Outcomes of integrated management versus specialized care for patients with type 2 diabetes: An observational study.

AIMS: To compare type 2 diabetes (T2D) patients included in a Diabetes Integrated Management (DIM) program with those followed in Diabetes Specialized Care (DSC), investigating differences in general characteristics, changes in clinical outcomes, and factors related with the inclusion in the DIM program. METHODS: T2D patients living in the ASLTO3 district and included into the DIM program, a shared disease management between general practitioners and diabetes specialists, from 2008 to 2014 were compared with T2D patients living in the same district and in charge of the local DSC. Demographic, anthropometric and clinical data for both groups of patients were obtained from the electronic records of DSC. RESULTS: 1326 DIM patients were compared with 3494 DSC patients. A higher proportion of females was observed among DIM patients than among DSC patients. DIM patients were older, more frequently in therapy with diet only or with oral hypoglycemic, and had HbA1c and creatinine lower than DSC patients. The analyses of changes in clinical parameters during the study period showed a good and statistically significant improvement of most parameters, independently of the inclusion in DIM or DSC, with the exception of creatinine level. CONCLUSIONS: Integrated Management is an efficient and effective way to achieve good long-term clinical outcomes for patients with diabetes.

Hyperhomocysteinemia in winter elite athletes: a longitudinal study.

Hyperhomocysteinemia is a well-established risk factor for cardiovascular diseases. The aims of this study were to longitudinally investigate, in a group of elite athletes, plasma homocysteine levels and to search for relationships with the muscular workload and the vitamin status. One hundred and three athletes (59 males and 44 females, respectively) were evaluated in different periods: namely the recovery period, the training period, and the competition period; 84 subjects (37 males and 47 females), served as controls. The evaluation sessions consisted in blood sampling and medical examination. The percentages of athletes with normal and elevated homocysteine levels, defined by levels below or above the limit of 15 mumol/l, were 68.0% and 32.0%, respectively, in the recovery period, and these percentages remained unchanged during the following periods. In the control group, relevant percentages were 92.9% and 7.1%, respectively. The comparison between plasma homocysteine of male and female, evaluated in the recovery period, showed significantly higher levels in the former group (18.8+/-18.0 micromol/l vs 10.7+/-5.9 micromol/l, p<0.001 respectively), as well as a higher proportion of individuals with hyperhomocysteinemia (24/59 vs 9/44, p<0.05). The correlation analyses showed a weak but significant negative correlation between homocysteine and folate in the three periods considered, while no significant relationship was observed between homocysteine and creatine-kinase. We found excess prevalence of hyperhomocysteinemia in elite athletes of winter sports. A strategy to understand which mechanisms in these athletes subserve hyperhomocysteinemia is essential in order to reduce the potential risk for future cardio-vascular morbidity and mortality.

Effects of the training status on the hormonal response and recovery from high-intensity isokinetic exercise: comparisons between endurance-trained athletes and sedentary subjects.

AIM: Aims of the study were: to determine the differences in the mechanical, hormonal and lactate responses to a high-intensity isokinetic exercise in two groups of endurance-trained athletes (EA, n = 11) and sedentary subjects (SED, n = 11); to evaluate the relationships between the hormonal and lactate responses; to evaluate the effects of the training status on the pituitary responsiveness to the exercise. METHODS: EA and SED completed, for each leg, 4 sets of 20 maximal concentric contractions of the knee extensor muscle groups at 180 degrees s-1 angular velocity. Blood and saliva for hormonal and lactate determinations were sampled before, immediately after the test and during the subsequent recovery of 2 hours. RESULTS: The exercise was completed by all subjects and elicited significant mechanical and biochemical responses both in EA and in SED subjects. No differences were found between the two groups both in the mechanical performances and in the increases of lactate and hormones of the pituitary-adrenal axis or in the comparison of the slopes of adrenocorticotropic hormone (ACTH), cortisol, and dehydroepiandrosterone recovery after the peak. The correlation analyses showed significant positive relationships between lactate peak values and percentages of change for ACTH (r2 = 0.16, P < 0.05), salivary cortisol (r2 = 0.42, P < 0.01), and serum cortisol (r2 = 0.56, P < 0.001). CONCLUSIONS: The adrenocortical activation was found, in this particular setting, at least partly dependent on the muscular lactate production, while no effect of the training status on the pituitary responsiveness to exercise was evident, as it was indirectly confirmed by no abnormalities in the rates of hormonal recovery after the exercise session.

