Late recurrences of Cushing's disease after initial successful transsphenoidal surgery

CONTEXT: Few studies have systematically analyzed the long-term recurrence rates of Cushing's disease after initial successful transsphenoidal surgery. SETTING: This was a retrospective review of patients treated at the University of Virginia Medical Center. PATIENTS: A total of 215 subjects with Cushing's disease who underwent initial transsphenoidal surgery for resection of a presumed pituitary microadenoma from 1992-2006 were included. MAIN OUTCOME MEASURES: Remission and recurrence rates of Cushing's disease were examined. Recurrence was defined as an elevated 24-h urine free cortisol with clinical symptoms consistent with Cushing's disease. RESULTS: Of the 215 patients who underwent transsphenoidal surgery for Cushing's disease, surgical remission was achieved in 184 (85.6%). The mean length of follow-up was 45 months. Actuarial recurrence rates of Cushing's disease after initially successful transsphenoidal surgery at 1, 2, 3, and 5 yr were 0.5, 6.7, 10.8, and 25.5%, respectively. Among the 184 patients who achieved remission, 32 (17.4%) patients followed for more than 6 months ultimately had a recurrence of Cushing's disease. The median time to recurrence was 39 months. Immediate postoperative hypocortisolemia (serum cortisol < or = 2 microg/dl within 72-h surgery) was achieved in 97 (45.1%) patients. Patients who had postoperative serum cortisol of more than 2 microg/dl were 2.5 times more likely to have a recurrence than patients who had serum cortisol less than or equal to 2 microg/dl (odds ratio = 2.5; 95% confidence interval 1.12-5.52; P = 0.022). CONCLUSIONS: A quarter of the patients with Cushing's disease who achieve surgical remission after transsphenoidal surgery, recur with long-term follow-up. This finding emphasizes the need for continued biochemical and clinical follow-up to ensure remission after surgery.     

Health-related quality of life after percutaneous coronary intervention versus coronary bypass surgery in high-risk patients with medically refractory ischemia

OBJECTIVES: We compared six-month health-related quality of life (HRQL) for high-risk patients with medically refractory ischemia randomized to percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG) surgery. BACKGROUND: Mortality rates after PCI and CABG surgery are similar. Therefore, differences in HRQL outcomes may help in the selection of a revascularization procedure. METHODS: Patients were enrolled in a Veterans Affairs multicenter randomized trial comparing PCI versus CABG for patients with medically refractory ischemia and one or more risk factors for adverse outcome; 389 of 423 patients (92%) alive six months after randomization completed an Short Form-36 (SF-36) health status survey. Primary outcomes were the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores from the SF-36. Multivariable analyses were used to evaluate whether PCI or CABG surgery was associated with better PCS or MCS scores after adjusting for over 20 baseline variables. RESULTS: There were no significant differences in either PCS scores (38.7 vs. 37.3 for PCI and CABG, respectively; p = 0.23) or MCS scores (45.5 vs. 46.1, p = 0.58) between the treatment arms. In multivariable models, there remained no difference in HRQL for post-PCI versus post-CABG patients (for PCS, absolute difference = 0.56 +/- standard error of 1.14, p = 0.63; for MCS, absolute difference = -1.23 +/- 1.12, p = 0.27). We had 97% power to detect a four-point difference in scores, where four to seven points is a clinically important difference. CONCLUSIONS: High-risk patients with medically refractory ischemia randomized to PCI versus CABG surgery have equivalent six-month HRQL. Therefore, HRQL concerns should not drive decision-making regarding selection of a revascularization procedure for these patients.     

Health-related quality of life and productivity impact in haemophilia patients with inhibitors

