Determinants and mediating mechanisms of quality of life and disease-specific symptoms among thyroid cancer patients: the design of the WaTCh study.

BACKGROUND: Thyroid cancer (TC) patients are understudied but appear to be at risk for poor physical and psychosocial outcomes. Knowledge of the course and determinants of these deteriorated outcomes is lacking. Furthermore, little is known about mediating biological mechanisms. OBJECTIVES: The WaTCh-study aims to; 1. Examine the course of physical and psychosocial outcomes. 2. Examine the association of demographic, environmental, clinical, physiological, and personality characteristics to those outcomes. In other words, who is at risk? 3. Reveal the association of mediating biological mechanisms (inflammation, kynurenine pathway) with poor physical and psychological outcomes. In other words, why is a person at risk? DESIGN AND METHODS: Newly diagnosed TC patients from 13 Dutch hospitals will be invited. Data collection will take place before treatment, and at 6, 12 and 24 months after diagnosis. Sociodemographic and clinical information is available from the Netherlands Cancer Registry. Patients fill-out validated questionnaires at each time-point to assess quality of life, TC-specific symptoms, physical activity, anxiety, depression, health care use, and employment. Patients are asked to donate blood three times to assess inflammation and kynurenine pathway. Optionally, at each occasion, patients can use a weighing scale with bioelectrical impedance analysis (BIA) system to assess body composition; can register food intake using an online food diary; and can wear an activity tracker to assess physical activity and sleep duration/quality. Representative Dutch normative data on the studied physical and psychosocial outcomes is already available. IMPACT: WaTCh will reveal the course of physical and psychosocial outcomes among TC patients over time and answers the question who is at risk for poor outcomes, and why. This knowledge can be used to provide personalized information, to improve screening, to develop and provide tailored treatment strategies and supportive care, to optimize outcomes, and ultimately increase the number of TC survivors that live in good health.

Low-Iodine Diet of 4 Days Is Sufficient Preparation for 131I Therapy in Differentiated Thyroid Cancer Patients.

CONTEXT: No consensus exists about the optimal duration of the low-iodine diet (LID) in the preparation of 131I therapy in differentiated thyroid cancer (DTC) patients. OBJECTIVE: This work aimed to investigate if a LID of 4 days is enough to achieve adequate iodine depletion in preparation for 131I therapy. In addition, the nutritional status of the LID was evaluated. METHODS: In this prospective study, 65 DTC patients treated at 2 university medical centers were included between 2018 and 2021. The patients collected 24-hour urine on days 4 and 7 of the LID and kept a food diary before and during the LID. The primary outcome was the difference between the 24-hour urinary iodine excretion (UIE) on both days. RESULTS: The median 24-hour UIE on days 4 and 7 of the LID were not significantly different (36.1 mcg [interquartile range, 25.4-51.2 mcg] and 36.5 mcg [interquartile range, 23.9-47.7 mcg], respectively, P = .43). On day 4 of the LID, 72.1% of the DTC patients were adequately prepared (24-hour UIE < 50 mcg), and 82.0% of the DTC patients on day 7 (P = .18). Compared to the self-reported regular diet, DTC patients showed a significantly (P < .01) lower percentage of nutrient intake (calories, protein, calcium, iodine, and water) during the LID. CONCLUSION: The 24-hour UIE on day 4 of the LID did not differ from day 7, and therefore shortening the LID from 7 to 4 days seems justified to prepare DTC patients for 131I therapy in areas with sufficient iodine intake and may be beneficial to maintain a sufficient nutritional intake during DTC treatment.

Correction: Thyroid Hormone Activates Brown Adipose Tissue and Increases Non-Shivering Thermogenesis-A Cohort Study in a Group of Thyroid Carcinoma Patients.

[This corrects the article DOI: 10.1371/journal.pone.0145049.].

Diabetic complications do not hamper improvement of health-related quality of life over the course of treatment of diabetic foot ulcers - the Eurodiale study.

