Breast cancer electron intraoperative radiotherapy: assessment of preoperative selection factors from a retrospective analysis of 758 patients and review of literature.

PURPOSE: To report our experience with full-dose 21 Gy IORT in early breast cancer patients after breast-conserving surgery to define most important selection factors. METHODS: Seven hundred and fifty eight patients, subjected to conserving surgery and IORT, were retrospectively analyzed evaluating most important clinical outcomes. RESULTS: Median follow up was 5.2 years. Results from Cox analyses defined 2 groups of patients, "suitable" (age > 50 years, non lobular histology, tumour size ≤ 2 cm, pN0 or pNmic, ki67 ≤ 20%, non triple negative receptor status and G1-G2) and "unsuitable" for IORT, with a higher rate of breast related events moving from "suitable" to "unsuitable" group. The 5 year rate of IBR is 1.8% in suitable group with significant differences versus unsuitable (1.8 vs. 11.6%, p < 0.005). Same differences between two groups were evidenced in true local relapse (0.6 vs. 6.9%, p < 0.005) and in new ipsilateral BC (1.1 vs. 4.7%, p < 0.015). CONCLUSIONS: In our current practice we consider the following preoperative factors to select patients suitable for IORT: age > 50 years, absence of lobular histology, tumor size ≤ 2 cm, pN0 or pNmic, according to APBI consensus statement, including also ki67 ≤ 20%, non triple negative receptor status and G1-G2.

Non-length-dependent small fibre neuropathy. Confocal microscopy study of the corneal innervation.

BACKGROUND: It has been recently observed that small fibre neuropathy (SFN) may present as distal symmetrical polyneuropathy and with atypical non-length-dependent pattern. OBJECTIVE: To describe a small series of patients with non-length-dependent SFN, investigating corneal innervation with corneal confocal microscopy (CCM). METHODS: Evaluation of the corneal nerve fibre density using CCM in six women with non-length-dependent SFN. The patients were characterised by sensory disturbance involving proximal regions of the limbs, face and trunks, and the diagnosis was confirmed by the findings of decreased intraepidermal nerve fibre density on skin biopsy. RESULTS: Six women, aged 35-64, had non-length-dependent SFN, related to Crohn disease, impaired glucose tolerance and Sjögren's syndrome, or idiopathic (three cases). In all patients, CCM demonstrated decreased corneal nerve fibre density (12.5-23.4/mm(2); normal, >30.6/mm(2)). CONCLUSION: Non-length-dependent SFN may represent an intriguing diagnostic problem because of its puzzling presentation and the need for special investigations for its confirmation. In this perspective, CCM may provide a useful, non-invasive tool to complement the diagnostic workup.

Post-operative remnants of brainstem cavernomas: incidence, risk factors and management.

INTRODUCTION: The risk of leaving a remnant after surgery for a cavernous malformation in the brainstem is generally not stressed enough, even though such remnants appear to have a high risk of re-bleeding. At least 40% of known cavernoma remnants after surgery have further bleeding episodes. A retrospective analysis of 30 patients with brainstem cavernoma who underwent surgery is presented, focusing on incidence, risk factors and management of post-surgical residuals. The sites were, medulla in three patients, pons-medulla in four, pons in 16, pons-midbrain in four and midbrain in three. All 30 patients came to our clinical observation with at least one episode of acute-onset neurological deficit and all were operated in the sub-acute phase. Only one patient had a worse stable outcome than the pre-surgical state, and 29 did better or were stable. All patients had a brain MRI scan within 72 h after surgery to confirm that complete removal had been achieved. In three, although the surgical cavity and its border appeared clean at the end of surgery, with no lesion remaining, post-operative MRI detected a residuum. These three patients were re-operated, but one had a further bleed prior to excision. MATERIALS AND METHODS: In our series, the surgical finding of a multi-lobular cavernoma (as opposed to the more frequent finding of a discrete lesion with a thick capsule), with a thin wall and satellite nodules separated by a thin layer of apparently intact white matter, was common (seven patients). This group included the three patients with evidence of residuum on post-operative MRI. In our experience, the surgical finding of a multi-lobular cavernoma carries a higher risk of residuum and post-surgical re-bleeding. CONCLUSION: Immediate post-operative brain MRI scans are therefore strongly recommended for their detection, especially in this group of patients, and if a residual is detected early re-intervention is less risky than the natural history.