Summary.  To measure health-related quality of life (HRQL), its determinants, and its association with patient and caregiver productivity among a sample of haemophilia patients with inhibitors in the United States (US). Data on demographical and clinical characteristics, treatment patterns, HRQL (SF-12v2), and productivity outcomes were reported for 53 patients. Mean SF-12v2 domain and mental (MCS) and physical (PCS) component summary scores were assessed and compared with US norms. Regression analyses explored the association of patient and treatment factors with HRQL and productivity. Patients' mean age was 20.7 years (SD = 18.8), 88.5% were type A, and 39.6% received on-demand therapy as their only mode of treatment. Mean PCS was significantly lower than the US norm (PCS, 39.9, P  < 0.01) and mean MCS showed no significant difference (MCS, 49.9, P  = ns). On-demand treatment ( B  = −0.336, P <  0.05) and number of haemorrhages ( B  = −0.366, P <  0.05) were negatively associated with PCS; and PCS was associated with patients' missed work or school days [incidence rate ratio (IRR) = 0.93, P <  0.001] and perceived impact on daily activities (OR = 0.72, P <  0.05). Younger age (IRR = 0.91, P <  0.01), lower PCS (IRR = 0.94, P <  0.01), more haemorrhages (IRR = 1.05, P < 0.05), and surgery (IRR = 2.74, P  < 0.05) were associated with fewer patients' productive days. Physical functioning among inhibitor patients in the US is compromised and is negatively associated with their daily activities and productivity. These data suggest a positive association of prophylactic and immunotolerance therapy with HRQL, specifically physical impairment.     

The effects of infliximab therapy on health-related quality of life in ulcerative colitis patients

OBJECTIVES: The impact of infliximab induction and maintenance therapy on health-related quality of life (HRQL) was evaluated in patients with ulcerative colitis (UC). METHODS: In two placebo-controlled, double-blind studies (the Active Ulcerative Colitis Trials 1 and 2 [ACT 1 and 2]), 728 patients were randomized to placebo or infliximab 5 mg/kg or 10 mg/kg. Infusions were administered at weeks 0, 2, 6, and every 8 wk thereafter, up to week 22 (ACT 2) or 46 (ACT 1). Changes in Inflammatory Bowel Disease Questionnaire (IBDQ) and Medical Outcomes Study 36-Item Short Form Health Survey physical and mental component summary (PCS and MCS, respectively) scores were analyzed. RESULTS: Baseline scores for the pooled patient population indicated substantial impairment in HRQL. Improvement at week 8 in the total IBDQ score was significantly greater in the infliximab 5-mg/kg (40, P < 0.001) and 10-mg/kg (36, P < 0.001) groups compared with the placebo group (28). Improvement at week 8 was also significantly greater in the infliximab 5- and 10-mg/kg groups for the PCS (6.8 and 5.9, respectively) and MCS (5.9 and 6.4, respectively) compared with placebo (PCS = 3.7, MCS = 3.0, P < 0.01 for all comparisons). Continued benefit was seen at weeks 30 and 54 with infliximab maintenance therapy (P < 0.001 for all comparisons). Improvement in total IBDQ score correlated significantly (P < 0.001) with improvement in both PCS and MCS scores, and Mayo score. CONCLUSIONS: Infliximab therapy substantially improved HRQL in patients with UC. This benefit was sustained through 1 yr with maintenance infliximab therapy.     

Quality of life in children and adolescents 1-year after cure of Cushing syndrome: a prospective study

Objective  Cushing syndrome (CS) in children is associated with symptoms that may impair health related quality of life (HRQL). There are no prospective reports of HRQL in children with CS.
Methods  Prospective study of 40 children (mean age 13 ± 3·2 years) with CS evaluated prior to and 1-year post-treatment. The Child Health Questionnaire (CHQ) was used to assess HRQL; Wechsler Intelligence Scale for Children (WASI) was used to assess cognitive function, and patient-reported symptoms were assessed with a CS symptom checklist.
Results  Active CS was associated with low physical and psychosocial summary scores compared to US population data ( P <  0·001). Despite improvement from pre- to 1-year postcure, residual impairment remained in physical summary and function, and role-physical, global health and emotional impact (parent) scores. Incomplete recovery of adrenal function at 1-year post-treatment was associated with impaired scores. WASI IQ scores declined and a correlation was noted between age at first evaluation and IQ score changes. Most self-reported CS symptoms showed improvement, but forgetfulness, unclear thinking and decreased attention span did not improve after cure of CS.
Conclusion  CS in children and adolescents is associated with impaired HRQL, with residual impairment 1 year after cure. Our results also suggest that younger children are more likely to experience negative changes in cognitive function. HRQL is an important outcome measure in children and adolescents with CS and identification of factors that contribute to HRQL may help to diminish the physical and psychological burden of disease in this population of patients.     

