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.

OBJECTIVERecent 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.DESIGNA retrospective study of 75 patients with CS followed at an academic center.METHODSCardiovascular 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.RESULTSIn 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).CONCLUSIONSSuccessful 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.

BACKGROUND:Breakthrough cancer pain (BTP) can place physical, psychological and economic burdens on patients and their productive life. By preventing instead of treating BTP after it occurs, the efficacy of analgesic treatment in cancer patients could be maximized. With this study, we investigated circadian variations in the occurrence of BTP events in cancer patients.METHODS:The circadian variation of BTP was assessed in two different series (group 1, n = 47; group 2, n = 76) of advanced cancer patients suffering from severe chronic pain and undergoing analgesic treatment with major opioids.RESULTS:BTP episodes showed a circadian pattern, with an acrophase occurring at 10:00 a.m. (p < 0.001) in all patients. When the two series of patients were considered separately, an acrophase was similarly observed, with 60% of BTP episodes recorded between 10:00 a.m. and 6:00 p.m. The circadian rhythm of BTP was maintained after stratifying the patients according to whether they had bone metastases or visceral metastases. BTP episodes negatively correlated with quality of life.CONCLUSIONS:BTP onset follows a circadian rhythm, with an acrophase occurring in the late morning.

The use of iron supplements should be a judicious choice, primarily when considering the possible risks deriving from an unjustified treatment. In trained athletes, levels of ferritin between 15 and 30 microg/L are frequently observed. Within this ferritin range, the usefulness of iron supplementation is still controversial. The aim of the present study is to evaluate the clinical usefulness of hepcidin assessment in the analysis of the iron status of young non-anemic athletes. Fifty young athletes were enrolled. The subjects were divided into 4 groups according to their ferritin levels. No statistically significant difference was found regarding hepcidin levels between athletes with ferritin lower than 15 microg/L and those in the 15-30 microg/L range. Similarly, no difference was found between athletes with ferritin higher than 50 microg/L and those in the 30-50 microg/L range. On the contrary, statistically significant differences were found between athletes with ferritin levels ranging from 15 to 30 microg/L and those in the 30-50 microg/L range. The present study suggests that serum ferritin levels below 30 microg/L indicate an asymptomatic iron deficiency status inhibiting hepcidin expression and that 30 microg/L should be considered the ferritin cut-off when considering an iron supplementation in young athletes.

AIM:Several studies suggest that intense exercise may increase the athlete's thrombotic tendency. Available data on those metabolic alteration are still conflicting and their clinical significance is still worth of interest. The aim of the present study was to investigate if widely used markers of cardiac damage such as NT-proBNP levels are affected by homocysteine concentrations during sustained sport activities.METHODS:Seventy-eight competitive, non-professional athletes were enrolled in the study; 70 healthy age matched subjects, recruited from blood donors, served as controls. Besides the general clinical determinations, the assessed variables included homocysteine, folate, vitamin B12, total and HDL cholesterol, LDH, CPK, NT-proBNP and IL-6.RESULTS:The percentages of athletes with normal and elevated homocysteine levels resulted 46% and 54%, respectively. Mean NT-proBNP levels were significantly higher in athletes than in controls (1176.66 + or - 442.15 pg/mL versus 450.34 + or - 180.39 pg/mL). No correlation was found between homocysteine and NT-proBNP values.CONCLUSIONS:The previously described "sport related" homocysteine is not related to other markers of cardiovascular stress such as NT-proBNP. Available data suggest that both hyperhomocysteinemia and high NT-proBNP levels in healthy young athletes could be interpreted as markers of metabolic and morphologic adaptation to training rather than a risk factor for cardio-vascular diseases.