Chronic rejection after combined liver and small bowel transplantation in a child with chronic intestinal pseudo-obstruction: a case report.

An 11-year-old boy with irreversible intestinal failure secondary to chronic intestinal pseudo-obstruction (CIPO) and intestinal failure-associated liver disease (IFALD) underwent a combined en bloc reduced liver and small bowel transplantation. He was discharged home after 9 weeks on full oral intake without requiring intravenous nutritional or fluid supplementation. The first episode of mild acute rejection, which occurred 18 months after transplantation, was successfully treated with steroids. An episode of rotavirus gastroenteritis led to severe exfoliative rejection of the bowel graft, which was resistant to steroid and Infliximab treatment but responded to OKT3. There was associated Epstein-Barr virus viremia with no evidence of posttransplant lymphoproliferative disease. Another episode of moderate to severe acute liver rejection occurred 5 months later. At the same time, multiple biliary strictures were diagnosed and treated. Persistent clinical symptoms of abdominal pain and increased stomal output as well as atrophy of the ileal mucosa on several biopsies, suggested the possibility of chronic rejection (CR). A second combined whole liver and small bowel transplant was performed. The diagnosis of CR was confirmed on histology of the explanted graft. The postoperative course was severely complicated and 71 days after the retransplantation, the boy died because of respiratory failure and multiorgan failure. In summary, intestinal transplantation can be successfully performed in children with CIPO, giving them the opportunity to be free from total parenteral nutrition. As survival following intestinal transplantation continues to improve, the problem of CR has become increasingly important and the only treatment available is retransplantation, which is associated with poor outcomes.

Complications of transsphenoidal surgery in patients with pituitary adenoma: experience at a single centre.

OBJECTIVE: This paper reports the complications of transsphenoidal surgery for pituitary adenomas in a series of 1240 consecutive patients operated at our Institute between 1990 and 2004 (first operations) and indicate the clinical characteristics of patients which affected surgical morbidity and mortality. METHODS: According to tumour type, there were 420 (33.9%) non-functioning pituitary adenomas (NFPA), 349 (28.1%) GH-secreting, 288 (23.2%) ACTH-secreting, 155 (12.5%) prolactin (PRL)-secreting, and 28 (2.3%) TSH-secreting adenomas. The mean age of patients was 43.7 +/- 0.4 yr and 122 patients (9.9%) were 65 yr or older; the female/male ratio was 1.5/1. There were 370 (29.8%) microadenomas and 870 (70.2%) macroadenomas of which 54 (4.4%) were giant adenomas. RESULTS: The series mortality was 0.2%, the medical morbidity 1.9%, and the surgical morbidity 3.5%. Medical complications were significantly more frequent in patients older than 65 yr (4.9 vs. 1.4%; p = 0.009) and in patients with giant adenomas (5.6 vs. 1.6%; p = 0.03). Multivariate analysis showed that both variables were independently associated with a higher morbidity rate. The surgical morbidity was increased in giant adenomas (15 vs. 3%; p = 0.0001), in NFPA (6.2 vs. 2.1% in secreting adenomas; p = 0.0002) and in patients older than 65 yr (6.6 vs. 3.1%; p = 0.05). Multivariate analysis showed that only giant size was independently associated with an increased surgical morbidity rate. CONCLUSIONS: In our experience, the size of the adenoma was a risk factor for medical and surgery related complications and age over 65 yr for medical complications alone.

Intrasellar paraganglioma: a case report and review of the literature.

Intrasellar paragangliomas are very rare lesions with only six previous cases described in the literature. We present a further case of intrasellar paraganglioma. The patient was a 52 yr-old man who developed two transient ischemic attacks. A CT scan showed an intra- and supra-sellar expanding lesion, which was regarded as a possible non-functioning pituitary macro-adenoma. Removal of the lesion was accomplished by transsphenoidal surgery. Histological examination was diagnostic of a paraganglioma. We review the literature and discuss pathological features and possible pathogenesis of sellar and parasellar paragangliomas, underlining the necessity to consider paraganglioma in the differential diagnosis of sellar lesions.

Coexistence of TSH-secreting pituitary adenoma and autoimmune hypothyroidism.

