Recommendations for post-surgical thyroid ablation in differentiated thyroid cancer: a 2015 position statement of the Italian Society of Endocrinology.

UNLABELLED: Post-surgical ablation of thyroid remnant with radioactive iodine (RAI) in differentiated thyroid cancer (DTC) is aimed to destroy any thyroid remnant in the thyroid bed (remnant ablation) and any microscopic foci of cancer cells eventually present within the thyroid remnant (adjuvant therapy). The present text is an attempt to offer practice guidelines for the indication of thyroid ablation and the preparation of DTC patients considering the latest achievement in the field and the changing epidemiology of DTC observed in the last 10 years. METHODOLOGY: The executive committee of the Italian Society of Endocrinology appointed a task force of thyroid cancer expert including Nuclear Medicine Physicians and Endocrinologists to provide a consensus on the post-surgical ablation in thyroid cancer patients. The task force had no conflict of interest and had no commercial support. A number of specific topics were selected and the members selected relevant papers by searching in the Pubmed for articles published from 2000 to January 2015. Selected studies were categorized by level of evidence, and the recommendations were graded according to the level of evidence as high (A), moderate (B), or low (C).

Soluble human leukocyte antigen-g and its insertion/deletion polymorphism in papillary thyroid carcinoma: novel potential biomarkers of disease?

INTRODUCTION: Human leukocyte antigen-G (HLA-G), a nonclassical major histocompatibility complex class I antigen, plays a pivotal role in immune tolerance and a paradoxical role in cancers. AIMS: Our aims were to evaluate plasma soluble HLA-G (sHLA-G) concentrations and the 14-bp insertion/deletion polymorphism of the HLA-G gene in patients with papillary thyroid carcinoma (PTC) or Hashimoto's thyroiditis (HT) and to assess the possible association of these parameters with PTC aggressiveness. METHODS: Samples for the analysis of sHLA-G and +14/-14-bp HLA-G polymorphism were obtained from 121 patients with HT and 183 with PTC; 245 gender- and age-matched healthy subjects served as controls. PTC histopathological aggressiveness was defined according to the last American Thyroid Association guidelines. RESULTS: Positive serum antithyroid antibody titers were observed in 22% of PTC patients and lymphocyte infiltration of thyroid parenchyma at histological examination in 21%, whereas both circulating and histological autoimmunity was detectable in 12% of PTC patients. No differences in the +14/-14-bp polymorphism frequencies were observed between the study groups. The prevalence of detectable sHLA-G was lower in healthy controls (52%) as compared with both HT (57%) and PTC (62%) patients. By stratifying the study groups according to sHLA-G level of positive subjects, significantly higher plasma sHLA-G values in PTC (42.9 ± 3.3 ng/ml; P = 0.002) and HT patients (49.1 ± 2.6 ng/ml; P < 0.002) as compared with healthy controls (8.5 ± 1.8 ng/ml) were obtained. Moreover, PTC patients with detectable plasma sHLA-G levels showed a higher aggressive behavior (P < 0.04) than those without. CONCLUSIONS: Although confirming the frequent association between PTC and chronic autoimmune thyroiditis, these data suggest that elevated circulating sHLA-G levels, besides an important signal of alterations of immune homeostasis, may be considered a potential, novel marker of PTC histopathological aggressiveness at diagnosis. Additional studies are needed to confirm the actual role and clinical relevance of the HLA-G complex in PTC development and progression.

SU-E-J-168: 4D-PET for Target Volume Delineation in Respiratory-Gated Radiation Therapy.