Clinical laboratory findings and results of therapy in 55 patients with Cushing's syndrome

In this study, 55 patients with Cushing's syndrome (CS) (50 female, 5 male; mean age 34 +/- 12.3 yr) who attended our clinics between the years 1983 and 2000 were retrospectively evaluated for clinical and laboratory features and modalities and results of therapy, due to a few similar studies over the last ten years. Cushing's disease was diagnosed in 39 patients (71%), adrenal adenoma in 13 patients (23.6%) and adrenal carcinoma in 3 patients (5.5%). Centripedal obesity, moon face, hypertension, hirsutism and purplish stria were the most frequent findings. Loss of normal serum F circadian rhythm was found in all patients with CS. The overnight 1 mg oral dexamethasone suppression test and low-dose dexamethasone suppression test (LDDST) yielded 100% and 100% diagnostic sensitivity for CS, respectively. Sensitivity and specivity of the high-dose dexamethasone suppression test (HDDST) in distinguishing Cushing's disease was found to be 82% and 100%, respectively. All of the patients with adrenal CS were not suppressed with HDDST. Sellar CT and/or MRI accurately identified the tumor in 58% of these patients. Recurrence was observed in 3 (11%) of the 28 patients with Cushing's disease, treated by transsphenoidal adenomectomy. Recurrence was diagnosed 1.5, 3 and 6 yr after the operation in these 3 patients. One patient had residue tumor. In our case series, bilateral adrenalectomy plus pituitary irradiation achieved the highest remission rate (100%) in Cushing's disease. In 2 out of 4 patients (50%) treated by left adrenalectomy associated with pituitary irradiation, recurrence was observed. Panhypopituitarism due to tumor apoplexy was observed in one of the patients with Cushing's disease. All of the patients with adrenal CS, the tumor was accurately localized with imaging methods before the operation. The appropriate operative procedure resulted in complete remission in patients with adrenal adenoma. Consequently, Cushing's disease was the most common form of CS. The overnight 1 mg oral DST and 24-h urine free F excretion (UFC) as screening tests, 2-day LDDST as diagnostic test and 2-day HDDST as differential diagnostic test were good studies. More successful outcomes have been achieved in treatment of Cushing's disease with the development of pituitary surgery in the recent years, as well as in our case series. Surgery is also curative for adrenal adenoma patients. Survival remains poor among carcinoma patients.     

Quality of life in patients after long-term biochemical cure of Cushing's disease

To evaluate the long-term impact of cured Cushing's disease on subjective well-being, we assessed quality of life by validated health-related questionnaires in 58 patients cured from Cushing's disease by transsphenoidal surgery (n = 58), some of whom received additional radiotherapy (n = 11) and/or bilateral adrenalectomy (n = 3). The mean duration of remission was 13.4 +/- 6.7 yr (range of 2-25 yr). Patient data were compared with a control group of 98 healthy subjects with the same age and sex distribution and with age-adjusted reference values available from the literature. General perceived well-being, measured by the Nottingham Health Profile and the Short Form, was reduced compared with controls for all subscales (P < 0.001). Patients with Cushing's disease had worse scores on subscales of fatigue Multidimensional Fatigue Index and anxiety and depression (Hospital Anxiety and Depression Scale). Compared with reference values from the literature, quality of life was also reduced in the patients according to all questionnaires and all items, except pain (Short Form), sleep (Nottingham Health Profile), and reduced activity (Multidimensional Fatigue Index). Despite conventional hormone replacement therapy, hypopituitarism was an important independent predictor of reduced quality of life. Patients without hypopituitarism (n = 28) showed reduced scores on physical items but normal scores on mental items compared with controls. In conclusion, despite long-term cure of Cushing's disease, patients experience a considerable decrease in quality of life, with physical and psychosocial impairments, especially in the presence of hypopituitarism.     

Remission in patients with Crohn's disease is associated with improvement in employment and quality of life and a decrease in hospitalizations and surgeries