OBJECTIVE: TSH-secreting pituitary adenomas account for about 1-2% of all pituitary adenomas. Their diagnosis may be very difficult when coexistence of other diseases masquerades the clinical and biochemical manifestations of TSH-hypersecretion. CLINICAL PRESENTATION: A 41-yr-old female patient, weighing 56 kg, was referred for evaluation of an intra- and suprasellar mass causing menstrual irregularities. Eight yr before, the patient had been given a diagnosis of subclinical autoimmune hypothyroidism because of slightly elevated TSH levels and low-normal free T4 (FT4). Menses were normal. Despite increasing doses of levo-T4 (L-T4; up to 125 microg/day), TSH levels remained elevated and the patient developed mild symptoms of hyperthyroidism. After 7 yr, the menstrual cycle ceased. Gonadotropins were normal, whereas PRL level was elevated at 70 microg/l and magnetic resonance imaging (MRI) of the hypothalamic- pituitary region revealed a pituitary lesion with slight suprasellar extension. The tumor was surgically removed and histological examinations revealed a pituitary adenoma strongly positive for TSH. Three months after surgery the patient was well while receiving L-T4 75 microg/day and normal menses had resumed. MRI of the hypothalamic-pituitary region showed no evidence of residual tumor. At the last follow-up, 16 months after surgery, serum TSH, free T3 (FT3), and FT4 levels were normal. CONCLUSIONS: Coexistence of autoimmune hypothyroidism and TSH-secreting pituitary adenoma may cause further delays in the diagnosis of the latter. In patients with autoimmune hypothyroidism, one should be aware of the possible presence of a TSH-secreting pituitary adenoma when TSH levels do not adequately suppress in the face of high doses of L-T4 replacement therapy and elevated serum thyroid hormone levels.

A non-functioning pituitary adenoma initially mimicking a microprolactinoma: The case for long-term follow-up of patients with mild hyperprolactinemia?

OBJECTIVE: A correct differential diagnosis of patients with mild hyperprolactinemia is essential to select the most appropriate treatment modality. CLINICAL PRESENTATION: A 50-yr-old woman presented to our Department for evaluation of an intra- and suprasellar mass causing progressive visual defect. Mild hyperprolactinemia causing menstrual irregularities was diagnosed in February 1989. In 1992, serum PRL levels ranged from 50 to 70 microg/l and magnetic resonance imaging (MRI) of the hypothalamic-pituitary region showed the presence of a 7 mm microadenoma. Bromocriptine therapy resulted in normalization of PRL levels and menstrual cycle, while a repeat MRI showed no change. Menses stopped in March 1998, when the patient was 46 yr old. Subsequently, the patient complained of worsening headaches and, starting from July 2001, visual disturbances. In March 2002, MRI showed a large pituitary tumor, measuring 40x37x28 mm. In May 2002, the patient was operated through the transsphenoidal approach with apparent total tumor removal. Histological examination confirmed a pituitary adenoma that stained negative for all pituitary hormones. Four months after surgery, the patient reported an improvement of visual function. MRI of the hypothalamic-pituitary region, performed 4, 13 and 25 months after surgery, showed a partially empty sella with no evidence of residual tumor. CONCLUSIONS: This case suggests that, to exclude the alternative diagnosis of nonfunctioning pituitary adenoma or another mass lesion of the hypothalamic-pituitary region, repeat neuroimaging studies during long-term follow-up may be advisable in patients with presumed microprolactinoma who did not show reduction of the tumor during dopaminergic therapy.

Transplantation for acute liver failure in children.

We reviewed the clinical data of 30 children-hospitalized for acute liver failure in the last 6 years. Ten patients were not listed for liver transplantation OLTX. Their clinical conditions gradually improved and they are all alive without deficit. Among 20 patients listed, 15 underwent urgent OLTX. Two children died on the waiting list and three were suspended from waiting list after few days because of improvement. Survival according to age class was analyzed dividing the patients into two groups: A, age 1 year or less versus B, age between 1 and 16 years. The patient survival was 86% at 6 months and 61% both at 1 and 2 years. Survival at 6 months and 1 and 2 years was 88%, 67%, and 45% for the patients in group A and 83%, 83%, and 83% for the patients in group B (P = NS). Observing graft-to-recipient weight ratio and donor-to-recipient weight ratio most patients received an optimal sized graft. The split-liver technique is considered the preferred method of liver transplantation even in the pediatric patients with acute liver failure; especially in the setting of a cooperative system in which all livers that are suitable for split-liver transplantation are shared between centers. In order to have the best chance for survival, children with acute liver failure should be referred as soon as possible to an highly specialized pediatric liver transplantation center that can offer all the treatment modalities that are currently available.