PURPOSE: To find an optimized workflow for the use of respiratory-gated PET (4D-PET) in target volume delineation of tumors subject to respiratory-gated radiation therapy. METHODS: 15 patients with lung (11) and pancreas (4) tumors who had FDG-PET-CT for target delineation prior to EBRT were studied. Patients were selected among the group that showed respiratory-induced tumor motion 〉5mm. 4D-PET was performed by means of a Philips Gemini BigBore scanner, using the Varian RPM gating system. An identical system was available at the linac for treatment. The breathing cycle was equally divided in 4 phases, according to a previous study. Since planning was made on a single CT-phase, no ITV was explicitly built from the set of phases. The BTV was identified with SUV=2.2 threshold and the PTV was obtained expanding the BTV by 8mm(S-I), 5mm(A-P) and 3mm(L-R) to account for residual motion and setup errors. The most advantageous CT-phase for treatment planning was then identified by simulating plans on each phase and analyzing the resulting DVHs of OARs (lung, trachea, oesophagus, spinal cord, left ventricle). RESULTS: The observed maximum range of motion was 5.5mm(L-R), 12.3mm(A-P) and 19.2mm(S-I). The standard deviation of the BTV volume in the 4 phases ranged from 6% to 13.7%. V20 (lung) ranged 7.1%-15.2% in inspiration and 7.8%-18.6% in expiration. The mean dose to the oesophagus ranged 0.1-2.2Gy in inspiration and 1.4-2.0Gy in expiration. In general, the dose to OARs was smaller when planning on a single phase than on the overall, respiratory-uncontrolled volume (p-value〈0.05). CONCLUSIONS: The BTV volume was almost constant between phases, confirming that the motion might be described by 4 phases. There was no obvious choice of the optimal phase for treatment planning, suggesting patient-by-patient studies. However, planning and delivery on one phase consistently allowed dose sparing to be obtained compared to non-gated techniques.

The emerging role of sunitinib in the treatment of advanced epithelial thyroid cancer: our experience and review of literature.

Tyrosine kinase receptors have been shown to play an important role in epithelial thyroid tumor growth and angiogenesis. Thyroid cancers commonly present oncogene mutations involved in MAPK kinase pathway like BRAF and RET; they are also frequently dependent on VEGF stimuli. Preliminary clinical experiences suggest a promising role of sunitinib (a tyrosine kinase inhibitor) for the treatment of advanced thyroid cancers. This review deals with the available data on the effect of sunitinib in the treatment of metastatic, radioiodine refractory thyroid cancers. We also report our experience with the off-label use of sunitinib in such patients.

Dual PET/CT with (18)F-DOPA and (18)F-FDG in metastatic medullary thyroid carcinoma and rapidly increasing calcitonin levels: Comparison with conventional imaging.

BACKGROUND: To evaluate the role of a multi-imaging PET with (18)F-DOPA and (18)F-FDG in comparison with conventional imaging (CI) in recurrent medullary thyroid carcinoma (MTC). METHODS: 18 MTC patients who had thyroidectomy were included; they presented with elevated and rapidly increasing calcitonin levels during follow up. CI had revealed metastatic deposits in 9 patients. Patients were referred to us for a PET/CT with (18)F-DOPA and (18)F-FDG. Histologic/cytologic confirmation of recurrent MTC was obtained in at least one PET-positive lesion in all patients. RESULTS: Foci of abnormal uptake were observed in 15 patients at (18)F-DOPA and in 11 at (18)F-FDG; 8 patients showed the same number of positive lesions with both tracers, 2 showed more lesions on (18)F-FDG, 1 was positive at (18)F-FDG alone and 5 at (18)F-DOPA alone. In 3 patients with a DOPA-positive loco-regional relapse a re-operation with curative intent was offered. SUV(max) values were higher for (18)F-FDG compared to (18)F-DOPA (mean 12.7+/-4.1 vs. 5.5+/-2.1, p<0.05). Calcitonin was higher in PET-positive patients compared to PET negative ones, while no significant differences were observed between (18)F-DOPA and (18)F-FDG positive patients. CONCLUSIONS: In MTC patients with rapidly increasing calcitonin levels during follow up, (18)F-DOPA has a good sensitivity and a complementary role with (18)F-FDG PET/CT in detecting metastatic deposits. In our experience, the sensitivity of a multi-imaging (18)F-DOPA &(18)F-FDG PET/CT approach is greater than that obtained with CI. The higher SUV(max) values found with (18)F-FDG in some patients may reflect more aggressive tumors.

Radioiodine ablation: when and how.