High prevalence of colonic polyps in patients with acromegaly. Influence of sex and age.

BACKGROUND: An association between acromegaly and colonic polyps has been reported, although risk factors are still uncertain. METHODS: Full colonoscopy was performed with a fiberoptic colonoscopy on 31 acromegalic patients, 11 men and 20 women aged 27 to 85 years (mean, 52.2 years), and on 236 subjects, 127 men and 109 women aged 23 to 84 years (mean, 50.1 years), referred for hemorrhoids, who were considered controls. The colonoscopic findings were evaluated in relation to demographic, clinical, and hormonal data pertaining to the two groups. RESULTS: The prevalence of either adenomatous or hyperplastic polyps was higher in acromegalic patients than in controls (38% vs 14% and 26% vs 10%, respectively; P < .001, respectively). Acromegalics with and without colonic adenomas did not differ significantly in growth hormone and insulinlike growth factor I levels or duration of acromegalic disease and its status (activity or remission); however, patients with adenoma were younger (median age, 50.5 vs 59 years; range, 27 to 85 years vs 39 to 66 years; P < .05). An opposite age pattern was observed in the control group. Indeed, the prevalence of adenoma in acromegalic patients was much higher than that in controls among those less than 50 years of age (46% vs 7%, P < .001); the difference was less remarkable at older ages. Adenomatous polyps were more frequently found in male subjects, in both patients and controls (45% vs 33% [not significant] and 19% vs 9% [P < .05], respectively). CONCLUSIONS: Acromegaly may carry an increased risk of colonic adenoma, especially in younger patients, who usually display more aggressive disease. A smaller increase in risk was observed in elderly patients, in whom disease is reportedly milder. We suggest that acromegalic patients should undergo screening colonoscopy.

Effects of ovine corticotropin-releasing hormone injection and desmopressin coadministration on galanin and adrenocorticotropin plasma levels in normal women.

The neuropeptide galanin (GAL) has been shown to be located in the pituitary gland and to modulate the secretion of several pituitary hormones. In the human pituitary, GAL is almost exclusively located within corticotrophs. We examined whether GAL is secreted from corticotrophs in response to stimuli that induce ACTH release. Plasma levels of GAL and ACTH were evaluated in six healthy female subjects in the follicular phase of the menstrual cycle after the following treatments: 1) ovine CRH (oCRH) injection during saline (SAL) infusion, 2) oCRH injection during infusion of the arginine vasopressin analog desmopressin (DP), 3) SAL injection during DP infusion, and 4) SAL injection during SAL infusion. DP (4.3 ng/min.kg BW) or SAL was infused from 0-60 min. oCRH (1 microgram/kg BW) or SAL was administered by a 2-min injection at 5 min. The expected ACTH response to oCRH was enhanced by the concomitant DP administration (peak level, 10.39 +/- 1.12 vs. 21.37 +/- 3.43 pmol/L in SAL infusion plus oCRH injection vs. DP infusion plus oCRH injection, respectively; P < 0.05). The mean integrated ACTH response, expressed as the area under the curve, to SAL infusion plus oCRH injection vs. that to DP infusion plus oCRH injection was 288.23 +/- 61.94 vs. 699.70 +/- 91.80 pmol/L.60 min, respectively (P < 0.05). A slight, but not significant, increase was observed in ACTH values after DP infusion plus SAL injection compared to that after SAL infusion plus SAL injection challenge. Plasma GAL levels were highly variable. No changes in GAL levels were found concomitant to ACTH values in either experimental group. In fact, GAL levels were not significantly affected by either treatment. These data confirm that DP potentiates the ACTH response to CRH in humans. Furthermore, our results suggest that GAL is probably not cosecreted with ACTH in normal subjects. The possibility exists that GAL produced by corticotrophs exerts its action principally through a locally mediated paracrine or autocrine mechanism without being secreted into the bloodstream.