AIMS: Diabetic complications, and in particular diabetic foot ulcers (DFUs), are associated with low health-related quality of life (HRQoL). We evaluated whether the presence of diabetic complications also influenced the improvement of HRQoL during DFU treatment. METHODS: 1088 patients presenting for DFU treatment at the centers participating in the Eurodiale study were followed prospectively up to one year. HRQoL was measured both at presentation and after healing or at end of follow up, using EQ-5D: a standardized instrument consisting of five domains and a summary index. The influence of diabetic comorbidity on the course of HRQoL was evaluated for each of the EQ-5D outcomes in multi-level linear regression analyses, adjusting for baseline characteristics. RESULTS: HRQoL improved in all EQ-5D outcomes over the course of treatment for those DFUs that healed. The few significant differences in the development of HRQoL between patients with and without comorbidity showed a more beneficial development for patients with comorbidity in DFUs that did not heal or healed slowly. CONCLUSIONS: Comorbidity does not hamper improvement of HRQoL in DFU treatment. On the contrary, HRQoL improved sometimes more in patients with certain comorbidity with hard-to-heal ulcers.

Thyroid Hormone Activates Brown Adipose Tissue and Increases Non-Shivering Thermogenesis--A Cohort Study in a Group of Thyroid Carcinoma Patients.

BACKGROUND/OBJECTIVES: Thyroid hormone receptors are present on brown adipose tissue (BAT), indicating a role for thyroid hormone in the regulation of BAT activation. The objective of this study was to examine the effect of thyroid hormone withdrawal followed by thyroid hormone in TSH-suppressive dosages, on energy expenditure and brown adipose tissue activity. SUBJECTS/METHODS: This study was a longitudinal study in an academic center, with a follow-up period of 6 months. Ten patients with well-differentiated thyroid carcinoma eligible for surgical treatment and subsequent radioactive iodine ablation therapy were studied in a hypothyroid state after thyroidectomy and in a subclinical hyperthyroid state (TSH-suppression according to treatment protocol). Paired two-tailed t-tests and linear regression analyses were used. RESULTS: Basal metabolic rate (BMR) was significantly higher after treatment with synthetic thyroid hormone (levothyroxine) than in the hypothyroid state (BMR 3.8 ± 0.5 kJ/min versus 4.4 ± 0.6 kJ/min, P = 0.012), and non-shivering thermogenesis (NST) significantly increased from 15 ± 10% to 25 ± 6% (P = 0.009). Mean BAT activity was significantly higher in the subclinical hyperthyroid state than in the hypothyroid state (BAT standard uptake value (SUVMean) 4.0 ± 2.9 versus 2.4 ± 1.8, P = 0.039). CONCLUSIONS: Our study shows that higher levels of thyroid hormone are associated with a higher level of cold-activated BAT. TRIAL REGISTRATION: ClinicalTrials.gov NCT02499471.

Predictors of lower-extremity amputation in patients with an infected diabetic foot ulcer.

OBJECTIVE: Infection commonly complicates diabetic foot ulcers and is associated with a poor outcome. In a cohort of individuals with an infected diabetic foot ulcer, we aimed to determine independent predictors of lower-extremity amputation and the predictive value for amputation of the International Working Group on the Diabetic Foot (IWGDF) classification system and to develop a risk score for predicting amputation. RESEARCH DESIGN AND METHODS: We prospectively studied 575 patients with an infected diabetic foot ulcer presenting to 1 of 14 diabetic foot clinics in 10 European countries. RESULTS: Among these patients, 159 (28%) underwent an amputation. Independent risk factors for amputation were as follows: periwound edema, foul smell, (non)purulent exudate, deep ulcer, positive probe-to-bone test, pretibial edema, fever, and elevated C-reactive protein. Increasing IWGDF severity of infection also independently predicted amputation. We developed a risk score for any amputation and for amputations excluding the lesser toes (including the variables sex, pain on palpation, periwound edema, ulcer size, ulcer depth, and peripheral arterial disease) that predicted amputation better than the IWGDF system (area under the ROC curves 0.80, 0.78, and 0.67, respectively). CONCLUSIONS: For individuals with an infected diabetic foot ulcer, we identified independent predictors of amputation, validated the prognostic value of the IWGDF classification system, and developed a new risk score for amputation that can be readily used in daily clinical practice. Our risk score may have better prognostic accuracy than the IWGDF system, the only currently available system, but our findings need to be validated in other cohorts.

