An Open-label Phase I/IIa Clinical Trial of 11ß-HSD1 Inhibitor for Cushing's Syndrome and Autonomous Cortisol Secretion.

CONTEXT: 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors demonstrate antimetabolic and antisarcopenic effects in Cushing's syndrome (CS) and autonomous cortisol secretion (ACS) patients. OBJECTIVE: To confirm the efficacy and safety of S-707106 (11ß-HSD1 inhibitor) administered to CS and ACS patients. DESIGN: A 24-week single-center, open-label, single-arm, dose-escalation, investigator-initiated clinical trial on a database. SETTING: Kyushu University Hospital, Kurume University Hospital, and related facilities. PATIENTS: Sixteen patients with inoperable or recurrent CS and ACS, with mildly impaired glucose tolerance. INTERVENTION: Oral administration of 200 mg S-707106 after dinner, daily, for 24 weeks. In patients with insufficient improvement in oral glucose tolerance test results at 12 weeks, an escalated dose of S-707106 (200 mg twice daily) was administered for the residual 12 weeks. MAIN OUTCOME MEASURES: The rate of participants responding to glucose tolerance impairment, defined as those showing a 25% reduction in the area under the curve (AUC) of plasma glucose during the 75-g oral glucose tolerance test at 24 weeks. RESULTS: S-707106 administration could not achieve the primary endpoint of this clinical trial (>20% of responsive participants). AUC glucose decreased by -7.1% [SD, 14.8 (90% CI -14.8 to -1.0), P = 0.033] and -2.7% [14.5 (-10.2 to 3.4), P = 0.18] at 12 and 24 weeks, respectively. S-707106 administration decreased AUC glucose significantly in participants with a high body mass index. Body fat percentage decreased by -2.5% [1.7 (-3.3 to -1.8), P < 0.001] and body muscle percentage increased by 2.4% [1.6 (1.7 to 3.1), P < 0.001]. CONCLUSIONS: S-707106 is an effective insulin sensitizer and antisarcopenic and antiobesity medication for these patients.

Medical management of secretory syndromes related to gastroenteropancreatic neuroendocrine tumours.

Although recent epidemiological evidence indicates that the prevalence of non-functioning gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) is rising, a significant number of GEP-NETs still present with symptoms related to the secretion of biologically active substances leading to the development of distinct clinical syndromes. In the past, these syndromes were associated with substantial morbidity and mortality due to the lack of specific therapies; however, since the introduction of long-acting somatostatin analogues and medications such as proton pump inhibitors, their control has been greatly improved. As a result, nowadays, the main cause of morbidity and mortality in GEP-NETs is mostly directly related to tumour growth and the extent of metastatic disease. However, in some patients with functioning tumours and extensive disease, control of the secretory syndrome still remains problematic, necessitating the employment of several cytoreductive techniques, which may not always be sufficient. Recently, new agents directed against tumour growth, or exerting increased binding activity to receptors expressed in these tumours, or interfering with the synthetic pathway of some of the compounds secreted by these tumours, have been developed. Since there are no specific guidelines addressing the totality of the management of the secretory syndromes related to GEP-NETs, this review aims at critically analysing the medical management of previously recognised secretory syndromes; it also addresses areas of uncertainty, assesses the newer therapeutic developments and also addresses recently described but poorly characterised secretory syndromes related to GEP-NETs.

Esophageal small-cell carcinoma with syndrome of inappropriate secretion of antidiuretic hormone.

Small-cell carcinoma (SCC) of the esophagus is rare, and its clinical characteristics remain poorly understood. A 54-year-old man was given a diagnosis of esophageal SCC and underwent esophagectomy. Four months after surgery, he was admitted to our hospital because of rapidly developing hyponatremia. Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) due to extensive recurrence of SCC was diagnosed. Combined chemotherapy with irinotecan and cisplatin has dramatically reduced metastatic tumors, and it was concomitantly effective for SIADH. This case demonstrates that esophageal SCC could induce SIADH as a paraneoplastic syndrome and that the above combined chemotherapy was feasible and effective.

Small cell neuroendocrine carcinoma of the ethmoid sinuses presenting with generalized seizure and syndrome of inappropriate antidiuretic hormone secretion: a case report and review of literature.