The patients with incidentally discovered adrenal adenoma (incidentaloma) are not at increased risk of osteoporosis.

The main problem in the management of the patients with incidentally discovered adrenal mass (incidentaloma) is whether and when the incidental mass puts the patient at increased risk for an adverse outcome. As osteoporosis is a well known complication of endogenous and exogenous glucocorticoid excess, it is likely that patients with incidentally discovered adrenocortical adenomas have impaired bone mass due to subclinical hypercortisolism. We measured spinal bone mineral density (BMD) by dual energy x-ray absorptiometry in 27 patients (9 men and 18 women) and 54 healthy subjects (18 men and 36 women) carefully matched for age, sex, body mass index, and menstrual status for a case-control analysis. BMD was also measured at the hip in the group of patients. A multiple regression analysis was performed to determine which biochemical variables might influence BMD values. Lumbar BMD values in patients with adrenal incidentaloma were not significantly different from those in control subjects (BMD, 0.926, 0.604--1.144 vs. 0.936, 0.645--1.268 g/cm(2); P = NS). No significant difference in lumbar and femoral BMD was found between patients with or without subclinical Cushing's syndrome. Among the variables processed, only PTH remained in the final model and was inversely correlated with lumbar spine and femoral neck BMD values (r = -0.5; r(2) = 0.25; P = 0.015 and r = -0.42; r(2) = 0.18; P = 0.03, respectively). In conclusion, our data do not suggest that the slight glucocorticoid excess associated with adrenal incidentaloma increases the risk of osteoporosis. The evaluation of BMD does not seem to be crucial in the management of incidentally discovered adrenal masses.

Endocrine evaluation of incidentally discovered adrenal masses (incidentalomas)

Since 1989, 45 patients [pts; 26 females and 19 males, aged 19-79 yr (median, 58)] bearing incidentally discovered adrenal masses were studied. The aim of the study was to verify the prevalence of hormone activity in clinically silent adrenal masses. Endocrine work-up included determination of urinary catecholamines and their metabolites, measurement of PRA and aldosterone levels in clino- and orthostatic posture, and basal and dynamic [dexamethasone (dex) suppression and ovine CRH stimulation] evaluation of hypothalamic-pituitary-adrenal axis. The most frequent finding was the reduction of dehydroepiandrosterone sulfate (DHEA-S) levels below the third percentile of controls in 19 (42%) pts. DHEA-S levels were significantly lower in pts than in controls [68 (range, 5-1000) vs. 208 (34-326) micrograms/dL; 1.8 (0.1-27.1) vs. 5.6 (0.9-8.8) mumol/L; P < 0.001]. Three pts (7%) had high 24-h mean serum cortisol levels, and 6 (14%) had blunted day-night amplitude of cortisol rhythm. Defective dex suppressibility was found in 15% of pts vs. 8% of controls (P < 0.05). ACTH and cortisol responses to ovine CRH did not significantly differ between pts and controls, although blunted ACTH responses were found in 22% of the cases. The above-mentioned endocrine alterations could be accounted for by autonomous cortisol secretion by the adrenal nodule at a rate not sufficient to give clinical expression, but able to inhibit to some extent the hypothalamic-pituitary-adrenal axis. These results indicate that silent cortisol hypersecretion is frequently observed in pts with adrenal incidentaloma even if progression to overt Cushing's syndrome seems unlikely. Indeed, the size of the mass and the hormone pattern remained substantially unchanged in 9 pts followed up for 12 months. From merely a cost/benefit ratio, the evaluation of DHEA-S levels and dex suppression has sufficient sensitivity to identify the occurrence of silent hypercortisolism.

Serum markers of bone and collagen turnover in patients with Cushing's syndrome and in subjects with adrenal incidentalomas.