Health-related quality of life predicts major amputation and death, but not healing, in people with diabetes presenting with foot ulcers: the Eurodiale study.

OBJECTIVE: Low health-related quality of life (HRQoL) has been consistently reported to be associated with poor prognosis for a variety of health outcomes in various settings. We aimed to evaluate whether HRQoL in patients presenting with new diabetic foot ulcers (DFUs) has prognostic significance for ulcer healing, major amputation, and death. RESEARCH DESIGN AND METHODS: We followed 1,088 patients with new DFUs presenting for treatment at one of the 14 centers in 10 European countries participating in the Eurodiale (European Study Group on Diabetes and the Lower Extremity) study, prospectively until healing (76.9%), major amputation (4.6%), or death (6.4%) up to a maximum of 1 year. At baseline, patient and ulcer characteristics were recorded as well as EQ-5D, a standardized instrument consisting of five domains and a visual analog scale for use as a measure of HRQoL. The prognostic influence of the EQ-5D domains was evaluated in multivariable Cox regression analyses on the time-to-event data, adjusting for baseline clinical characteristics of the ulcer and comorbidities. RESULTS: While predictive effects of HRQoL, adjusted for possible confounders, were absent for healing, decreased HRQoL, especially in the physical domains, was statistically significant for major amputation (mobility, self-care, usual activities) and death (self-care, usual activities, pain/discomfort). CONCLUSIONS: Low HRQoL appears to be predictive for major amputation and death, but high HRQoL does not increase healing. Future studies into the influence of HRQoL on ulcer outcome are important in attempts to decrease treatment failure and mortality.

Diabetic foot disease: impact of ulcer location on ulcer healing.

BACKGROUND: Healing of heel ulcers in patients with diabetes is considered to be poor, but there is relatively little information on the influence of ulcer location on ulcer healing. METHODS: The influence of ulcer location on time to healing of diabetic foot ulcers was analysed by multivariate Cox regression analysis for 1000 patients included in the Eurodiale study, a prospective cohort study of patients with diabetic foot disease. RESULTS: Median time to healing was 147 days for toe ulcers [(95% confidence interval (CI) 135-159 days)], 188 days for midfoot ulcers (95% CI 158-218 days) and 237 days for heel ulcers (95% CI 205-269 days) (p < 0.01). The median time to healing for plantar ulcers was 172 days (95% CI 157-187 days) and 155 days (95% CI 138-172 days) for nonplantar ulcers (p = 0.71). In multivariate Cox regression analysis, the hazard ratio for ulcer healing for midfoot and heel ulcers compared with toe ulcers was 0.77 (95% CI 0.64-0.92) and 0.62 (95% CI 0.47-0.83), respectively; the hazard ratio for ulcer healing for plantar versus nonplantar ulcers was 1 (95% CI 0.84-1.19). Other factors significantly influencing time to healing were the duration of diabetes, ulcer duration, the presence of heart failure and the presence of peripheral arterial disease. CONCLUSIONS: Time to ulcer healing increased progressively from toe to midfoot to heel, but did not differ between plantar and nonplantar ulcers. Our data also indicate that risk factors for longer time to healing differ from factors that affect the ultimate number of ulcers that heal (healing rate).

Minimal intensity physical activity (standing and walking) of longer duration improves insulin action and plasma lipids more than shorter periods of moderate to vigorous exercise (cycling) in sedentary subjects when energy expenditure is comparable.