A hyperactive hypothalamic-pituitary-adrenal axis (HPA-axis) is a well-known phenomenon in bipolar disorder (BD). However, hypocortisolism has also been described and found associated with depression, low quality of life and cardiovascular risk factors in BD patients. Although the pathophysiology related to hypocortisolism in BD is largely unknown, hypocortisolism is associated with chronic stress exposure and after inducing an initial rise in cortisol long-term stress may result in a transition to hypocortisolism. BD patients are throughout life often exposed to chronic stress. We therefore hypothesized that higher age would be associated with lower HPA-axis activity especially among patients without previous mood stabilizing treatment.This cross-sectional study consisted of 159 bipolar outpatients and 258 controls. A low-dose-dexamethasone-suppression-test (DST) was used to measure HPA-axis activity.Patients with BD showed a negative association between post DST cortisol and age (−3.0 nmol/l per year; p=0.007). This association gradually increased in subgroups that were naïve to lithium (−7.7 nmol/l per year; p=0.001) and "all mood stabilizers" (−11.4 nmol/l per year; p=0.004). Patients exhibiting hypercortisolism were characterized by younger age and female gender, whereas patients exhibiting hypocortisolism were characterized by long disease duration without prophylactic lithium treatment as well as absence of current lithium medication.Cross sectional study design.There was a negative association between HPA-axis activity and age in BD, rendering BD patients at risk for developing hypocortisolism. This association was most pronounced among patients without previous or current lithium prophylaxis.

The aim of the study was to examine the effects of strenuous training on the hypothalamic-pituitary-adrenal axis activity. Exercise tests and saliva collections for analysis of awakening cortisol response (ACR) and midnight cortisol were performed before and after a 7-day period of intensified training in a group of 15 soccer players. Intensified training resulted in a performancedecrement as shown by the pre-post-training changes in maximal values of counter movement jump (CMJ) height ( p =0.008). Cortisol assessment during the first 30 min after awakening showed significant increases both before and after the 7-day period and post-training ACR higher than pre-training ACR ( p <0.001). Midnight cortisol also significantly increased after training (mean±SD, before: 3.0±0.7 nmol/l vs after: 5.9±3.3 nmol/l; p =0.017). The analysis of individual data showed an important inter-individual variability in the pre-post-training changes: several subjects increased post-awakening peak of cortisol, rate of cortisol increase from awakening to peak, and area under the curve (AUC) values, whereas other subjects showed no training-related increases. Significant correlations were observed between pre-post-training change in CMJ and in the following variables: awakening cortisol (r=0.74), post-awakening peak of cortisol (r=0.81), rate of cortisol increase (r=0.75), and AUC (r=0.79). Briefly, the lower the performance decrease, the higher the training-associated ACR increase. These data could indicate that a dys-regulated adaptation to exercise occurred in athletes who experienced a higher performance decrease after training and lower (or absent) hormonal changes. Future studies are needed to elucidate the physiological determinants which underlie the exercise-elicited changes in ACR and in midnight cortisol levels and their value in predicting impaired adaptations to exercise.

Objective: Regular physical activity is associated with a reduction of cardiovascular morbidity and mortality; however, evidence of unfortunate cardiovascular events accompanying elite sport involvement continues to accumulate. To date, no information is available on possible peculiarities of the cardiovascular risk profile in athletes. Design: The aim of this study was to evaluate plasma homocysteine levels in a group of athletes and to search for relationship with vitamin status and other metabolic variables in order to confirm the existence of a “sport-related hyperhomocysteinaemia” and to explain its clinical significance. The study population was composed of 82 athletes (59 male and 23 female) practising different sports and 70 healthy age-matched subjects (40 male and 30 female) as a control group. Besides the general clinical and analytical determinations, the assessed variables included homocysteine, folate, vitamin B12, total and high-density lipoprotein (HDL) cholesterol, lactate dehydrogenase (LDH), creatine kinase (CPK) and interleukin-6 (IL-6). Results: The prevalence of hyperhomocysteinaemia (>15 μmol/l) in athletes and controls was 47% and 15%, respectively. No correlation was found between homocysteine and any of the other investigated variables, in particular plasma folate, blood pressure, LDH, CPK, total and HDL cholesterol and IL-6. Conclusion: The results of this study confirm the existence of a sport-related hyperhomocysteinaemia which appears linked neither to the same variables found in the general population, nor to specific training-related variables. We suggest that it would represent an adaptation to training but the possibility of a secondary vascular damage cannot be excluded.