Differentiated thyroid cancer (DTC) is the most common endocrine malignancy with the highest mortality although with appropriate treatment has a good long-term prognosis and cure rate. Over the last 30 years there is a worldwide trend showing an increasing incidence of thyroid cancer. In DTC patients, total thyroidectomy has been for many decades routinely followed by the administration of radioiodine (131I) activity to destroy remnant thyroid tissue. Several reasons are in favour to routine ablation of postoperative thyroid remnants. The combination of both surgery and radioiodine has proven as a safe and effective treatment, resulting in improved life expectation and reduced recurrence rate for DTC patients. Recently, however, 131I ablation is not uniformly recommended for cancers smaller than 10 mm, and its use is debated for papillary tumours with diameter between 10 and 20 mm. Indeed, the decision about subsequent 131I thyroid remnant ablation is recommended as "individualized and selective". Even if new evidence has emerged that provides additional support for performing 131I treatment, the possible presence of radioiodine-associated side effects should be not overlooked. Moreover, a lot of discussion has taken place as to whether, and to what extent, 131I may cause secondary malignancies. Blood-based dosimetry is important to avoid surplus bone marrow toxicity while treating DTC patients. In this regard, the availability of a genetically engineered version of recombinant human TSH (rhTSH) provides an alternative tool to enhance serum TSH levels without inducing hypothyroidism. The administration of rhTSH to thyroid cancer patients still on LT4 therapy promotes radioiodine uptake and thyroglobulin production by thyroid cells to an extent comparable with hypothyroidism, preserving patients' quality of life, increasing the renal clearance of 131I and decreasing both the whole body and the blood dose. In this review the authors will discuss the pros and cons of postoperative radioiodine-induced thyroid remnant ablation.

Serum thyroglobulin measurement in the follow-up of patients treated for differentiated thyroid cancer.

Determination of thyroglobulin (Tg) in serum represents a key element in the follow-up of patients treated for differentiated thyroid cancer (DTC). The sensitivity and the specificity of the assay strongly affects the clinical impact. Most of patients are disease-free after thyroidectomy and iodine radioablation; 15% of them show over time persistent or recurrent disease; of these, 5% dies due to worsening of disease. This implies that the follow-up procedures should have a high negative predictive value to reduce as possible the unnecessary diagnostic tools and a high positive predictive value to identify the few patients with persistent/recurrent disease. The recent international guidelines are based on thyroglobulin measurement after thyroid-stimulating hormone (TSH) stimulation. More recent studies suggest that follow up based on serial measurements of basal (i.e. unstimulated) Tg show a higher predictive value than the single measurement after stimulation. Large and multicenter studies are necessary to modify the current guidelines.

The role of 18F-FDG PET/CT in detecting metastatic deposits of recurrent medullary thyroid carcinoma: a prospective study.

AIM: To assess the diagnostic role of 18F-FDG PET/CT performed with a hybrid tomograph in the detection of tumoral deposits of recurrent medullary thyroid carcinoma (MTC). METHODS: Nineteen MTC patients with elevated serum calcitonin levels (58-1350 pg/ml) after first treatment were enrolled (11 F, 8 M, mean age 53.4 years, 14 sporadic MTC, 5 MEN-related MTC). All patients had previously undergone total thyroidectomy and lymphoadenectomy. When referred to us, they were studied with ultrasound (US), 18F-FDG PET/CT, (111)In-pentetreotide scan, and contrast-enhanced whole-body CT (c.e. CT). In 4 patients with equivocal abdominal findings at 18F-FDG PET/CT and/or at c.e. CT, laparoscopy was also performed. RESULTS: 18F-FGD PET/CT depicted metastases in 15 patients, 111In-pentetreotide in 8, c.e. CT in 11, US in 6. In 2 patients, liver micrometastases were detected at laparoscopy only. At a lesion-by-lesion analysis, 18F-FDG PET/CT visualized a total of 26 metastatic deposits, c.e. CT 18, 111In-pentetreotide 12, US 8. Final diagnosis was obtained by cytological or surgical findings. Four patients with evidence of limited metastatic spread to neck/upper mediastinum were re-operated, and in 2 of them serum calcitonin levels normalized. CONCLUSIONS: In our study, 18F-FDG PET/CT was the most sensitive imaging modality in detecting metastases in recurrent MTC patients with increased serum calcitonin levels. Moreover, 18F-FDG PET/CT was useful in some patients to plan a more accurate re-operation. From a diagnostic point of view, a multimodality imaging approach is recommended in recurrent MTC, especially based on the combination of c.e. CT and 18F-FDG PET/CT.