BACKGROUND: Epidemiological studies suggest that excessive sitting time is associated with increased health risk, independent of the performance of exercise. We hypothesized that a daily bout of exercise cannot compensate the negative effects of inactivity during the rest of the day on insulin sensitivity and plasma lipids. METHODOLOGY/PRINCIPAL FINDINGS: Eighteen healthy subjects, age 21±2 year, BMI 22.6±2.6 kgm(-2) followed randomly three physical activity regimes for four days. Participants were instructed to sit 14 hr/day (sitting regime); to sit 13 hr/day and to substitute 1 hr of sitting with vigorous exercise 1 hr (exercise regime); to substitute 6 hrs sitting with 4 hr walking and 2 hr standing (minimal intensity physical activity (PA) regime). The sitting and exercise regime had comparable numbers of sitting hours; compared to the exercise regime, the minimal intensity PA regime had a higher estimated daily energy expenditure (238kcal/day) [corrected]. PA was assessed continuously by an activity monitor (ActivPAL) and a diary. Measurements of insulin sensitivity (oral glucose tolerance test, OGTT) and plasma lipids were performed in the fasting state, the morning after the 4 days of each regime. In the sitting regime, daily energy expenditure was about 500 kcal lower than in both other regimes. Area under the curve for insulin during OGTT was significantly lower after the minimal intensity PA regime compared to both sitting and exercise regimes 6727.3±4329.4 vs 7752.0±3014.4 and 8320.4±5383.7 mU•min/ml, respectively. Triglycerides, non-HDL cholesterol and apolipoprotein B plasma levels improved significantly in the minimal intensity PA regime compared to sitting and showed non-significant trends for improvement compared to exercise. CONCLUSIONS: One hour of daily physical exercise cannot compensate the negative effects of inactivity on insulin level and plasma lipids if the rest of the day is spent sitting. Reducing inactivity by increasing the time spent walking/standing is more effective than one hour of physical exercise, when energy expenditure is kept constant.

Effective pharmacological treatment of painful diabetic neuropathy by nurse practitioners: results of an algorithm-based experience.

OBJECTIVE: To improve the care of patients with painful diabetic polyneuropathy (PDP) by a specialized outpatient clinic for individuals referred by general practitioners and to determine the effects on pain, quality of life, and patient satisfaction. MATERIAL AND METHODS: One hundred twenty-one patients were prospectively enrolled. At baseline and after 12 months at end of treatment, patients filled in a set of validated questionnaires on severity and interference of pain, quality of life, anxiety and depression, and patient satisfaction with the service offered. SETTING: The outpatient clinic is part of a regional chronic care management program, which includes both hospital-based endocrinologists and general practitioners. RESULTS: Twenty-eight patients (27%) did not need any further treatment after one visit to the outpatient clinic. As initial drug, pregabalin was the most commonly prescribed drug (65%); amitriptyline was prescribed in only 30% due to its contraindications. Improvements were found in all pain scores (P < 0.05). Pain interference was improved in sleep (P < 0.01), general activity, and mood (P < 0.05). More than half of the patients (65%) were satisfied with the treatment and wished no further medication changes; 52% had a treatment success defined as pain relief ≥ 30%. Medication was stopped due to inefficacy in 9% of patients and changed due to adverse effects in 20% of the patients. CONCLUSIONS: A specialized outpatient clinic for patients with PDP is an effective health care service. Using diagnostic instruments and a defined treatment algorithm, significant pain reduction was achieved in the majority of patients in a relative short period of time.

Multiorgan insulin sensitivity in lean and obese subjects.

OBJECTIVE: To provide a comprehensive assessment of multiorgan insulin sensitivity in lean and obese subjects with normal glucose tolerance. RESEARCH DESIGN AND METHODS: The hyperinsulinemic-euglycemic clamp procedure with stable isotopically labeled tracer infusions was performed in 40 obese (BMI 36.2 ± 0.6 kg/m(2), mean ± SEM) and 26 lean (22.5 ± 0.3 kg/m(2)) subjects with normal glucose tolerance. Insulin was infused at different rates to achieve low, medium, and high physiological plasma concentrations. RESULTS: In obese subjects, palmitate and glucose R(a) in plasma decreased with increasing plasma insulin concentrations. The decrease in endogenous glucose R(a) was greater during low-, medium-, and high-dose insulin infusions (69 ± 2, 74 ± 2, and 90 ± 2%) than the suppression of palmitate R(a) (52 ± 4, 68 ± 1, and 79 ± 1%). Insulin-mediated increase in glucose disposal ranged from 24 ± 5% at low to 253 ± 19% at high physiological insulin concentrations. The suppression of palmitate R(a) and glucose R(a) were greater in lean than obese subjects during low-dose insulin infusion but were the same in both groups during high-dose insulin infusion, whereas stimulation of glucose R(d) was greater in lean than obese subjects across the entire physiological range of plasma insulin. CONCLUSIONS: Endogenous glucose production and adipose tissue lipolytic rate are both very sensitive to small increases in circulating insulin, whereas stimulation of muscle glucose uptake is minimal until high physiological plasma insulin concentrations are reached. Hyperinsulinemia within the normal physiological range can compensate for both liver and adipose tissue insulin resistance, but not skeletal muscle insulin resistance, in obese people who have normal glucose tolerance.