Orthotopic liver transplantation for Byler's disease.

In this study we analyzed the features of 12 patients who underwent liver transplantation for progressive familial intrahepatic cholestasis (Byler's disease [BD]) in view of the technical features of the OLTx, incidence and type of complications, need for retransplantation, as well as patient and graft survivals. BD was the indication in 12 patients of median age 1.32 years and median weight 10 kg. Median follow-up was 670 days. Major surgical complications requiring reintervention occurred in three patients. No thrombosis of the hepatic artery was observed. Infections with positive blood cultures were diagnosed in four patients. One patient had a biliary anastomotic stenosis successfully treated by percutaneous techniques. Four patients had episodes of acute rejection treated with steroids. Two patients were retransplanted, both of whom died in the early postoperative period due to hepatic vein thrombosis and venoenteric fistula. The actuarial patient and graft survival was 83% at 1 year and 83% at 5 years. Split-liver grafts represent an excellent organ supply for these patients, achieving good results with no mortality on the waiting list.

Orthotopic liver transplantation for biliary atresia.

Biliary atresia (BA) represents the most frequent indication for liver transplantation (OLTX) in the pediatric population. The aim of this paper was to present a series collected over the last 7 years from October 1997 through July 2004, including 260 pediatric OLTX in 231 patients. BA was the indication in 137 patients. There were 69 boys and 68 girls of mean weight 10.68 kg and median age 0.9 years. As a primary transplant, 99 patients received a LLS graft; 27 a whole graft; four a I+IV-VIII segment, and two a I-IV segment. Mean follow up was 1047 days (range, 1-2496 day). Infections were diagnosed in 45 patients, vascular complications in 27 patients. Surgical complications that required reintervention occurred in 25 patients. In 41 cases biliary complications occurred, 11 requiring reintervention. 16 patients were retransplanted. In two cases another re-OLTx was performed. Currently 126 patients are alive, showing an actuarial 1 year survival of 92% and 5 year 91%, with actuarial graft survivals of 85% at 1 year and 82% at 3 and 5 years. Our results confirm the effectiveness of OLTx for the treatment of children with BA and a failed Kasai procedure. Split liver grafts represent an excellent organ supply for these patients, achieving optimal results with no mortality on the waiting list.

Orthotopic liver transplantation for alagille syndrome.

Alagille syndrome (AS) is a dominantly inherited, multisystem disorder involving the liver, heart, eyes, face, and skeleton. From October 1997 through July 2004, 260 pediatric orthotopic liver transplantations (OLTx) were performed in 231 patients. This report describes 21 patients of median age 1.95 years (range, 0.7-16.7) who had alagille syndrome. We present the technical features of the OLTx, incidence and type of complications, medical conditions related to the syndrome, need for retransplantation, as well as patient and graft survival rates. A split liver technique was used in 16 patients (76%) who received a left lateral segment (LLS) graft whereas 7 patients (33%) received a whole liver. Only cadaveric donors were used. The major surgical complications requiring reintervention in 11 patients (52%) included biliary problems (19%) and vascular complications (17%). One case of hepatic artery thrombosis required retransplantation. Three recipients (14%) died. All other patients are alive with an actuarial survival rate of 90% at 1 year and 80% at 5 years. The actuarial graft survival rate is 85% at 1 year and 75% at 5 years. Patients with AS, despite the associated cardiovascular anomalies, can be treated successfully by a combined approach between cardiologist, radiologist, cardiothoracic, and liver transplant surgeons. With careful planning and operative management, the results are comparable with those obtained with other more common cholestatic diseases.

Correlation between clinical characteristics and proliferative activity in patients with craniopharyngioma.