Anticlastogenic effect of Ginkgo biloba extract in Graves' disease patients receiving radioiodine therapy.

BACKGROUND: Chromosomal damage, as assessed by clastogenic factors (CFs) and micronuclei (MN) appearance, after radioiodine therapy of Graves' disease has been reported. OBJECTIVE AND METHODS: Our objective was to evaluate the effect of Ginkgo biloba extract (EGb 761) supplementation on the time course (up to 120 d) of CFs and MN appearance in lymphocytes from patients with Graves' disease after iodine-131 ((131)I) therapy. Patients were randomly assigned to EGb 761 or placebo, in a blinded manner. RESULTS: In the placebo group, MN increased early (P < 0.001) after (131)I, peaking at the 21st day (P = 0.0003) and declining thereafter. In EGb 761-treated patients, MN increased early (P < 0.05), while returning toward baseline value thereafter. Therefore, mean MN increment was significantly higher in the placebo group as compared with EGb 761-treated patients (P < 0.01). Moreover, an early (P < 0.0001) and sustained (up to 35 d; P < 0.001) MN increase induced by CFs was observed in the placebo group. Conversely, in EGb 761-treated patients, MN increase induced by CFs never reached the statistical significance; therefore, the mean of the MN increments was significantly lower than in placebo (P < 0.05). A significant positive correlation between MN maximum increment and the bone marrow dose was observed in the placebo group only (P = 0.03). No significant difference was observed in clinical outcome between the two groups. CONCLUSIONS: EGb 761 supplementation neutralized genotoxic damage induced by radioiodine treatment, without affecting the clinical outcome. Although (131)I therapy is generally safe, our data suggest that Gingko biloba extracts may prevent genetic effects of radioiodine therapy for hyperthyroid Graves' disease.

Clinical relevance of highly sensitive Tg assay in monitoring patients treated for differentiated thyroid cancer.

OBJECTIVE: Serum thyroglobulin (Tg) represents a highly specific biomarker for detecting residual thyroid tissue/recurrence/metastases after treatment for differentiated thyroid cancer (DTC). We evaluated the clinical impact of a highly sensitive Tg assay during routine follow-up of DTC patients. DESIGN: Tg values were measured by a highly sensitive Tg assay during L-T4 suppressive therapy and after recombinant human thyrotropin (rh-TSH) stimulation and were compared with those obtained by using a routinely employed Tg assay. PATIENTS: One hundred and sixty consecutive DTC-treated patients (papillary carcinoma n = 124, follicular carcinoma n = 36) were studied. MEASUREMENTS: Measured variables included neck ultrasonography, (131)I whole body scanning, and Tg assayed by Immulite (Diagnostic Products Corporation, Los Angeles, CA) and by the highly sensitive Access assay (Beckman Coulter, Brea, CA). RESULTS: During L-T4 therapy, measurable Tg was found in only two patients (1% of total) by Immulite and in 23 patients (14% of total) by Access assay. Using the institutional cut-off of 2 microg/l after rh-TSH, a negative response was associated with undetectable Immulite Tg during L-T4 therapy in all patients (negative predictive value, NPV, 100%) and in 137 out of 152 patients with Access assay (NPV 90%). Measurable Tg during L-T4 therapy was found in 17% of positive patients with Immulite and in 100% of patients with Access, respectively. CONCLUSIONS: The use of a highly sensitive Tg assay may represent a useful diagnostic tool for improving the interpretation of Tg results during monitoring of DTC-treated patients for the early detection of recurrence and for optimizing the use of the more expensive rh-TSH test.

Predictive factors of efficacy of the somatostatin analogue octreotide as first line therapy for advanced pancreatic endocrine carcinoma.