Tauroursodeoxycholic Acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women.

OBJECTIVE: Insulin resistance is commonly associated with obesity. Studies conducted in obese mouse models found that endoplasmic reticulum (ER) stress contributes to insulin resistance, and treatment with tauroursodeoxycholic acid (TUDCA), a bile acid derivative that acts as a chemical chaperone to enhance protein folding and ameliorate ER stress, increases insulin sensitivity. The purpose of this study was to determine the effect of TUDCA therapy on multiorgan insulin action and metabolic factors associated with insulin resistance in obese men and women. RESEARCH DESIGN AND METHODS: Twenty obese subjects ([means +/- SD] aged 48 +/- 11 years, BMI 37 +/- 4 kg/m2) were randomized to 4 weeks of treatment with TUDCA (1,750 mg/day) or placebo. A two-stage hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled tracer infusions and muscle and adipose tissue biopsies were used to evaluate in vivo insulin sensitivity, cellular factors involved in insulin signaling, and cellular markers of ER stress. RESULTS Hepatic and muscle insulin sensitivity increased by approximately 30% (P < 0.05) after treatment with TUDCA but did not change after placebo therapy. In addition, therapy with TUDCA, but not placebo, increased muscle insulin signaling (phosphorylated insulin receptor substrate(Tyr) and Akt(Ser473) levels) (P < 0.05). Markers of ER stress in muscle or adipose tissue did not change after treatment with either TUDCA or placebo. CONCLUSIONS: These data demonstrate that TUDCA might be an effective pharmacological approach for treating insulin resistance. Additional studies are needed to evaluate the target cells and mechanisms responsible for this effect.

Dissociation between intrahepatic triglyceride content and insulin resistance in familial hypobetalipoproteinemia.

BACKGROUND & AIMS: Hepatic steatosis is associated with insulin resistance, but it is not clear whether increased intrahepatic triglyceride (IHTG) content causes the resistance or is a marker. Subjects with familial hypobetalipoproteinemia (FHBL) have high levels of IHTG because of a genetic defect in hepatic export of triglycerides, and provide a unique cohort to study the relationship between steatosis and insulin sensitivity. METHODS: One group of lean subjects with normal IHTG content (2.2% +/- 0.6% of liver volume) (n = 6), and 3 groups of overweight and obese subjects matched for body mass index, were studied: (1) normal IHTG content (3.3% +/- 0.5%; n = 6), (2) high IHTG content (21.4% +/- 2.6%) due to nonalcoholic fatty liver disease (NAFLD; n = 6), and (3) high IHTG content (18.1% +/- 2.2%) due to FHBL (n = 3). A hyperinsulinemic-euglycemic clamp procedure, in conjunction with glucose tracer infusion, was used to determine multiorgan insulin sensitivity. RESULTS: Hepatic insulin sensitivity (reciprocal of glucose rate of appearance [micromol x kg fat-free mass(-1) x min(-1)] x insulin [mU/L]) was greatest in the Lean group (2.0 +/- 0.4); it was the same among subjects with FHBL (0.8 +/- 0.1) and the group with normal IHTG content, matched for body mass index (0.7 +/- 0.1), but greater than the NAFLD group (0.3 +/- 0.1) (P < .01). Muscle insulin sensitivity (percent increase in glucose uptake during insulin infusion) was greatest in the Lean group (576% +/- 70%). Muscle insulin sensitivity was similar in subjects with FHBL and those with normal IHTG (319% +/- 77%, 326% +/- 27%, respectively), but greater than the NAFLD group (145% +/- 18%) (P < .01). CONCLUSIONS: Steatosis is dissociated from insulin resistance in FHBL, which suggests that increased IHTG content is a marker, not a cause, of metabolic dysfunction.