The aim of this study was to assess serum levels of some markers of bone turnover and collagen synthesis in 22 patients with adrenal incidentalomas (AI), a model of silent glucocorticoid excess, and to compare the results with those obtained in 18 patients with Cushing's syndrome (CS). Osteocalcin (BGP), bone isoenzyme of alkaline phsophatase, carboxy-terminal propeptide of type I procollagen, and carboxy-terminal cross-linked telopeptide of type I collagen were measured as biochemical indexes of bone turnover, and amino-terminal propeptide of type III procollagen was determined as an index of collagen synthesis. Two groups of healthy volunteers evenly matched for sex, age, and menstrual status were used for a case-control analysis of AI and CS groups, respectively. Patients with AI showed a slight, albeit significant, reduction in serum BGP and a mild increase in carboxy-terminal cross-linked telopeptide of type I collagen levels compared with controls [median, 6.6 vs. 7.8 ng/mL (P < 0.05) and 4.2 vs. 3.1 micrograms/L (P < 0.01), respectively]. No significant differences were found when comparing the other markers. Patients with CS had BGP, bone isoenzyme of alkaline phosphatase, and amino-terminal propeptide of type III procollagen levels significantly lower than control values [median, 3.0 vs. 7.3 ng/mL (P < 0.0001); 4.4 vs. 11.5 micrograms/L (P < 0.01); 2.2 vs. 4.3 micrograms/L (P < 0.0001), respectively], but no significant difference in the other markers. These results confirm a clear inhibition of osteoblastic activity in CS and could suggest an enhanced bone metabolism in patients with AI. The degree of impairment of bone turnover in patients with AI does not seem enough to recommend surgery (removal of the adrenal adenoma) in the absence of other indications.

Different patterns of steroid secretion in patients with adrenal incidentaloma.

We previously found that a remarkable number of patients with adrenal incidentaloma display partially autonomous cortisol secretion. The amount of hypercortisolism is insufficient to give clinical expression, but enough to inhibit, in some cases, normal adrenal tissue. Other researchers found with high frequency a partial deficiency of 21-hydroxylase. The aim of the present study was to make a combined evaluation of these aspects of adrenal steroidogenesis. Twenty patients (6 men and 14 women, aged 25-74 yr; median, 59 yr) with incidentally discovered adrenal masses were studied. All had an adrenal adenoma histologically proven or diagnosed on the basis of size (< or = 4.0 cm in all but 1) and computed tomography picture (hypodense homogeneous mass with well defined margins). The following parameters were used to evaluate the ACTH-cortisol axis: overnight 1-mg dexamethasone suppression (4 nonsuppressors), ovine CRH stimulation (blunted ACTH-cortisol response in 2 cases), circadian serum cortisol rhythm (blunted night/day ratio in 4 and increased 24-h mean in 1), and 24-h urinary free cortisol excretion (always within the normal range). Three patients had 2 concomitant alterations, and 5 had a single abnormality. Partial deficiency of 21-hydroxylase was assumed in 6 patients who showed an exaggerated 17-hydroxyprogesterone response to ACTH, with a peak value of more than 10 ng/mL (> 30 nmol/L), according to New's nomogram. No abnormalities of the ACTH-cortisol axis were found in these patients, with the exception of low amplitude cortisol rhythm in 1 case. Therefore, 2 distinct patterns, dysregulated and partially autonomous cortisol secretion, on the one hand, and reduced 21-hydroxylase activity, on the other, can be found in a high number of patients bearing an adrenal incidentaloma. They appear mutually exclusive, and the differentiation by endocrine testing is quite clear. Serum dehydroepiandrosterone sulfate was below the third percentile in 13 of 20 patients and could represent a specific marker of cortical adenomas. This finding was evenly distributed among patients with subclinical hypercortisolism or partial enzymatic defect; therefore, low serum dehydroepiandrosterone sulfate is not readily attributable to suppressed ACTH secretion, which actually occurs in only some patients with subclinical hypercortisolism.

The value of dehydroepiandrosterone sulfate measurement in the differentiation between benign and malignant adrenal masses.