About 40% of nonfunctioning pancreatic endocrine carcinomas (NF-PEC) cannot be cured by surgery due to advanced stage disease. Somatostatin analogues have been proposed as first line therapy in these cases. We performed a prospective phase IV study to assess the efficacy of octreotide in advanced NF-PEC and identify factors predictive of response to therapy. Twenty-one consecutive patients with octreoscan-positive advanced-stage well-differentiated NF-PEC were treated with long-acting release octreotide 20 mg i.m. at diagnosis. The immunohistochemical expression of somatostatin receptor 2 (SSTR2) and the quantitative mRNA analysis of SSTR2 and SSTR5 were assessed in 12 tumours. The tumour proliferative fraction was assessed by immunohistochemistry for Ki-67. Eight patients (38%) had stable disease (SD) after a median follow-up of 49.5 months. Thirteen patients (62%) developed progression after a median of 18 months. Tumour progression correlated with a proliferative index>or=5% (P=0.016), weight loss (P=0.006) and absence of abdominal pain (P=0.003) at diagnosis. Other clinical (age, gender and primary tumour resection) or pathological parameters (site, size and liver metastasis) lacked significant correlation with tumour progression. No difference in the amount of SSTR2 mRNA and protein or SSTR5 mRNA was found between tumours that were stable (n=5) and seven tumours that progressed (n=7). Treatment with long-acting release octreotide was associated with stabilization of disease and a good quality of life in 38% of patients. A Ki-67 index>or=5% and/or the presence of weight loss may justify more aggressive therapy without waiting for radiologically proven progression of disease.

Carcinoid crisis induced by receptor radionuclide therapy with 90Y-DOTATOC in a case of liver metastases from bronchial neuroendocrine tumor (atypical carcinoid).

SS receptors are overexpressed in many tumors, mainly of neuroendocrine origin, thus enabling the treatment with SS analogs. The clinical experience of receptor radionuclide therapy with the new analog [90Y-DOTA0-Tyr3 ]-octreotide [90Y-DOTATOC] has been developed over the last decade and is gaining a pivotal role in the therapeutic workout of these tumors. It is well known that some procedures performed in diagnostic and therapeutic management of endocrine tumors, such as agobiopsy and hepatic chemoembolization, can be associated with the occurrence of symptoms related to the release of vasoactive amines and/or hormonal peptides from tumor cell lysis. This is the first report of a severe carcinoid crisis developed after receptor radionuclide therapy with 90Y-DOTATOC administered in a patient affected by liver metastases from bronchial neuroendocrine tumor (atypical carcinoid). Despite protection with H1 receptor antagonists, octreotide and corticosteroids, few days after the therapy the patient complained of persistent flushing of the face and upper trunk, severe labial and periocular oedema, diarrhoea and loss of appetite. These symptoms increased and required new hospitalisation. The patient received iv infusion of octreotide associated with H1 and H2 receptor antagonists and corticosteroid therapy, which induced symptom remission within few days. The case here reported confirms that radionuclide therapy is highly effective in determining early rupture of metastatic tissue and also suggests that pre-medication should be implemented before the radiopeptide administration associated with a close monitoring of the patient in the following days.

Long-term quiescence of ectopic Cushing's syndrome caused by pulmonary neuroendocrine tumor (typical carcinoid) and tumorlets: spontaneous remission or therapeutic effect of bromocriptine?

In 1990, a 55-yr-old woman was admitted to the Medical Department of our hospital for severe hypercortisolism complicated by secondary diabetes mellitus and serious hypokalemia. Although inferior petrosal sinus sampling did not show any significant difference between central and peripheral ACTH concentration, suggesting an ectopic source of ACTH secretion, diagnostic imaging was negative and Cushing's disease due to hyperplasia of the pituitary intermediate lobe was suspected. Medical treatment with bromocriptine and cyproheptadine led to a rapid and stabile normalization of adrenal function, so that after two months cyproheptadine was stopped and bromocriptine was tapered to a smaller dose. An attempt to discontinue medical treatment, carried out 3 yr later, was followed by a quick increase of ACTH and cortisol levels, which were normalized by the resumption of the bromocriptine. Adrenal function remained normal until 1994 when hypercortisolism relapsed despite the treatment. Chest radiography and computed tomography (CT) scan detected a 6 mm nodule in the middle lobe of the lung which proved to be a neuroendocrine tumor, with immunohistochemical positivity for ACTH. Nests of neuroendocrine cells (tumorlets) were also demonstrated in the surrounding lung tissue. After the lobectomy, the patient recovered completely from Cushing's syndrome and no symptoms and/or signs of recurrence have been observed over the subsequent follow-up period. Although cyclical spontaneous Cushing's syndrome could not be excluded, there was strong evidence that medical treatment with bromocriptine might have played a key role in long-lasting remission. To our knowledge, this is the second case described in literature of Cushing's syndrome caused by neuroendocrine lung tumor responsive to bromocriptine.