Small cell neuroendocrine carcinoma of the paranasal sinuses is extremely rare. We present a case of small cell neuroendocrine carcinoma of the ethmoid sinuses associated with syndrome of inappropriate antidiuretic hormone secretion that resolved after chemotherapy, followed by a review of the literature.

[Long-term follow-up of patients with suprasellar germinomas]. / Langzeitverlauf bei Patienten mit suprasellären Germinomen.

BACKGROUND: Suprasellar germinomas are rare intracranial neoplasms, which mainly occur in children and adolescents and manifest with endocrine symptoms and/or compression syndromes. PATIENTS AND METHODS: The clinical, hormonal and morphological findings as well as treatment and complications were investigated in seven patients (six male, one female) with germinomas. RESULTS: Mean age at diagnosis was 19.7 years (range 15-32 years). First disease-related symptoms were diabetes insipidus (three patients), loss of libido (two patients), pseudopubertas praecox (one patient), and dwarfism (one patient). However, decisive symptoms leading to final diagnosis were visual disturbances (five patients), pubertas tarda (one patient), and hypogonadism (one patient). All patients were treated by transcranial radiation with a dose of 40-54 Gy. One patient received additional chemotherapy with cisplatin, etoposide, and ifosfamide (PEI). Patients were followed up for 14.6 years (range 7-27 years). Intracranial and pulmonary relapses were observed in two patients. Panhypopituitarism and diabetes insipidus were seen in all patients after treatment. Two patients suffered from loss of vision, two further patients from unilateral amaurosis. One patient developed epilepsy and persistent cognitive impairment. Long-term follow-up shows that two patients died from recurrent disease and decompensated liver cirrhosis, respectively. The other patients are long-term survivors. Full social integration with employment was possible in one case. CONCLUSION: Suprasellar germinomas cause endocrine symptoms during early tumor stages, however, diagnosis is generally established when ocular symptoms related to tumor compression are already present. Long-term survival is characterized by panhypopituitarism, diabetes insipidus and, partly, ocular or cerebral defects.

[Monosymptomatic hyperthyroidism and TSH-producing adenoma: successful therapy with octreotide]. / Monosymptomatische Hyperthyreose und TSH-produzierendes Adenom: Erfolgreiche Therapie mit Octreotid.

HISTORY AND FINDINGS: Magnetic resonance imaging (MRI) of the central nervous system was performed on a 72-year-old woman who was hyperthyroid without suppression of the thyroid-stimulating hormone (TSH) and had complained of a recent onset of headaches. MRI demonstrated a space-occupying lesion, 1 cm in diameter, in the anterior pituitary. The clinical symptoms were marked by a long-standing monosymptomatic illness of rapidly changing mood swings with depressive and manic phases. INVESTIGATIONS: Endocrinological-biochemical tests showed hyperthyroidism (fT3 10.55 pmol/l and fT4 39 pmol/l) but no TSH suppression (TSH: 2.9 microU/ml). Octreotide scintigraphy documented an activity-rich area in the anterior pituitary and the upper anterior mediastinum. Mediastinal MRI revealed a 5 cm space-occupying mass lying on the right atrium. 131I scintigraphy identified the mass as a retrosternal goitre. TREATMENT AND COURSE: As an operation on the anterior pituitary would have carried a high risk for the patient who was in a poor general condition and she had refused to be operated, treatment with octreotide, a long-acting somatostatin analogue, was initiated. This achieved a euthyroid state with partly suppressed TSH, and the patient's emotional swings ceased. CONCLUSION: If hyperthyroidism coexists with non-suppressed TSH levels, a TSH-producing hypophyseal adenoma should be considered in the differential diagnosis despite its rarity. Octreotide administration is an effective and safe treatment and is the method of choice, especially when there are contraindications to surgical resection of the anterior pituitary.

Transient regression of an intracranial germ cell tumour after intravenous steroid administration: a case report.

Magnetic resonance imaging showed transient regression of the lesion after intravenous steroid administration in a patient with intracranial multifocal germ cell tumour. Prominent lymphocyte infiltration of the tumour was seen at histological examination and presumably accounts for the regression. Germ cell tumour must be included in the differential diagnosis of intracranial mass lesions sensitive to steroids.