OBJECTIVES: The aim of the study was to correlate the Ki-67 and cyclin A labelling index (LI) with clinical characteristics and risk of recurrence of craniopharyngiomas. METHODS: 47 consecutive patients were studied, 21 female and 26 male, aged 34.3 (2.8) years. Immunohistochemical analysis was performed on paraffin wax embedded material using monoclonal antibodies directed against the proliferation associated nuclear antigen Ki-67 and cyclin A. RESULTS: The median Ki-67 LI was 8.6% (interquartile range, 4.4%-14.0%). Ki-67 LI was significantly higher in tumours with a heavy inflammatory reaction and diabetes insipidus at presentation, whereas other clinical and histological features were not associated with the proliferation index. There was a strong linear correlation between Ki-67 LI and cyclin A LI (r = 0.77; p<0.0001); therefore, cyclin A LI showed the same clinical and histological relations described for Ki-67 LI. Recurrence of craniopharyngioma occurred in 13 of 46 patients (28.3%). The median Ki-67 LI in the 13 recurrent craniopharyngiomas (9.0%) was not significantly different from that of non-recurring tumours (7.9%). Cyclin A LI was also not associated with the risk of relapse. CONCLUSIONS: This study confirms the great variability of proliferative activity in craniopharyngiomas. Ki-67 and cyclin A LIs were associated with the presence of a heavy inflammatory reaction and diabetes insipidus, but did not correlate with the long term risk of tumour regrowth.

[The role of somatostatin analogues in the treatment of hypophyseal adenomas]. / Ruolo degli analoghi della somatostatina nel trattamento degli adenomi ipofisari.

Somatostatin analogues are widely employed in the treatment of hypophyseal adenomas. The most widely used analogues at the present time are octreotide and lanreotide. Both are available in slow release formulations using the parenteral route and show a preferential affinity for the sst(2) receptor of somatostatin. Both octreotide and lanreotide have proved their effectiveness in the treatment of GH- and TSH-secretory hypophyseal adenomas. In those patients who respond to pharmacological treatment we often achieve not only the control of hormonal hypersecretion, but also a reduction in the volume of hypophyseal neoplasia. In the other types of hypophyseal adenoma, on the other hand, somatostatin analogues have proved to have little effect: apart from isolated cases of effectiveness in non-functioning adenomas, the administration both of octreotide and lanreotide to patients with Cushing's disease or prolactinoma did not significantly modify the hormonal hypersecretion or tumoural volume. The side-effects of somatostatin analogues are comparatively rare and of moderate entity: only a small percentage of patients requires the treatment to be suspended owing to the occurrence of side-effects. New analogues are currently under study. These have a different receptor profile and they could therefore find new applications in hypophyseal pathology. Octreotide, bound to radioactive substances or to toxins, has also been utilised for the selective destruction of neoplastic tissues expressing the sst(2) receptor of somatostatin.

Surgical excision of clival tumors via the enlarged transcochlear approach. Indications and results.

BACKGROUND: The results of the surgical resection of 9 clival tumors using the enlarged transcochlear approach (ETCA) are evaluated. The literature is reviewed to compare the ETCA with other approaches to the clival and petroclival region; the surgical indications are discussed. METHODS: Between June 1996 and June 1997, 9 patients were operated on through the ETCA either alone or combined with other approaches. Only meningiomas and chordomas with a significant involvement of the clivus and huge extension into the posterior fossa were included into this study. RESULTS: Gross total tumor removal was achieved in 5 cases and in 4 cases a residual meningioma was left in place inside the cavernous sinus and treated by radiosurgery. No postoperative mortality or major neurological morbidity were recorded. The postoperative facial nerve function was good in 75% of cases. No tumor recurrence was recorded (mean follow-up = 45.9 months). CONCLUSIONS: The indications to the ETCA should be as strict as possible. The ETCA is an effective procedure in the treatment of large clivopetrous tumors. Tumor characteristics like consistency, vascularity, encasements of vertebro-basilar vessels, bone erosion and previous surgery are also indicative. The transient postoperative facial nerve palsy and deafness should be considered as major disadvantages related to this approach.

Effects of octreotide treatment on the proliferation and apoptotic index of GH-secreting pituitary adenomas.