Long-term outcome of patients with macroprolactinomas initially treated with dopamine agonists.

OBJECTIVE: Dopamine agonists are the first line therapy for the treatment of prolactinomas. The aim of this study was to assess the outcome of macroprolactinomas during long-term follow-up after initial treatment with dopamine agonists. DESIGN: Retrospective follow-up study. PATIENTS: We included 72 consecutive patients (age 39+/-17 years, men 46%) diagnosed with macroprolactinoma, and initially treated with dopamine agonists between 1980 and 2004. RESULTS: Initial presentation included headache in 49%, and visual field defects in 38% of the patients. Nine patients were already treated with dopamine agonists at presentation. Median prolactin level of the untreated patients was 460 microg/L (range 96-35,398 microg/L) at presentation. Hypopituitarism, other than hypogonadism, was present in 6% of the patients. Mean duration of follow-up was 10.2+/-6.1 years. Additional transsphenoidal surgery was necessary in 35% of the patients, because of resistance and/or intolerance of dopamine agonists. Postoperative radiotherapy was provided to 18% of all patients. During long-term follow-up, normoprolactinemia was present in 85% of the patients, but biochemical remission (normal prolactin levels in the absence of dopamine agonists) was present in only 22% of the patients. Tumor shrinkage was evident on MRI in 57% of the patients. Hypopituitarism developed in 39% of the patients, especially in those who received additional surgery with or without radiotherapy. CONCLUSION: Dopamine agonists are effective in normalizing prolactin values, and inducing tumor shrinkage. However, in one-third of the patients, additional therapy was necessary due to dopamine agonist resistance and/or intolerance, associated with a high incidence of hypopituitarism.

Perioperative glucocorticosteroid supplementation is not supported by evidence.

Ever since the first descriptions of adrenal insufficiency following exogenous supplementation physicians dread to abolish perioperative glucocorticosteroid supplementation. Now, 55 years after the first publications we can challenge those first reports. However, these cases have resulted in the supplementation of supraphysiological doses of glucocorticosteroids to patients that use exogenous corticosteroids: the so-called perioperative glucocorticosteroid supplementation or "(gluco)corticosteroid stress scheme". It is very questionable whether a dose that exceeds the normal daily production of 5.7 mg cortisol per square meter of body surface area is necessary to prevent perioperative hypotension. Retrospective, prospective and randomised studies, though all methodologically flawed, are discussed and show that continuation of the "basal" amount of glucocorticosteroids is sufficient to counterbalance surgical stress. The current and rather defensive strategy of perioperative supraphysiological glucocorticosteroid supplementation is not embedded in medical evidence. Additionally, high doses of glucocorticosteroids have disadvantages that should not be ignored.

Aortic valve calcification and mild tricuspid regurgitation but no clinical heart disease after 8 years of dopamine agonist therapy for prolactinoma.