A prospective multicenter trial of octreotide in 24 patients with visual defects caused by nonfunctioning and gonadotropin-secreting pituitary adenomas. French Multicenter Octreotide Study Group.

OBJECTIVE: The somatostatin analog octreotide has been demonstrated to improve optic tract compression caused by pituitary macroadenomas within hours of its administration and/or reduce tumor size in some patients. We report the results of a prospective multicenter study of the effects of octreotide on visual function and tumor size in patients with nonfunctioning pituitary adenomas or gonadotropin-secreting adenomas. METHODS: Twenty-four patients with visual defects caused by histologically confirmed macroadenomas were administered octreotide via continuous subcutaneous infusion, as follows: 100 micrograms the 1st day and, if necessary, 200 micrograms the 2nd and then 100 or 200 micrograms three times daily if visual function improved. Vision was assessed after 4 days, 1 month, and 2 months, including tumor size evaluation. Visual improvement was defined by a net gain of at least 2/10 in acuity and/or of more than 20% of the surface of one isopter (a reduction in tumor volume of > or = 20% of the initial measurement); opposite changes were defined as deterioration. RESULTS: Visual improvement was noted in 13 of 24 patients, 10 of 23 patients and 9 of 22 patients, and was not noted in 11 of 24 patients, 14 of 23 patients, and 13 of 22 patients after 4 days, 1 month, and 2 months, respectively. After 2 months, three adenomas had shrunk, three had not changed in size, and one had increased; visual function improved in the seven patients with these adenomas. Octreotide was discontinued in 13 patients for lack of efficacy. CONCLUSION: The incidence of visual improvement and tumor shrinkage noted in this study was higher than previously reported. Our data suggest that early onset of visual improvement might help in deciding which patients profit from octreotide. However, concomitant gain in visual acuity with deterioration in visual fields or visual improvement with an increase (moderate) in tumor size can occur.

Somatostatin receptor scintigraphy in patients with pituitary adenoma.

Presence of high-affinity somatostatin (SST) receptors in most endocrine tumor cells allow in vivo scintigraphic visualization of these neoplasms after intravenous administration of a radionuclide-labeled somatostatin analog. 111In-octreotide is at present the most often used substance for imaging of the SST receptor expression in vivo. The aim of this study is to investigate the correlation between presence of in vivo scintigraphically detectable SST receptors in pituitary tumors and clinical parameters such as patients' age, tumor size, hormonal hypersecretion, and response to octreotide therapy. Forty-two-consecutive patients were enrolled in this trial. Twenty-five of them had nonsecreting pituitary tumors, 11 were acromegalic, and 6 had macro- or microprolactinoma. Scintigraphic images of the head were obtained at 10 min and 24 hours after injection of the radionuclide. In 23 patients, no specific binding of 111In-octreotide was found. Five patients showed a weak positive, 5 had a positive, and 9 a strong positive signal in the region of interest. Uptake of octreotide was significantly correlated with tumor size and age (p < 0.01). Small-size pituitary adenomas were most likely to be scintigraphically receptor-negative, while large suprasellar tumors tended to exhibit a rather strong receptor positivity. Statistical analysis of the data could not confirm the hypothesized correlation between endocrine activity of the pituitary tumors and the scintigraphically proven SST receptor expression in vivo. A positive Octreoscan was not predictive for the result of octreotide therapy.

[Somatostatin receptor scintigraphy in preoperative diagnosis of the site of endocrine gastrointestinal tumors]. / Die Somatostatinreceptor-Szintigraphie in der präoperativen Lokalisationsdiagnostik endokriner gastrointestinaler Tumoren.

To determine the value of somatostatin-receptor scintigraphy in the localization of various endocrine gastrointestinal tumors, we compared the results obtained with this new technique with the results obtained with computed tomography and sonography. We could not find an overall advantage of somatostatin-receptor scintigraphy as compared to computed tomography or sonography in the localization of intestinal carcinoids (n = 13), gastrinomas (n = 12), functionally non-active endocrine pancreatic tumors (n = 8) and various other endocrine pancreatic tumors (n = 4). In 2 patients with endocrine pancreatic tumors however, the tumors were localized preoperatively only by somatostatin-receptor scintigraphy. Somatostatin-receptor scintigraphy may occasionally be helpful in the localization of gastrointestinal endocrine tumors if these tumors are not localized by conventional imaging studies. Somatostatin-receptor scintigraphy does not solve the problem to localize small endocrine tumors.