OBJECTIVES: Hospitalization, surgery, work loss, and impaired quality of life contribute to the cost and burden of care for patients with Crohn's disease. We examined the impact of remission on patients' employment, quality of life, and hospitalization and surgery in a clinical trial to validate clinical remission, as defined by the Crohn's disease activity index (CDAI), as the key treatment goal in managing Crohn's disease. METHODS: ACCENT I evaluated the efficacy and safety of long-term dosing of infliximab compared to a single dose of infliximab in 573 patients with moderately-to-severely active Crohn's disease. At wk 54, employment status was compared between patients in CDAI remission and those not in CDAI remission, for those not employed at baseline. Physical component summary (PCS) and mental component summary (MCS) scores of the SF-36 questionnaire were also compared between these two groups. The numbers of Crohn's-related hospitalizations and surgeries were compared among four groups of patients who spent 0-25%, 25-50%, 50-75%, and 75-100% of time, respectively, in CDAI remission during the study. RESULTS: At baseline, patients had a severely impaired quality of life and a high unemployment rate (38.4%). Among the group of patients who were unemployed at baseline, 31% of those patients who achieved CDAI remission (CDAI < 150) at wk 54 were employed, compared to 16% who were not in CDAI remission at wk 54 (p < 0.05). PCS and MCS scores of patients in CDAI remission at wk 54 were significantly higher (p < 0.0001), indicating better mental and physical functioning, than those of patients not in CDAI remission at wk 54, and were similar to those of the general U.S. population. Hospitalization and surgery rates decreased as the percentage of time patients were in CDAI remission increased (p < 0.01 and p < 0.05, respectively). CONCLUSIONS: CDAI remission is associated with reduced hospitalizations and surgeries, increased employment, and normalized quality of life. Sustained CDAI remission should be the key therapeutic goal in managing Crohn's disease.     

Anterior pituitary function after transsphenoidal selective adenomectomy in patients with Cushing's disease

The anterior pituitary function in 25 patients with Cushing's disease was assessed before and after transsphenoidal adenomectomy. Pituitary adenoma was detected and removed in 24 cases, resulting in clinical remission in 22. Postoperative hypoadrenocorticism was observed in all of the cases with remission, necessitating substitution of glucocorticoid. One case had a recurrence after a year in remission. Plasma ACTH and cortisol rapidly decreased after surgery and remained at subnormal levels. However, diurnal rhythmicity of ACTH and cortisol appeared in 5 of 9 cases within 6 months after surgery and exhibited normal suppressibility in response to low dose dexamethasone. The impaired ACTH response to hypoglycemia was restored after surgery. The GH response to hypoglycemia and the TSH response to TRH were improved by correction of hypercorticism and became evident over time. These results suggest that preoperative impairment of anterior pituitary hormone secretion is secondary to hyperadrenocorticism and that ACTH hypersecretion by a primary pituitary adenoma is the primary etiology in Cushing's disease. We conclude that transphenoidal pituitary exploration should be considered as a first choice of treatment of Cushing's disease because of its high clinical remission rate in association with normalization of other endocrine functions.     

Clinical review: Early morning cortisol levels as a predictor of remission after transsphenoidal surgery for Cushing's disease

INTRODUCTION: We describe the use of serum cortisol and ACTH levels on postoperative d 1 and 2 as remission predictors after transsphenoidal surgery for Cushing's disease (CD). METHODS: Morning cortisol and ACTH levels were drawn daily after surgery; glucocorticoids were withheld until evidence of hypocortisolemia. Early remission was defined retrospectively as a subnormal morning cortisol level [< or =140 nmol/liter (< or =5 microg/dl)] on postoperative d 1 or 2 and sustained remission as subsequent eucortisolemia. RESULTS: Of 40 consecutive adults with CD (mean age 39 yr), 80% achieved early remission. Of 39 patients with a minimum follow-up of 14 months (mean 33 months), 31 (79.5%) achieved sustained remission at a mean follow-up of 32 months, including 30 of 31 (97%) with early remission and one of eight (12%) without early remission (P < 0.0001). Sustained remission was achieved in 26 of 28 (93%) patients having their first operation, compared with five of 11 (45%) with a prior unsuccessful operation (P < 0.001). For the 32 patients in early remission vs. the eight in nonremission, mean nadir cortisol levels were 57.6 +/- 33.0 (2.05 +/- 1.2 microg/dl) vs. 631.1 +/- 352.2 nmol/liter (22.9 +/- 12.8 microg/dl) (P < 0.0001), and nadir ACTH levels were 11.9 +/- 6.5 vs. 64.1 +/- 54.6 ng/liter (P < 0.001). Of 31 patients with sustained remission, 100% had subnormal morning cortisol levels, whereas 31% had subnormal ACTH levels (P < 0.0001). CONCLUSIONS: Serum morning cortisol levels on postoperative d 1 and 2 without glucocorticoid replacement provide a safe, simple, and reliable measure of early remission for CD and are predictive of sustained remission. This method allows for consideration of a repeat operation during the same hospitalization in patients with persistent hypercortisolemia.     