OBJECTIVE: Owing to their increasing rate of discovery as incidental findings, the characterization of adrenal masses is an important diagnostic problem which frequently challenges the clinician's skill. DESIGN: The results of dehydroepiandrosterone sulfate (DHEAS) measurement were evaluated in a consecutive series of 107 patients with an adrenal mass (39 men, 68 women aged 15-81 years, median 56 years). DHEAS levels observed in the patients were categorized as reduced, normal or elevated according to sex- and age-adjusted reference ranges obtained by measuring DHEAS in 214 healthy women and 142 healthy men aged 17-93 years. The working hypothesis was that a low DHEAS level is a marker of benignity. METHODS: In 84 patients, the adrenal mass was discovered serendipitously, while in the remainder the mass was clinically symptomatic. Patients with known extra-adrenal malignancies were excluded. The adrenal masses were categorized as benign or malignant by computerized tomography (CT) criteria. All patients with suspected malignant tumors or with overtly hypersecreting tumors underwent adrenalectomy. The patients with a presumptive benign tumor were followed-up for at least 12 months. RESULTS: In the overall series, the sensitivity and specificity of a low DHEAS level in the identification of a benign lesion were 41% and 100% respectively. Superimposable figures were obtained when considering only adrenal incidentalomas. DHEAS levels in adrenal cancers displayed some overlap with adrenal adenomas, but in only 2/11 adrenal cancers were DHEAS levels normal, while they were elevated in the remainder. CONCLUSIONS: The present data suggest that DHEAS measurement may help to differentiate benign from malignant adrenal masses as a complementary test of CT in a clinical research setting. The value of DHEAS measurement in general practice is limited because it may be difficult to differentiate between low and low-normal values, particularly in the elderly.

High frequency of p53 expression in colo-rectal adenomatous polyps.

Previous studies on p53 protein expression in colonic adenomas showed controversial results. The present study evaluates the p53 expression in colonic adenomas, at different dysplasia degrees, by immunohistochemical analysis, using a newly introduced monoclonal anti-p53 antibody. Paraffin embedded sections of 48 colorectal adenomas, 5 colonic carcinomas and 11 normal colonic biopsies were studied by immunohistochemical analysis using a monoclonal mouse anti-p53 antibody (clone DO-1). Normal colonic mucosa specimens and 5/48 adenomas were found negative for p53 staining. p53-positive nuclei were less than 10% in 22/48 and between 10 and 40% in 15/48 adenomas. In 6/48 adenomas and in 4/5 carcinomas we found a high percentage of p53-positive nuclei (> 40%). Immunohistochemical p53-positivity is a common event in colonic adenomas, not dependent on dysplasia degree. It might be the result of p53 wild-type increase, due to the typical genomic instability of colonic adenomas.

Circadian profile of serum melatonin in Cushing's disease and acromegaly.

We evaluated the circadian profiles of serum melatonin (MT) and cortisol in 6 patients with Cushing's disease while those of serum MT and GH were evaluated in 8 patients with acromegaly. The control group consisted of 15 healthy subjects in whom MT, cortisol and GH were determined. The presence of a circadian rhythmicity was validated by the cosinor method, while the diurnal and nocturnal amount of MT secretion were expressed in terms of area under the curve. Gross alterations of MT rhythm were not apparent in Cushing's patients. In acromegalics, we observed a blunted day-night oscillation of MT accounted for by a significant increase of its secretion during the day-time period.

24-hour profiles of blood pressure and heart rate in Cushing's syndrome: relationship between cortisol and cardiovascular rhythmicities.

We monitored the circadian profiles of cortisol, systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR) in 33 matched normotensive subjects, 32 patients with essential hypertension and 16 patients with Cushing's Syndrome (8 pituitary adenomas, 6 adrenal adenomas and 2 adrenal carcinomas). Each subject underwent serial blood drawings at 4-hr intervals along the 24-hr cycle. BP and HR were automatically recorded every 30 min. Data were analyzed by conventional statistics and by chronobiological procedures (cosinor rhythmometry). Both the control subjects and essential hypertensives showed a circadian profile of BP and HR characterized by a peak in the early afternoon and a clear nocturnal fall (rhythm detection: P less than 0.001). The rhythmicity of BP was disrupted in patients affected by Cushing's Syndrome, whereas the 24-hr oscillation of HR was preserved (P less than 0.001). Our data are compatible with the view that glucocorticoids are involved in the control of BP circadian rhythm, whereas HR is not under their control.

Cytotoxic chemotherapy for adrenocortical carcinoma.