OBJECTIVE: Treatment with ergot-derived dopamine agonists, pergolide, and cabergoline has been associated with an increased frequency of valvular heart disease in Parkinson's disease. The aim of the present study was to assess the prevalence of valvular heart disease in patients treated with dopamine agonists for prolactinomas. DESIGN: This was a cross-sectional study. PATIENTS: We performed two-dimensional and Doppler echocardiography in 78 consecutive patients with prolactinoma (mean age 47 +/- 1.4 yr, 26% male, 31% macroprolactinoma) treated with dopamine agonists for at least 1 yr (mean 8 +/- 0.6 yr) and 78 control subjects. Patients were classified according to treatment: patients treated with cabergoline (group 1: n = 47) and patients not treated with cabergoline (group 2: n = 31). RESULTS: Clinically relevant valvular heart disease was present in 12% of patients (nine of 78) vs. 17% of controls (13 of 78) (P = 0.141) and 17% (eight of 47) of patients treated with cabergoline vs. 3% (one of 31) of patients not treated with cabergoline (P = 0.062). Mild tricuspid regurgitation was present in 41% of patients vs. 26% of controls (P = 0.042), and aortic valve calcification was present in 40% of patients, compared with 18% of controls (P = 0.003). There was no relation between the cumulative dose of cabergoline and the presence of mild, moderate, or severe valve regurgitation. CONCLUSION: Several years of dopamine agonist treatment in patients with prolactinomas is associated with increased prevalence of aortic valve calcification and mild tricuspid regurgitation but not with clinically relevant valvular heart disease. Therefore, additional studies on the adverse cardiac effects of dopaminergic drugs in prolactinoma are warranted, especially in patients with much longer use of these drugs.

Disease-specific impairments in quality of life during long-term follow-up of patients with different pituitary adenomas.

OBJECTIVE: Quality of life (QoL) is impaired in patients treated for pituitary adenomas. However, differences in age and gender distributions hamper a proper comparison of QoL. Therefore, we compared age- and gender-specific standard deviations (SD) scores (Z-scores) of QoL parameters in patients treated for pituitary adenomas. PATIENTS AND METHODS: We determined Z-scores for health-related questionnaires [the Hospital Anxiety and Depression Scale (HADS), Multidimensional Fatigue Inventory (MFI)-20, Nottingham Health Profile (NHP), and Short Form Health Survey (SF-36)] in patients during long-term follow-up (13 +/- 8 years) after treatment for pituitary adenomas. Z-scores were calculated by comparing the data for 403 patients with acromegaly (n = 118), Cushing's disease (CD; n = 58), prolactinoma (n = 128), and nonfunctioning macroadenoma (n = 99) with a control population (n = 440) for each subscale of the questionnaires and for total QoL score. RESULTS: All subscales of the questionnaires and the total QoL score were negatively affected in patients compared to controls. Comparing the Z-scores, patients treated for acromegaly reported more impairment in physical ability and functioning and more bodily pain compared to patients treated for nonfunctioning macroadenoma and those treated for prolactinoma. Patients with CD reported impairment in physical functioning compared to patients treated for nonfunctioning macroadenoma. Linear regression analysis, with correction for age and gender, confirmed these findings. Additionally, CD was associated with increased anxiety. Hypopituitarism negatively influenced multiple aspects of QoL. CONCLUSION: QoL is impaired in patients during long-term follow-up after treatment of pituitary adenomas. Patients with pituitary adenomas should be informed of these persistent adverse effects of their disease on QoL to prevent inappropriate expectations with respect to the long-term results of treatment.

Malignant prolactinoma: case report and review of the literature.

Pituitary carcinomas are extremely rare. In general, the initial clinical, biochemical, and histological characteristics are of minimal utility in distinguishing benign adenomas from pituitary carcinomas. We describe a 63-year-old woman with a macroprolactinoma, who presented with diplopia and blurred vision. This unusual initial presentation and the subsequent aggressive clinical course, with diffuse local and distant intramedullary metastases, prompted us in retrospect to make a detailed analysis of the therapeutic interventions and histology. In addition, we reviewed all available literature on published cases of malignant prolactinoma and detailed their epidemiological, clinical, and histopathological characteristics. In brief, it is postulated that pituitary carcinomas arise from the transformation of initially large, but benign, adenomas. Unusual and/or atypical clinical manifestations appear to occur more frequently. In vivo, the development of dopamine agonist resistance in invasive macroprolactinoma is indicative of malignancy and should prompt the clinician to perform a biopsy of the tumor. For pituitary tumors that exhibit high mitotic activity, increased Ki-67 and/or p53 immunoreactivity, it may be useful to denote these tumors as 'atypical' prolactinomas to raise the possibility of future malignant development.