Incidence and late prognosis of cushing's syndrome: a population-based study

The main purpose was to assess the incidence and late outcome of Cushing's syndrome, particularly in Cushing's disease. Information for all patients diagnosed with Cushing's syndrome during an 11-yr period in Denmark was retrieved. The incidence was 1.2-1.7/million.yr (Cushing's disease), 0.6/million.yr (adrenal adenoma) and 0.2/million.yr (adrenal carcinoma). Other types of Cushing's syndrome were rare. In 139 patients with nonmalignant disease, 11.1% had died during follow-up (median, 8.1 yr; range, 3.1-14.0), yielding a standard mortality ratio (SMR) of 3.68 [95% confidence interval (CI), 2.34-5.33]. The SMR was partly attributable to an increased mortality within the first year after diagnosis. Eight patients died before treatment could be undertaken. The prognosis in patients with malignant disease was very poor. Patients in whom more than 5 yr had elapsed since initial surgery were studied separately, including a questionnaire on their perceived quality of health. In 45 patients with Cushing's disease who had been cured through transsphenoidal neurosurgery, only 1 had died (SMR, 0.31; CI, 0.01-1.72) compared with 6 of 20 patients with persistent hypercortisolism after initial neurosurgery (SMR, 5.06; CI, 1.86-11.0). In patients with adrenal adenoma, SMR was 3.95 (CI, 0.81-11.5). The perceived quality of health was significantly impaired only in patients with Cushing's disease and appeared independent of disease control or presence of hypopituitarism. It is concluded that 1) Cushing's syndrome is rare and is associated with increased mortality, in patients with no concurrent malignancy also; 2) the excess mortality was mainly observed during the first year of disease; and 3) the impaired quality of health in long-term survivors of Cushing's disease is not fully explained.     

Mortality in patients treated for Cushing's disease is increased, compared with patients treated for nonfunctioning pituitary macroadenoma

CONTEXT: Increased mortality in patients with pituitary tumors after surgical treatment has been reported. However, it is unknown to what extent excess mortality is caused by pituitary tumors and their treatment in general and to what extent by previous exposure to hormonal overproduction. OBJECTIVE: The aim of the study was to compare mortality between patients treated for Cushing's disease and nonfunctioning pituitary macroadenomas (NFMAs). DESIGN: This was a follow-up study. PATIENTS: We included 248 consecutive patients with pituitary adenomas treated by transsphenoidal surgery in our hospital for NFMAs (n = 174) and ACTH-producing adenomas (n = 74). The mean duration of follow-up after surgery was 10.1 +/- 7.2 yr for the whole cohort. OUTCOME MEASURES: The standardized mortality ratio (SMR) was calculated for the whole cohort and also for the two diseases separately. Cox regression analysis was used to compare mortality in patients with Cushing's disease with NFMA patients. RESULTS: Patients with Cushing's disease (39.1 +/- 16.1 yr) were significantly younger at time of operation than NFMA patients (55.3 +/- 13.4 yr). The SMR for the whole cohort was 1.41 [95% confidence interval (CI), 1.05-1.86]. The SMR in NFMA patients was 1.24 (95% CI, 0.85-1.74) vs. 2.39 (95% CI, 1.22-3.9) in patients with Cushing's disease. In patients with Cushing's disease, compared with NFMAs, the age-adjusted mortality was significantly increased: hazard ratio 2.35 (95% CI, 1.13-4.09, P = 0.008). CONCLUSIONS: Mortality in patients previously treated for Cushing's disease is increased, compared with patients treated for NFMAs. This implies that previous, transient overexposure to cortisol is associated with increased mortality.     

Cushing's syndrome during pregnancy: personal experience and review of the literature

Cushing's syndrome (CS) occurs rarely during pregnancy. We investigated and treated four patients with pituitary-dependent Cushing's syndrome during pregnancy over a 15-yr period at the National Institutes of Health. Except for preservation of menses before conception, our patients presented with typical clinical features, increased urinary free cortisol, and loss of diurnal variation of cortisol. The diagnosis was facilitated, without complications, by the use of CRH testing and inferior petrosal sinus sampling in three women. Transsphenoidal pituitary surgery achieved remission in three women, but there were two fetal/neonatal deaths. This experience and review of 136 previous reports suggest that: 1) urinary free cortisol in CS patients overlaps the normal pregnant range; 2) ACTH levels are not suppressed in adrenal causes of CS, which may be identified by the 8-mg dexamethasone test; 3) inferior petrosal sinus sampling and transsphenoidal pituitary surgery, the optimal diagnostic test and treatment for nonpregnant patients with pituitary-dependent Cushing's syndrome, can safely facilitate the management of pregnant patients; and 4) surgery may achieve remission during pregnancy, but the prognosis for the fetus remains guarded. It is likely that earlier recognition and treatment would improve outcome. There is a need for development of criteria for interpretation of diagnostic tests and increased consideration of CS in pregnancy.     