The efficacy of mitotane in providing objective tumour responses in patients with adrenocortical carcinoma (ACC), has been recently questioned. Experience with non specific chemotherapy is limited. Tumour responses have been reported with cisplatin administered as a single agent or in combination. Other reports however failed to show benefit from cytotoxic chemotherapy. The very low number of patients included in each study, mostly of them previously treated with mitotane, may account for these controversial results. The finding that multidrug resistance mediated by MDR-1/P-glycoprotein can be reverted by mitotane provides a rational basis for exploring the use of mitotane in combination with chemotherapeutic agents. In a multicenter cooperative (SWOG) phase II study, a combination of mitotane+cisplatin appeared active in advanced ACC, with 30% response rate in 37 eligible patients. These results prompted us to evaluate the activity of a combination chemotherapy of Eto-poside, Adriamycin and Cisplatin (EAP) in association with mitotane (4 g daily per os). Up to now we treated 6 patients, obtaining 3 partial responses. Recently, new drugs as suramin and gossypol have been show to have some activity in patients with surgically unresectable ACC, suggesting the need for further investigation. In conclusion, cytotoxic drugs+mitotane and new adrenocorticolytic/cytotoxic agents, should be explored as first line treatments in patients with advanced ACC. However, due to the extreme rarity of the disease, coordinated multicenter investigations should be highly encouraged.

Adrenal incidentaloma, a five year experience.

Since 1989, 45 patients 26 females and 19 males, aged 19-79 years (median 58) bearing incidentally discovered adrenal masses were studied. Endocrine work-up included determination of urinary catecholamines and their metabolites, measurement of plasma renin activity and aldosterone levels in clino- and orthostatic posture, basal and dynamic (dexamethasone-suppression, o-CRH stimulation) evaluation of hypothalamic-pituitary-adrenal (HPA) axis. The most frequent finding was the reduction of DHEA-S levels below the 3rd percentile of controls in 19 (42%) patients. As a whole group, DHEA-S levels were significantly lower in patients than in controls: 68 (5-1000) micrograms/dL vs 208 (34-326) micrograms/dL; p < 0.001. Three patients (7%) had high 24-h mean serum cortisol levels and 6 (14%) had blunted day-night amplitude of cortisol rhythm. Defective dexamethasone suppressibility was found in 15% of patients vs 8% of controls (p < 0.05). ACTH and cortisol responses after o-CRH did not significantly differ between patients and controls although blunted ACTH responses were found in 22% of cases. The above mentioned endocrine alterations could be accounted for by autonomous cortisol secretion by the adrenal nodule at a rate not sufficient to give clinical expression but able to inhibit to some extent the HPA axis. These results indicate that silent cortisol hypersecretion is frequently observed in patients with adrenal incidentaloma even if progression to overt Cushing's syndrome seems unlikely, at least in a short-term follow-up. From a mere cost-benefit ratio, the evaluation of DHEA-S levels and dex-suppression has sufficient sensitivity to identify the occurrence of silent hypercortisolism.

Favorable response of metastatic adrenocortical carcinoma to etoposide, adriamycin and cisplatin (EAP) chemotherapy. Report of two cases.

The usefulness of non-specific chemotherapy for advanced adrenocortical carcinoma (ACC) is controversial. We report on 2 young female patients (25 and 19 yr) who presented with a clinical picture of Cushing's syndrome due to histologically confirmed ACC. The first patient underwent radical surgery, but after a disease-free interval of 6 months a local recurrence was apparent. She was reoperated and treated with 6 courses of cisplatin and etoposide chemotherapy. Mitotane (8 g daily) was begun, but 2 months later debulking surgery was again performed. A second-line chemotherapy with the etoposide, adriamycin, cisplatin (EAP) scheme attained a partial remission lasting 7 months, then metastatic spread to the brain led to death of the patient. The survival time was 30 months. The second patient underwent radical surgery and adjuvant mitotane (4 g daily), but multiple lung and mediastinal metastases were diagnosed after an interval of 29 months. Chemotherapy with the EAP regimen (6 courses) without interrupting mitotane attained a partial remission lasting 21+ months. We suggest that the EAP scheme is active in advanced ACC and that its association with mitotane is feasible.