Paraneoplastic Cushing's syndrome as an adverse prognostic factor in patients who die early with small cell lung cancer.

The potential role of paraneoplastic Cushing's syndrome (CS) was assessed on the clinical course of patients with small cell lung cancer. A retrospective comparison was done of complications and survival rates according to the presence or absence of CS in patients with small cell lung cancer who died within 90 days of initial administration of chemotherapy. The setting was a comprehensive cancer center. Eleven patients with clinical and/or biochemical features of CS were identified from among 90 patients who presented between 1979 and 1989 with previously untreated small cell lung cancer. The group with CS and the control patients were compared in terms of clinicopathologic prognostic factors, treatment, and outcome. Patients with CS were comparable to the control patients in all prognostic factors, including tumor stage and cancer treatment. Eighty-two percent of patients with CS (nine of 11) died within 14 days of initiation of chemotherapy compared with 25% of the control patients (19 of 77). The median survival from initiation of chemotherapy was 12 days for the 11 patients with CS and 27 days for the 77 control patients. In 45% of the patients with CS (five of 11), death was attributed to opportunistic fungal or protozoal infection compared with 8% of control patients (six of 77). Paraneoplastic CS is a previously unrecognized adverse prognostic factor for patients with small cell lung cancer. Those with both small cell lung cancer and CS have severe opportunistic infections soon after the initiation of chemotherapy, leading to clinical deterioration and death before antineoplastic benefit from chemotherapy can be achieved. Biochemical control of CS for at least 1 to 2 weeks before initiation of chemotherapy may ameliorate the poor prognosis.

The use of somatostatin analog in gastroenteropancreatic tumors other than carcinoid.

We have used the gastrinoma syndrome to examine the effects of SMS. Acutely, SMS decreased acid secretion and restored the BAO/MAO to normal in eight of eight patients. Basal and secretin-stimulated gastrin responses were suppressed but not normalized. Treatment for up to 2 years with SMS controlled symptoms, suppressed serum gastrin, and suppressed acid secretion. Treatment for 1 year or longer decreased tumor secretion of gastrin and diminished basal acid secretion, an effect that persisted for 48 hours after withdrawal of SMS. SMS treatment arrested progression of tumor growth only in patients in whom there was a reduction in gastrin and gastric acid secretion. In patients with metastatic disease who had high levels of gastrin, SMS treatment for 5 to 24 months did not inhibit tumor growth or decrease gastrin levels. In those patients in whom a reduction in the blood flow to liver tumors was shown angiographically, there was a progressive improvement in hormone secretion and in tumor size in the ensuing year of treatment, suggesting that a major target of SMS is that vascular supply of the tumors. Tumors shown to produce peptides other than gastrin, for example ACTH, were found to be markedly resistant to the action of SMS and continued to grow in an unbridled manner.

Inhibition of follicle-stimulating hormone secretion from gonadotroph adenomas by repetitive administration of a gonadotropin-releasing hormone antagonist.

As a preliminary step in searching for a pharmacological treatment for gonadotroph adenomas, we administered the GnRH antagonist analog Nal-Glu GnRH to five patients, four men and a woman, with FSH-secreting gonadotroph adenomas in order to determine its effect on FSH secretion. Administration of a single 10-mg dose of Nal-Glu GnRH to four of the patients produced a significant decrease in the serum FSH concentration in two patients and returned the FSH level to normal in only one. Administration of 5 mg Nal-Glu every 12 h for 7 days, however, produced a significant (P less than 0.001) decrease, and to within the normal range, in four of the five patients (mean +/- SEM, 32.7 +/- 5.6 IU/L during the 3 days before treatment and 9.8 +/- 1.4 IU/L during the last 3 days of treatment). Also, in response to the 7-day treatment, LH fell significantly in all five patients, alpha-subunit fell in three, and testosterone fell in all four men. Administration for 6 weeks of the GnRH agonist analog leuprolide did not decrease the serum FSH concentration of one of the patients whose serum FSH did decrease in response to Nal-Glu GnRH. We conclude that repetitive administration of Nal-Glu GnRH may often inhibit FSH secretion by gonadotroph adenomas and that FSH secretion by gonadotroph adenomas may be dependent on endogenous GnRH secretion.