Strenuous exercise activates the hypothalamic-pituitary-adrenal (HPA) axis. Several reports showed that physical training is associated with a decreased efficiency of the feedback control of HPA axis. The aims of the present study were: 1) to evaluate the differences in the mechanical, hormonal, and lactate responses to a high-intensity isokinetic exercise among different groups of competitive athletes (CA, no.=20) of power and endurance disciplines and sedentary controls (SED, no.=10); 2) to determine the effects of the training status on the HPA axis responsiveness following exercise, as indirectly evaluated by the rates of ACTH, cortisol, and DHEA recovery after exercise. CA and SED fulfilled eight sets of twenty concentric contractions of the knee extensors at 180°/sec angular velocity throughout a constant range of motion (100°). There was a rest period of 30 sec between each set and a 3-min rest period between the two legs. Before, immediately after the isokinetic exercise and at different times in the subsequent 120 min of recovery, blood and saliva were sampled to determine plasma ACTH, salivary cortisol, serum DHEA, and serum lactate concentrations. CA showed a higher cortisol response to exercise than SED, whereas no differences were found in the responses of ACTH, DHEA and lactate. In the athlete group the exercise-induced increases of ACTH, cortisol, and lactate were higher in power athletes with respect to endurance athletes. No differences were observed between athletes and SED in the rates of hormonal recovery after exercise: this finding does not support the concept that a reduced feedback control of HPA axis can represent a feature of trained individuals.

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 (r(2)=0.16, P<0.05), salivary cortisol (r(2)=0.42, P<0.01), and serum cortisol (r(2)=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.

Physical exercise is associated with increases of serum and salivary levels of cortisol. The concomitant increase in serum lactate has been implicated as one of the mechanisms responsible for adrenocortical activation. We evaluated the responses of serum lactate and serum and salivary cortisol to an acute bout of high-intensity isokinetic exercise in eleven non-competitive and twenty competitive athletes (NCA and CA, respectively). The latter group was composed of endurance- and power-trained athletes (EA and PA, respectively). Aims of the study were to determine interindividual differences in the lactate and cortisol responses as a function of type and intensity of training and to search for relationships both between lactate and cortisol production and between serum and salivary cortisol levels.The isokinetic exercise test elicited significant cortisol and lactate responses. No difference was evident in the lactate responses between NCA and CA, while the PA showed a higher response during and after the exercise in comparison to EA (peak levels immediately after the exercise: PA 15.0 +/- 1.5 mmol/l vs. EA 11.1 +/- 2.6 mmol/l, p < 0.01). Serum cortisol was higher in the CA in comparison to the NCA group at 30 and 120 minutes after the termination of the exercise, while no differential response was evident between EA and PA groups. Salivary cortisol response was higher in the CA group in comparison to NCA immediately after the exercise and at 90 and 120 minutes after the termination and was higher in PA in comparison to EA at 60, 90, and 120 minutes after the termination (peak levels at 60 minutes: PA 51.2 +/- 18.5 nmol/l vs. EA 27.5 +/- 20.8 nmol/l, p < 0.05). No significant correlations were found between serum or salivary cortisol and lactate levels. The relationship between serum and salivary cortisol was markedly non-linear, the slope of the serum-saliva regression line being lower for serum cortisol concentrations over 500 nmol/l than for concentrations below that value (0.019 and 0.037, respectively, p < 0.01).We have confirmed in this particular setting the existence of an important adrenocortical response that can be reliably and non invasively assessed by a serial saliva sampling and have supported the concept that cortisol and lactate responses to a high-intensity isokinetic exercise are independent. The interindividual differences in cortisol changes are likely to be related to the training status and mode as well as to the correspondence between the evaluation protocol and the discipline individually performed.