To investigate the effects of octreotide administration on the growth rate of GH-secreting pituitary adenomas, we measured both the Ki-67 labeling index (LI) and the apoptotic index in tumor specimens from octreotide-treated or matched untreated acromegalic patients. Thirty-nine patients who received octreotide until the day of or the day before surgery and 39 untreated patients matched for sex, age, tumor size, extension, and invasiveness were studied. Immunocytochemical analysis was performed on paraffin-embedded material using a monoclonal antibody (MIB-1) directed against a proliferation-associated nuclear antigen, Ki-67, to measure the growth fraction. Apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick endlabeling method, using a monoclonal antibody recognizing areas of DNA fragmentation. The Ki-67 LI and apoptosis were counted on separate slides in at least 1000 evaluable cells. Octreotide-treated patients showed a lower Ki-67 LI (1.8 +/- 0.3%) than untreated controls (3.8 +/- 0.7%; P < 0.02). Overall, the mean Ki-67 LI of treated patients was 53% lower than that in untreated patients. The antiproliferative effect of octreotide occurred independently of tumor extension and invasiveness. Octreotide-treated and untreated patients showed similar apoptotic indexes (0.6 +/- 0.2% and 0.8 +/- 0.3%, respectively). There was a positive correlation between the Ki-67 LI and the apoptotic index (r = 0.29; P < 0.03). Our study demonstrates that acromegalic patients receiving chronic octreotide treatment have a lower value of the proliferation marker Ki-67, but no significant difference in the apoptotic index compared with matched untreated patients. The antiproliferative effect of octreotide on GH-secreting adenomas should imply a lower risk of tumor growth during long-term chronic treatment with the drug.

A comparative evaluation of effectiveness of medical and surgical therapy in patients with macroprolactinoma.

BACKGROUND: The surgical success rate in macroprolactinomas is quite low, while medical treatment is more effective in reducing PRL levels and tumour mass. In this study the effectiveness of surgical, medical and radiant approaches on clinical symptoms, PRL levels and tumour size were compared in a large series of patients with macroprolactinomas. METHODS: One hundred and thirty-two patients (63 males and 69 females) were followed-up. Eighty-three patients were operated by trans-sphenoidal (TSS) approach: 18 underwent only TSS, 10 were operated and then irradiated; 30 patients underwent TSS and dopamine agonists, 25 were treated by TSS, radiotherapy and dopamine agonists. One hundred and four patients were treated by medical therapy: 49 patients were only administered dopamine agonists and 55 were given dopamine agonists after unsuccessful surgery and/or radiotherapy. RESULTS: In 83 patients serum PRL levels decreased from 1873+/-319.9 ng/ml to 831.6+/-297.8 ng/ml after trans-sphenoidal surgery: a significant PRL reduction was obtained in 18 cases (22%) and a full PRL normalization was found in 15 patients (18%). The pituitary adenoma was completely removed in the 15 cases, in whom serum PRL normalized. Sexual function was restored in 57 percent; of women and in 29 percent; of men. In contrast, dopaminergic drugs normalized PRL levels (from 1590.5+/-232.7 to 19.2+/-4.8 ng/ml) in 93/104 patients (89 percent;). Sexual function was restored in 74 percent; of women and in 75 percent; of men. Radiotherapy, performed after unsuccessful TSS, was ineffective in normalizing PRL levels. CONCLUSIONS: Medical therapy should be considered the first choice treatment in macroprolactinomas, while the surgical approach is recommended when neurological compressive symptoms are present and in patients resistant or intolerant to dopamine agonists. Radiotherapy may be indicated only in the patients in whom medical and surgical therapy have not been successful.

Chondrosarcoma of the thoracic spine: total en bloc sagittal resection. A case report.

Chondrosarcomas located in the spine are uncommon tumors and are challenging to manage. A case of a 65-year-old man with a T3-T4 spine chondrosarcoma is reported. The onset of symptoms consisted in progressive dorsal pain with sometimes a girdle-like radiation and, successively, in dysaesthesia and paresthesia from the lower limbs to the thoracic region. After preoperative oncologic and surgical planning the patient underwent a total en bloc resection of the mass. No postoperative adjunctive neurological deficits were recorded. An adjuvant radiation therapy with a dose of 5.500 centigrays (cGy) over four weeks was performed. At one year follow-up the patient is alive with no signs of recurrence on computed tomographic scans and magnetic resonance imaging. We discuss this case with particular emphasis on the preoperative planning, the surgical procedure and related prognosis.

Assessment of cure and recurrence after pituitary surgery for Cushing's disease.