Long-term predictive value of postsurgical cortisol concentrations for cure and risk of recurrence in Cushing's disease

We assessed the value of postoperative plasma cortisol concentrations to predict cure and recurrence of Cushing's disease after transsphenoidal surgery (TS). Seventy-eight of 80 consecutive patients treated by TS for Cushing's disease were evaluated. TS cured 72% (n = 56) of the patients. Two weeks after surgery, patients with plasma cortisol levels below 138 nmol/liter (n = 50; three macroadenomas) and eight (27%) of 30 patients (nine macroadenomas) with cortisol greater than 138 nmol/liter were cured. Six (five with a macroadenoma) of these eight patients had cortisol values less than 50 nmol/liter 3 months after surgery. Therefore, the optimal cut-off value of cortisol predicting remission was 138 nmol/liter, measured 3 months after surgery (positive and negative predictive values 87 and 90%, respectively). Five patients (9%) had recurrent Cushing's disease during a median follow-up of 7 yr. Recurrence occurred in four of 24 (17%) patients with a follow-up of more than 10 yr. Therefore, cortisol levels above 138 nmol/liter, obtained 2 wk after TS, should be repeated, because they do not predict persistent Cushing's disease in 27% of those patients. Postoperative cortisol levels do not positively predict recurrence of disease during long-term follow-up of initially cured patients.     

Long-Term Cognitive Impairments and Attentional Deficits in Patients with Cushing's Disease and Cortisol-Producing Adrenal Adenoma in Remission

Context: Cognitive function is impaired in patients with active Cushing's syndrome (CS). Objective: The aim was to study cognitive function in patients with CS in long-term remission. Design: We conducted a cross-sectional, case-controlled, single center study. Patients: Fifty-five patients previously treated for Cushing's disease (n = 43) and cortisol-producing adrenal adenoma (n = 12) and 55 controls matched for age, gender, and educational level participated in the study. Methods: Working memory, attention, information-processing speed, verbal fluency, and reading speed were studied using standardized neuropsychological testing and alerting, orienting, and executive control using the Attentional Network Test. Fatigue impact scale and the comprehensive psychopathological rating scale were used to evaluate fatigue and affective disorder. Results: Median (interquartile range) duration of remission was 13 (5-19) yr and the mean ± sd age at follow-up was 54 ± 14 yr. Compared to controls, patients had a higher score on the fatigue impact scale, indicating greater burdens of fatigue, and a higher score on the comprehensive psychopathological rating scale subscales for depression and anxiety. In a multivariate analysis, attention, spatial orienting, alerting, working memory, verbal fluency, and reading speed were all diminished in comparison to controls, independent of scores for affective disorder and fatigue. No overall difference in outcome was seen between patients in long-term remission for Cushing's disease and cortisol-producing adrenal adenoma. Conclusion: Patients with CS in remission have impaired cognitive function that cannot be explained by the coexistence of affective disorder or chronic fatigue. The pattern of cognitive and attentional deficits suggests a more global involvement of the brain function than has previously been suggested.     

Repeated transsphenoidal pituitary surgery (TS) via the endoscopic technique: a good therapeutic option for recurrent or persistent Cushing's disease (CD)