Glucocorticoid (GC)-induced osteoporosis is the leading form of secondary osteoporosis. Bone loss can be rapid. However, longitudinal studies at the very beginning of treatment are scarce. Patients relapsing from multiple sclerosis are treated with high-dose, short-term iv GCs. A number of them are young, without concomitant disease affecting bone and with no substantial impairment of mobility. Such patients were selected for the present study. Thirteen patients suffering from multiple sclerosis [11 females, two males; age 32 +/- 2 yr (mean +/- se)] and receiving iv methylprednisolone 15 mg/kg daily for 10 d completed the study. We measured serum osteocalcin (OC), aminoterminal propeptide of type I collagen (PINP), bone isoform of alkaline phosphatase (bALP), carboxyterminal telopeptide of type I collagen (CTX), and urinary calcium/creatinine ratio (uCa/Cr) during the 10-d cycle and 3 months later. Dual-energy x-ray absorptiometry and calcaneal quantitative ultrasonometry were performed before and 6 months after therapy. We found an immediate, impressive fall of OC and PINP (-80 +/- 3 and -54 +/- 5% at d 2, respectively), which persisted throughout the whole treatment period (P < 0.0001 for both markers). bALP levels showed only a modest decrease at d 6 (-19 +/- 7%, P < 0.05), with subsequent return to baseline in d 7-10. After 3 months, OC, PINP, and bALP levels rose to +51 +/- 22, +37 +/- 16 (not significant), and +61 +/- 17% (P < 0.01) with respect to baseline, respectively. uCa/Cr and CTX showed a progressive, marked increase during treatment, peaking at d 7-9 (+92 +/- 44 and +149 +/- 63%, respectively), with subsequent decrement at d 10 (P < 0.01 and P < 0.05, respectively) despite continuing GC administration. After 3 months, uCa/Cr and CTX levels were also higher than baseline. No change in quantitative ultrasonometry parameters and bone mineral density was observed 6 months after therapy. In conclusion, high-dose, short-term iv GC regimens cause an immediate and persistent decrease in bone formation and a rapid and transient increase of bone resorption. Our data also support the concept that discontinuation of such regimens is followed by a high bone turnover phase.

BACKGROUND: Natural killer (NK) cells are a key component of innate immunity; their activity is modulated by cytokines and hormones and is influenced by diet. In obesity, a higher risk of cancer and infections has been demonstrated. Studies on NK cell activity have yielded inconsistent results; NK cell sensitivity to modulators has not been assessed before. OBJECTIVE: In this case–control study, we assessed both spontaneous NK cell activity and responsiveness to positive (interleukin (IL)-2) and negative (cortisol) modulators in uncomplicated obesity; we searched for correlations between NK cell activity and anthropometric, dietary and metabolic variables. METHODS: In all, 21 obese (six males/15 females) and 21 age- and sex-matched healthy nonobese subjects underwent clinical examination and dietary and laboratory analyses. Spontaneous and modulated NK activities of peripheral blood mononuclear cells were measured by enzyme-release cytotoxicity assay. RESULTS: Spontaneous NK cell activity was not different in obese subjects vs controls. IL-2 stimulated and cortisol inhibited NK cell activity in both populations. Cortisol-dependent inhibition was lower in the obese than in the control group (−24.4±2.9 vs −38.6±3.3%, P =0.002), but decreased sensitivity was restricted to women ( P =0.0007). In obese subjects, cortisol-dependent inhibition negatively correlated with serum leptin levels ( r =−0.54, P =0.02) and, in women, with body mass index ( r =−0.63, P =0.01); IL-2-dependent stimulation positively correlated with dietary carbohydrates ( r =0.61, P =0.005) and serum LDL levels ( r =0.55, P =0.009) and negatively correlated with dietary lipids ( r =−0.71, P =0.0006). CONCLUSION: Spontaneous and IL-2-inducible NK cell activity is normal in uncomplicated obesity. Sensitivity to IL-2 correlates with fat and carbohydrate intake. Sensitivity to glucocorticoids negatively correlates with serum leptin levels and is significantly diminished in obese women, in whom it correlates with body mass index.