24-hour profiles of blood pressure and heart rate in Cushing's syndrome. Evidence for differential control of cardiovascular variables by glucocorticoids.

We monitored the circadian profile of cortisol, systolic and diastolic blood pressure (SBP and DBP), heart rate (HR) in 33 normotensive subjects aged 20-40 years, 20 normotensive subjects aged 40-60, 32 patients with essential hypertension and 13 patients with Cushing's syndrome (6 pituitary adenomas, 5 adrenal adenomas and 2 adrenal carcinomas). All controls and patients underwent serial blood drawings at 4-h intervals during the 24-h cycle. BP and HR were recorded every 30 min by an automatic, room-restricted instrument. Data were analyzed by conventional statistics and by chronobiological procedures (cosinor rhythmometry) to quantify rhythm parameters such as the MESOR (rhythm-adjusted average), amplitude (difference between maximum and MESOR) and acrophase (timing of the crest of the rhythm). Both the control and essential hypertensive subjects showed a BP and HR circadian profile characterized by a peak in the early afternoon and a clear nocturnal fall (rhythm detection: p less than 0.001). The chronobiological analysis did not reveal any significant difference between healthy young and aged subjects. BP rhythmicity was disrupted in patients affected by Cushing's syndrome, whereas the 24-h oscillation of HR was preserved (p less than 0.001). Patients with pituitary-dependent Cushing's syndrome had higher BP levels than adrenal-dependent subjects (p less than 0.001). Our data are compatible with the view that glucocorticoids are involved in the control of BP circadian rhythm, whereas HR is not under their control.

Surgical remission of Cushing's syndrome reduces cardiovascular risk.

OBJECTIVE: Recent studies have questioned the reversibility of complications of Cushing's syndrome (CS) after successful surgical treatment. The aim of this study was to assess the outcome of patients with CS who achieved disease remission compared with those patients with persistent hypercortisolism and matched controls. DESIGN: A retrospective study of 75 patients with CS followed at an academic center. METHODS: Cardiovascular risk profile was evaluated in 51 patients with CS in remission (group 1) and 24 patients with persistent disease (group 2) and compared with 60 controls. Mortality of patients with CS was compared with the background population. RESULTS: In group 1, the frequency of cardiovascular risk factors dropped after disease remission even if it remained higher at the last follow-up than in the control group. In group 2, the frequency of cardiovascular risk factors remained unchanged during follow-up. The rate of cardiovascular and thromboembolic events was higher in group 2 than in group 1, as was the mortality rate (two deaths in group 1 and nine in group 2; ratio of two SMRs, 0.11; 95% CI, 0.011-0.512). Survival was significantly longer in group 1 than in group 2 (87 months, 80-98 vs 48 months, 38-62; P<0.0001). CONCLUSIONS: Successful surgical treatment of hypercortisolism significantly improves cardiovascular risk and may reduce the mortality rate. Patients with persistent disease have increased morbidity and mortality when compared with patients in remission.

Long-term disease free survival in a patient with metastatic adreno-cortical carcinoma after complete pathological response to chemotherapy plus mitotane.

Adreno-cortical carcinoma (ACC) is a rare cancer with poor prognosis. Complete surgical resection of the primary tumor and, when feasible, of the local and distant metastases offers the best prospects for long-term survival; conversely, the role of systemic therapy in patients developing unresectable metastatic disease is unclear. We describe the case of a young female patient (36 yr) who presented with an androgen-releasing metastatic ACC. Treatment consisted of five courses of chemotherapy with etoposide, doxorubicin and cisplatin (EDP scheme) plus oral mitotane, which caused the complete disappearance of distant metastases and reduction of the primary tumor, as documented by serial computed tomography (CT) scans of the chest and the abdomen. Moreover, during treatment, clinical and biochemical resolution of the hypersecretory status occurred. The left adrenal gland was then removed and histopathological examination showed extensive tumor necrosis and the absence of viable cancer cells. The patient is currently alive without evidence of recurrence 3 yr after surgery. This report shows that chemotherapy plus mitotane could result in complete pathological remission, which may be a surrogate for long-term progression- free survival in metastatic ACC patients.