Background  No data on results of repeated transsphenoidal surgery via the endoscopic technique for patients with persistent or recurrent Cushing's disease are available.
Design and patients  We retrospectively evaluated the remission rates and complications of repeated transsphenoidal surgery via the endoscopic technique in 14 patients with persistent ( N  = 6) or recurrent ( N  = 8) Cushing's disease treated in our centre between 1999 and 2007.
Main outcomes  Remission was defined as the disappearance of symptoms of hypercortisolism with basal plasma cortisol level ≤ 50 nmol/l 24–48 h after glucocorticoid withdrawal and/or suppression of plasma cortisol level ≤ 50 nmol/l after 1 mg dexamethasone overnight within the first 3 months after transsphenoidal surgery.
Results  With repeated endoscopic transsphenoidal surgery a remission rate of 10/14 (71%) was achieved. No patient had a relapse during a median follow-up of 24 months. Cerebrospinal fluid leakage was the most frequent complication (6 patients) and 11 patients required hormonal substitution after surgery. The success of repeated transsphenoidal surgery could not be predicted by visualization of an adenoma on MRI before first or second surgery, histopathological confirmation of an ACTH secreting adenoma after first or second surgery, treatment with cortisol lowering agents before first or second surgery, the operation technique used during the first surgery, persistent vs. recurrent disease after the first surgery, age, gender and interval between the two surgeries.
Conclusion  Repeated transsphenoidal surgery via the endoscopic technique is a good treatment option for selected patients with recurrent or persistent Cushing's disease following primary pituitary surgery.     

Significant GH deficiency after long-term cure by surgery in adult patients with Cushing's disease

OBJECTIVE: Impaired GH secretion usually accompanies Cushing's syndrome and a variable proportion of patients reportedly fail to recover normal GH secretion after successful treatment. This wide variability is most probably due to differences in the treatment (i.e. surgery and/or radiotherapy), timing of patient re-evaluation after surgery and dynamic tests employed to challenge GH secretion, and hinders a precise assessment of risk of GH deficiency after cure. The aim of the present study is to evaluate GH secretory status after long-term cure of Cushing's disease achieved by surgery alone. DESIGN AND METHODS: We studied 34 patients (27 females and 7 males, age range 21-68 years) formerly affected by Cushing's disease. Patients were studied 2-20 years (median 3.3 years) following remission of hypercortisolism; all patients underwent transsphenoidal surgery with the removal of an ACTH-secreting adenoma; repeat pituitary surgery for relapse was performed in two patients while bilateral adrenalectomy was necessary in two patients. In all subjects, the GH response to GHRH+arginine stimulation was evaluated. At the time of testing, 13 patients were still on steroid replacement therapy. RESULTS: In long-term surgical remission, 22 patients (65.0%) presented subnormal GH secretion; partial GH deficiency (GH peak <16.5 microg/l) was found in 11 patients and severe GH deficiency (GH peak <9 microg/l) in another 11. Male gender and length of hypercortisolism were risk factors for postsurgical GH deficiency. CONCLUSIONS: This study demonstrates the presence of GH deficiency in a high percentage of patients with Cushing's disease after long-term remission of hypercortisolism obtained by surgery alone. Male gender and length of hypercortisolism are the most significant predictors of postsurgical GH deficiency. This finding is significant as it highlights that even the most favourable therapeutical course, i.e. remission achieved by surgery alone, is accompanied by impaired GH secretion. Assessment of GH secretion is therefore recommended for all patients cured from Cushing's disease, even if not submitted to radiotherapy. Studies on the clinical impact of GH deficiency and the use of GH replacement therapy seem warranted in patients cured from Cushing's disease.     

Health-related quality of life and patient-provider relationships in HIV-infected patients during the first three years after starting PI-containing antiretroviral treatment

The aim of this study was to investigate factors associated with better health-related quality of life (HRQL) during the first three years after starting PI-containing antiretroviral treatment. Clinical, social and behavioural data from the APROCO cohort enabled us to analyze simultaneously the association between HRQL and patients' relationships with their health care providers. A self-administered questionnaire collected information about HRQL (MOS-SF36) and relationships with medical staff (trust and satisfaction with information). Two aggregate scores, the physical (PCS) and mental (MCS) component summaries (adjusted for baseline HRQL), were used as dependent variables in the linear regressions to identify factors associated with HRQL. We had complete longitudinal data for 360 of the 611 patients followed through M36. Factors independently associated with a high MCS were (male) gender, no more than one change in treatment, (few) self-reported symptoms and trust in the physician. Factors independently associated with high PCS levels were employment, no children, (few) self-reported symptoms and satisfaction with the information and explanations provided by the medical staff. These results underline the need to improve patient-provider relationships to optimize long-term HRQL. Socio-behavioural interventions should focus on this goal.     