Physical exercise is associated with elevation of serum levels of interleukin-6 (IL-6) because of its production in the muscles. The use of IL-6 measurements in saliva has been proposed in the field of immunopathology, mainly involving salivary gland disease. We evaluated the responses of serum and salivary IL-6 in two different groups of athletes submitted to different types of controlled strenuous exercise (spinning activity and maximal isokinetic test). Serum and salivary samples for IL-6 measurements, and serum samples for lactate and myoglobin determination before and after exercise, were obtained. Salivary IL-6 was measured by ELISA after dilution experiments and compared with results obtained by immunoradiometric assay. Spinning activity elicited significant increases in all the variables, and no correlation was found among the respective variations. A significant response to the isokinetic exercise was observed for serum IL-6, lactate and myoglobin only; no correlation was found between serum and salivary IL-6. Our study demonstrated that serum and salivary IL-6 responses to exercise are dissociated, possibly in relation to the lack of relationships between the systemic/muscular and the salivary routes of IL-6 production. Analytical issues that concern IL-6 measurement in saliva deserve attention, notably regarding the collection method used to absorb saliva. Concomitant monitoring of serum markers of inflammation, muscle metabolism and damage can provide information about muscle function properties and adaptations to physical effort in different types of athletes.

Background: Chromogranin A (CgA) is a secretory protein present in dense-core vesicles of neuroendocrine (NE) cells. Its ubiquitous presence in NE tissues makes it a suitable circulating marker of neoplasms of NE origin.Patients and Methods: Plasma CgA was determined in 178 patients with NE tumors and in 36 patients with non-endocrine malignancies. Circulating CgA was also serially evaluated in 39 NE cancer patients with advanced disease submitted to systemic therapy and in 14 patients with no evidence of disease (NED).Results: Supranormal CgA values were found in 81% of patients with advanced NE tumors and in only 91% of NED cases. Plasma CgA in patients with well differentiated NE tumors, such as carcinoids, carcinoma of gastrointestinal tract, pheocromocytoma, pancreatic NE carcinoma (either functioning or not functioning), medullary thyroid carcinoma and NE tumors from various primary sites, was higher and more frequently elevated than in patients with small-cell lung cancer (P < 0.001). Plasma CgA did not discriminate patients with NE from those with non NE neoplasms since it was found elevated in 44% of the latter cases. Plasma CgA pattern correlated with the disease response in patients submitted to cytotoxic treatment and with changes in clinical symptomathology in patients receiving somatostatin analogs.Conclusions: Our data confirm that CgA is the best circulating neuroendocrine marker available up to now available for the management of differentiated neuroendocrine malignancies irrespective of tumor location and functional status. CgA plasma levels could also identify the coexistence of neuroendocrine differentiation in the context of non-endocrine malignancies. Circulating CgA seems to be less useful in undifferentiated tumors such as small-cell lung cancer.

Galectin-3 is a carbohydrate-binding protein endowed with an affinity for beta-galactosides. It has been shown to play an important role in cell-cell and cell-matrix interactions and in pre-mRNA splicing. Furthermore, it is involved in the control of cell growth, neoplastic transformation, and metastasis. Interestingly, high levels of galectin-3 expression have been recently described in malignant thyroid neoplasias, but not in adenomas or in normal thyroid tissue. We investigated galectin-3 expression in human presurgical specimens obtained by fine-needle aspiration biopsy. We analyzed galectin-3 expression by immunoperoxidase staining in both paraffin-embedded cytological thyroid sediments (cell blocks) obtained by fine-needle aspiration biopsy and their histological counterparts. A total of 64 samples were examined: 17 follicular carcinomas; 18 papillary carcinomas; and 29 follicular adenomas. All cell blocks and histological samples of papillary carcinomas expressed high levels of galectin-3 at either the cytoplasmic or nuclear level. Among follicular carcinomas, all histological samples expressed galectin-3, whereas 14 of 17 corresponding cell blocks were positive in the cytoplasm. No evidence of cytoplasmic galectin-3 expression was observed in 26 of 29 follicular adenomas. Hence, cytoplasmic galectin-3 staining seems to be a reliable, easy, and cheap marker for presurgical diagnosis of follicular carcinomas and an even more suitable one for papillary carcinomas.

