delayed its onset (p = 0.025). On the other hand, subnormal dose or noncontinuous glucocorticoid replacement therapy was associated with increased risk of development of Nelson's syndrome (p = 0.047). The incidence of Nelson's syndrome increased with prolonged follow-up, and female patients seemed to be at increased risk. Quality-of-life assessment showed less favorable scores on mental health and health perception scales, for which no explanation can be found except the long-lasting metabolic effects of Cushing's disease, even when successfully treated. In conclusion, total adrenalectomy remains the final treatment for Cushing's disease. The presence of adrenal remnants which can cause recurrent disease and the development of Nelson's syndrome during prolonged follow-up enhance the need for continued regular follow-up. Pituitary irradiation prior to total adrenalectomy delays the onset of Nelson's syndrome.

In the assessment of health-related quality of life, nonpreference-based methods usually show only moderate correlations with utility-based measures. One cause may be that patients assign different weights to the various domains of health-related quality of life, for which nonpreference-based methods usually do not allow. Utilities reflect a weighted sum of these domains. The aim of this study is to assess whether the relationship between utility-based methods and nonpreference-based measures improves through the use of individual importance weights for the various domains of health-related quality of life. For this purpose, weights were obtained from 41 early-stage breast cancer patients, both before and during treatment, for seven pre-selected health status attributes representing important domains of health-related quality of life during chemotherapy. The importance weights were combined with the level of functioning on the attributes. These scores were regressed against patients' utilities for their actually experienced health state during chemotherapy, measured by means of a visual analog scale (VAS), a time trade-off (TTO), and a standard gamble (SG). Before weighting, the seven attribute scores were more strongly related to TTO and SG utilities than the nonpreference-based questionnaires. However, when they were combined with the importance weights, only the correlation with the SG utilities improved, and only so with the importance weights obtained before chemotherapy. In this study, assigning individually assessed preference weights to self-reported level of functioning did not result in stronger relationships with utilities.

To find out which procedure was the safest for each indication for operation in diseases of the thyroid gland.Retrospective study.Two teaching hospitals, The Netherlands.599 consecutive patients who had 601 thyroid operations between 1 October 1985 and 1 June 1993.Incidence of complications, particularly postoperative hypocalcaemia and injuries to the recurrent laryngeal nerve.Accidental injuries to the recurrent laryngeal nerve occurred in 0.7% of the nerves at risk (7/948) and the incidence of permanent hypocalcaemia was 5.2% (31/599). In subtotal procedures (bilateral subtotal thyroidectomy with the remnant left dorsally or total hemithyroidectomy combined with subtotal hemithyroidectomy on the other side with a remnant left at the upper pole) the rate was 11/390 (2.8%) compared with 18/525 (3.4%) after total resections. The corresponding numbers of accidental injuries to the recurrent laryngeal nerve were 2 and 4.Total thyroidectomies are more likely to be done for malignant disease, so the slightly higher complication rates probably reflect the nature of the disease, which requires more radical resection. Both subtotal procedures can be done with comparable low morbidity.

Background —The main goal of follow-up after carotid endarterectomy is to prevent new strokes caused by recurrent stenosis. To determine the most cost-effective follow-up schedule, it is necessary to know the incidence of recurrent stenosis and the risk of stroke it carries. Methods —A systematic review of the literature was performed using standard meta-analytical techniques. Results —Incidence of recurrent stenosis: The data were very heterogeneous. The risk of recurrent stenosis was 10% in the first year, 3% in the second, and 2% in the third. Long-term risk of recurrent stenosis is about 1% per year. Risk of stroke: The reported relative risks of stroke in patients with recurrent stenosis compared with patients without recurrent stenosis showed extreme heterogeneity and ranged from 10 to 0.10. The random effects summary estimator of relative risk was 1.88. Conclusions —The data were very heterogeneous, and much better data are needed to arrive at truly reliable estimates of these important parameters of follow-up. It is clear, though, that the risk of recurrent stenosis is highest in the first few years after carotid endarterectomy and very low in later years. By use of general decision-analytic arguments, it can be argued that, given the test characteristics of carotid ultrasound, a small number of tests can be done in the first few years and that testing for restenosis should not be done after 4 years.