Linear growth and final height after treatment for Cushing's disease in childhood

Cushing's disease is associated with growth failure in childhood and adolescence. Growth and final height were analyzed in 10 patients who were cured or in remission after treatment of Cushing's disease. Seven males and 3 females, aged 6.8-17.6 yr (bone age, 3.3-15.4 yr), had transsphenoidal surgery, which was combined with pituitary irradiation (4,500 cGy in 25 fractions) in 5 patients. At presentation, 5 patients were prepubertal (males), and 5 were pubertal (2 males and 3 females). The mean height SD score was -2.15 +/-1.26 (range, -0.21 to -4.32) compared with mean target height SD score of -0.43 +/- 0.58. Height velocity in 6 patients was subnormal (0.9-3.8 cm/yr). After treatment, short-term height velocity, over a mean interval of 0.57 yr, in 8 patients not receiving human GH (hGH) therapy, was variable (range, 0.8-7.6 cm/yr). GH stimulation tests (insulin tolerance test/glucagon) in 9 subjects showed peak GH levels of 0.5-20.9 mU/L. Eight were treated with hGH (14 IU/m2 wk), combined in 2 girls and 1 boy with a GnRH analog. After 1 yr of hGH, the mean height SD score had increased from -2.45 +/- 1.0 at initiation of hGH to -2.07 +/- 1.2 (P = 0.01). GH therapy was continued until final height or latest assessment. The mean final height SD score (n = 6) was - 1.24 +/- 1.38, and at the latest assessment the mean height SD score (n = 4) was - 1.52 +/- 1.33. Combining these 2 groups, the mean height so score was -1.36 +/- 1.29. The difference between final or latest height SD score and target height SD score was 0.93 +/- 1.13, i.e. less (P = 0.005) than the difference between height and target height SD score of 1.72 +/- 1.26 at presentation. In conclusion, catch-up and favorable long-term growth was seen after treatment for Cushing's disease. Posttreatment GH deficiency was frequent, and early hGH replacement may have contributed to the encouraging outcome.     

Ten-year follow-up results of transsphenoidal microsurgery in acromegaly

Fifty-nine acromegalic patients, transsphenoidally operated by a single neurosurgeon (H.v.D.) were followed for at least 10 yr to assess the late outcome of surgery. Mean follow-up was 16 +/- 0.4 yr (range, 10-22). Criteria for remission were a serum GH concentration below 2.5 microg/L, a normal glucose-suppressed GH (oral glucose tolerance test), and a normal serum insulin-like growth factor I (IGF-I) concentration. Mean serum GH concentration decreased from 59 +/- 8.7 microg/L to 5.6 +/- 1.4 microg/L after surgery. Early postoperative remission rates were 61% (GH, <2.5 microg/L), 67% (suppressed GH), and 60% (both GH <2.5 microg/L and suppressed GH). Early postoperative remission was significantly related to preoperative serum GH concentration (P: = 0.023), but not to tumor size. Of 36 patients with postoperative remission (GH, <2.5 microg/L), 9 patients received (prophylactic) radiotherapy for persistent paradoxical reaction to TRH or probable invasive tumor growth. All nine patients are in remission at the end of follow-up. Of the other 27 patients with postoperative remission, 5 (19%) developed recurrence, becoming evident within 5 yr in 4 patients and after 10 yr in 1 patient. Of these 27 patients, surgical remission rates at the end of follow-up are 78% (random GH, <2.5 microg/L), 73% (normal glucose-suppressed GH), 74% (normal IGF-I), and 65% (normal IGF-I and GH suppression). Of the patients with postoperative persistent disease, 18 patients were irradiated and 5 patients were followed without further treatment. Two of five nontreated patients had spontaneous normalization of GH concentration at the 6 months visit and remained in remission by surgery only. The long-term efficacy of multimodality treatment was evaluated after exclusion of the prophylactically irradiated patients. At the end of follow-up, 48% of patients had not required adjuvant therapy and the rest received radiotherapy (34%), octreotide (10%), or both (8%). Remission rates of multimodality therapy were 96% (serum GH, <2.5 microg/L) and 94% (normal serum IGF-I concentration). Remission rates of transsphenoidal surgery alone were 46% (serum GH, <2.5 microg/L), 44% (normal IGF-I concentration), 41% (suppressed serum GH), and 37% (normal serum IGF-I and suppressed GH). In this first report on separate 10 or more years results of transsphenoidal surgery for acromegaly, using strict criteria for remission, 19% of patients with postoperative remission developed recurrence. Nevertheless, about 40% of patients remain in remission after only surgical intervention, even after a mean follow-up of 16 yr.