The evaluation of response of osseous metastases to systemic treatments is often low as a consequence of the different radiologic appearances that make objective assessment not only difficult but sometimes impossible. Radiographic evidence of recalcification, the UICC criterion of response, is often evident for 6 months and sometimes may be delayed even more. This accounts for lower response rates in bone with respect to other metastatic sites in clinical trials. A transient rise in bone formation indices may provide an early indication of bone healing and, along with measurement of symptomatic changes, could ameliorate the response evaluation. Among the biochemical markers of bone formation, total alkaline phosphatase (TALP) is widely employed, but it lacks specificity. Estimation of bone isoenzyme (E-BALP) by electrophoretic techniques is time consuming and semiquantitative. The immunoradiometric assay (I-BALP) seems to overcome these limitations. In this study, we compared the two methods of bone isoenzyme estimation with each other and with the levels of bone gla protein (BGP) and carboxyterminal propeptide of type I procollagen (PICP) in a group of 136 cancer patients with bone metastases stratified as having lytic or mixed and blastic lesions at X-ray, and in 62 cancer patients without apparent bone involvement. The same indices were also evaluated prospectively in a patient subset submitted to chemotherapy associated with pamidronate. The aims of the study were to evaluate whether I-BALP is superior to E-BALP and whether both methods of bone isoenzyme estimation are more advantageous than TALP, BGP, and PICP in the assessment of osteoblast activity either in baseline conditions or in response to treatment. In bone metastatic patients with lytic appearances, values above the cut-off limit were observed in 32.1%, 23.3%, 48.9%, 32.9%, and 14% for, TALP, E-BALP, I-BALP, PICP, and BGP, while the corresponding percentages in those with blastic/mixed appearances were 74.0%, 84.8%, 76.9%, 51.9%, and 43.8%, respectively. In the patients without bone involvement, values within the normal range were 90.2%, 98.2%, 89.6%, 71.7%, and 90.2%, respectively. Levels of TALP, E-BALP, and I-BALP were reciprocally correlated in the three groups examined. In bone metastatic patients, however, the degree of correlation of the enzymes with PICP and BGP was weak. Liver isoenzyme of alkaline phosphatase (LALP) was found to correlate with E-BALP, but not with I-BALP, in patients with mixed/blastic lesions. Thirty-eight patients were submitted to pamidronate therapy (60 mg every 3 weeks, administered 4 times) in association with cytotoxic treatment. Osteoblastic markers were determined before any administration. Serum TALP, E-BALP, and I-BALP showed a transient rise in 9 cases, a progressive reduction in 12, no change in 2, and a progressive increase in 6. Changes in E-BALP and I-BALP from baseline were greater than those of TALP. A divergent pattern between TALP and both I-BALP and E-BALP was found in 9 patients, whereas a divergent temporal profile between the two methods of bone isoenzyme estimation was recorded in only 3 patients. Eight out of 38 cases obtained a partial recalcification of lytic and mixed lesions. Seven of them showed the concomitant early increase in TALP, E-BALP, and I-BALP followed by a gradual decline (osteoblastic flare), whereas 1 patient demonstrated the flare of E-BALP and I-BALP but not of TALP. No relationship was found between response and temporal changes in in BGP and PICP serum levels. We conclude that I-BALP is a useful marker for detecting excess osteoblastic activity in patients who have at imaging ``pure'' lytic bone metastases. In the longitudinal evaluation of patients receiving multiple pamidronate infusions plus chemotherapy, TALP, E-BALP, and I-BALP, but not BGP and PICP, appeared to be useful to identify responders in bone. A slight advantage of measurements of serum bone isoenzyme (by both techniques) over TALP is apparent, but this study fails to demonstrate a clear superiority of I-BALP over E-BALP.

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.