BACKGROUND: The treatment of choice in Cushing's disease is transsphenoidal adenomectomy with a recurrence rate ranging 9-23%. We investigated whether abnormal hormonal responses may predict the relapse in "operated" patients followed-up for a long period. METHOD: Sixty-eight surgically treated patients with Cushing's disease were followed-up for 12-252 months. Forty-eight patients underwent selective adenomectomy, 17 enlarged adenomectomy and 3 underwent total hypophysectomy. After surgery ACTH and cortisol levels were measured after stimulatory (desmopressin and CRH) and inhibitory tests (dexamethasone and loperamide). FINDINGS: After operation 46 patients were cured (group A), 15 patients only normalized cortisol levels (group B), 7 patients were surgical failures. During the follow-up, a disease-free condition was maintained in 48 of 61 cases (79%), while a recurrence occurred in 13 patients (21%, 5 of group A and 8 of group B). In 5/13 patients who relapsed an absent inhibition after dexamethasone and an exaggerated response to CRH test preceded the recurrence. In 5 other patients the relapse was suspected by loperamide test. In the 3 remaining cases, positive responses to desmopressin preceded the recurrence. In 7/13 patients who relapsed the pituitary tumour was visualized by MRI/CT imaging. INTERPRETATION: During the follow-up a careful assessment of ACTH dynamics is needed. Although no single test can reliably predict the late outcome, individual patients at risk for relapse may be identified by abnormal responses to desmopressin, CRH and loperamide tests; particularly, the persistent responsiveness to desmopressin may be a criterion of risk for recurrence in patients who only normalized cortisol levels after surgery.

Desmopressin stimulation test before and after pituitary surgery in patients with Cushing's disease.

OBJECTIVE: The desmopressin test has been proposed as a useful tool for the differential diagnosis of Cushing's disease. The aim of our study was to investigate, in a large series of patients with Cushing's disease, the incidence of a positive ACTH and cortisol response to desmopressin. Moreover, we repeated the test soon after surgery to verify its usefulness in the assessment of early and late surgical results. PATIENTS AND METHODS: One hundred and seven consecutive patients with Cushing's disease, 89 female and 18 male patients, with a mean age of 37.2 +/- 1.3 years, were studied. All patients, except three, repeated the test 5-6 days after surgery. Desmopressin (10 microg) was injected i.v. and blood samples were drawn 15, 30, 45 and 60 minutes thereafter. Plasma ACTH and serum cortisol were measured in duplicate by commercially available immunoassays. A positive response to desmopressin was considered to be a plasma ACTH and serum cortisol increment of at least 30% and 20% above baseline, respectively. RESULTS: Mean basal plasma ACTH level was 17.3 +/- 1.7 pmol/l and rose to a peak level of 42.7 +/- 4.9 pmol/l at 15 minutes Mean basal serum cortisol level was 574 +/- 19 nmol/l and rose to a peak level of 814 +/- 28 nmol/l at 45 minutes. ACTH and cortisol incremental changes were inversely correlated with their respective basal levels. Ninety patients (84.1%) had an ACTH and 84 patients (78.5%) had a cortisol response to desmopressin. Several clinical and demographic characteristics were not significantly different among desmopressin responders and non responders, except that basal ACTH and cortisol levels were significantly higher in desmopressin non responders (27.2 +/- 8.3 pmol/l, 781 +/- 86 nmol/l) than in desmopressin responders (15.4 +/- 1.2 pmol/l, 535 +/- 14 nmol/l). Disappearance of the ACTH and cortisol response to desmopressin after surgery occurred in 50 of 87 (57%) ACTH responders and in 57 of 81 (70.4%) cortisol responders, respectively. However, concordance between the desmopressin test and surgical outcome was not complete. Indeed, 18 patients considered in remission still showed an ACTH increase after desmopressin and, on the contrary, four patients with disappearance of the ACTH response had persistence of hypercortisolism. During follow-up monitoring, three patients, who had persistence of the ACTH response to desmopressin, relapsed 24, 38 and 54 months after surgery. CONCLUSIONS: Desmopressin administration elicits a significant rise in ACTH and cortisol levels in the majority but not all patients with Cushing's disease. There is a good, but not complete, concordance between the response to the desmopressin test and the surgical outcome. Our preliminary data show that persistence of the ACTH response to desmopressin in the early postoperative period might be associated with a higher risk of late relapse.