Inhibition of human adrenal androgen secretion by ketoconazole.

The effect of ketoconazole on adrenal androgen secretion was examined in 15 patients with elevated serum androgens. In a dose of 600 mg per day orally ketoconazole inhibited the biosynthesis of all measured androgens. The mean reduction in serum levels of dehydroepiandrosterone sulfate was 32%, of dehydroepiandrosterone 54%, of androstenedione 52%, and of testosterone 43%; mean serum levels of cortisol only fell by 19%. The reduction in serum androgen levels was first significant 24 h after beginning of treatment and persisted as long as the drug was administered. We conclude that ketoconazole inhibits adrenal androgen biosynthesis more pronouncedly than cortisol biosynthesis more pronouncedly than cortisol biosynthesis. This might be of clinical benefit in the treatment of hirsutism and other states of androgen hypersecretion.

Suppression of ectopic adrenocorticotropin secretion by the long-acting somatostatin analog octreotide.

The long-acting somatostatin analog (octreotide) was administered to a 37-yr-old woman with the ectopic ACTH syndrome. The patient had diffuse metastatic spread of a nonpituitary tumor, presumably of pancreatic origin, and severe and rapidly progressive hypercortisolism with extreme myopathy, hypokalemia, and diabetes mellitus. Plasma ACTH and lipotropin levels and 24-h urinary cortisol excretion were greatly elevated [218 pg/mL (48 pmol/L), 1340 pg/mL (220 pmol/L), and up to 830 micrograms/24 h (2290 nmol/day), respectively]. Urinary cortisol excretion decreased to normal within 3 days after the initiation of octreotide therapy (150, 300, and 600 micrograms/day), and plasma ACTH and lipotropin levels also decreased. Urinary cortisol excretion remained normal for 2 months during chronic octreotide therapy, and her general condition improved dramatically. The only side-effect was a slight increase in the number of bowel movements. Tumor progression, however, was not controlled, and she eventually died of hepatic insufficiency. These data indicate that octreotide can be a highly effective treatment for patients with the ectopic ACTH syndrome.

Total suppression of cortisol excretion by ketoconazole in the therapy of the ectopic adrenocorticotropic hormone syndrome.

Ketoconazole, an antifungal imidazole derivative, has been shown to inhibit adrenal steroidogenesis in vitro and in vivo. This has led to its use clinically as an effective treatment for various forms of Cushing's syndrome. The clinically effective doses have been reported to be between 800 to 1,200 mg per day, usually without glucocorticoid replacement. Herein is reported the first case of Cushing's syndrome due to ectopic adrenocorticotropic production from a metastatic carcinoid tumor of the thymus that was treated with ketoconazole. Urinary cortisol excretion was totally suppressed at the initial dose and optimal control was achieved with relatively low doses of ketoconazole (200 to 400 mg per day), along with dexamethasone replacement. Use of glucocorticoid replacement is advisable in this setting to avoid symptomatic hypoadrenalism.

Positive iodine-131 6 beta-iodomethyl-19-norcholesterol (NP-59) adrenal images can precede return of adrenocortical function after o,p' DDD treatment.

A patient with bilateral adrenal hyperplasia, due to the ectopic adrenocorticotrophic hormone (ACTH) syndrome, received a 3-month course of treatment with 1,1 dichloro-2(o-chlorophenyl)-2-(p-chlorophenyl)ethane (o,p' DDD), which caused adrenal hypofunction requiring steroid therapy. Eleven months later, Cushing's syndrome recurred. His CT scan showed a left adrenal gland that was enlarged and a normal-sized right adrenal gland. However, the NP-59 image showed increased uptake by both glands. Venous effluent was sampled from each adrenal vein. The plasma cortisol level from the left gland was 1392 ng/ml, and that from the right gland was 667 ng/ml. The latter value was not significantly different from the values obtained at peripheral sites (517-744 ng/ml). In the course of recovery from o,p' DDD damage, the ability of the adrenal gland to take up NP-59 may be restored before the return of its biosynthetic and secretory functions. Serial NP-59 adrenal images can anticipate the recurrence of Cushing's syndrome after adrenolytic therapy, thereby permitting early retreatment.