Oxidative and genotoxic damage after radio-iodine therapy of Graves' hyperthyroidism.

PURPOSE: To evaluate genetic damage and oxidative stress following a single therapeutic dose of 131I in Graves' disease patients monitored up to 180 days after treatment. MATERIALS AND METHODS: Genetic damage induction was estimated as the increase in micronuclei in peripheral lymphocytes of patients. As indicators of radiogenic oxidative stress, vitamin E and lipoperoxide levels were assessed in the plasma of patients, as well as the release of plasmic clastogenic factors measured by the induction of micronuclei in vitro in peripheral lymphocytes of a healthy donor. RESULTS: Vitamin E depletion lasted at least 3 days and the basal level was restored within 7 days. No statistically significant variations were observed in lipoperoxide plasma levels. A sharp increase of micronuclei in the peripheral lymphocytes of patients was correlated (p < 0.001) with the release of clastogenic factor in the plasma. The highest micronucleus value was negatively correlated (p < 0.03) with the lowest vitamin E level observed in each patient. CONCLUSIONS: Micronuclei induction was the direct consequence not only of the energy deposition of 131I on the genetic material, but also of oxidative stress, likely via the release of clastogenic factor.

Relationship between renal function and blood level of chromogranin A.

Chromogranin A (CGA) is a low MW (49,000) acidic hydrophilic protein. It is synthesized in the chromaffm granules of the neuroendocrine cells, and has been found circulating in the blood of healthy subjects. The aim of this study was to assess the relationship between serum levels of CGA and renal function. One hundred two renal patients (45 M and 57 F; age 14-76 years, mean 52) participated in the study. Glomerular filtration rate (GFR) was measured by the bladder cumulative method, using 99mTc-DTPA as a tracer. Blood CGA was determined by RIA. Plasma creatinine, beta2microglobulin (beta2m) and tumor associated trypsin inhibitor (TATI) were also determined. The reduction in renal function was associated with an increase in all of the above studied parameters. In patients with advanced renal failure (GFR <20 mL/min) CGA levels increased by 22-fold as compared to the patients with normal renal function (GFR> 100 mL/min). The other studied parameters were also increased but to a lesser degree, e.g., TATI 14-, beta2m 8- and creatinine 5-fold. The results of this study demonstrate that renal handling of the CGA is similar to other low MW proteins, and it accumulates in the blood in renal failure.

The clinical relevance of serum CYFRA 21-1 assay in patients with ovarian cancer.

CYFRA 21-1 assay, which detects serum fragments of cytokeratin 19, has been widely assessed as a serum marker of several malignancies. Preoperative serum CYFRA 21-1 levels were retrospectively measured in 60 patients with ovarian cancer and in 59 control patients with benign ovarian disease. CYFRA 21-1 levels were also serially measured in 90 serum samples drawn from patients with advanced (FIGO stage III-IV) ovarian cancer followed after surgery and chemotherapy. Preoperative serum CYFRA 21-1 levels were higher in patients with ovarian cancer compared with controls (median, range = 2.6, 0.1-51.4 ng/ml versus 0.4, 0.0-3.6 ng/ml, P < 0.0001), and among the former, antigen values were higher in the 39 patients with advanced-stage than in the 21 patients with early (FIGO stage I-II) disease (P < 0.0001). In advanced ovarian cancer patients, the 25%, 50%, and 75% quantiles of preoperative CYFRA 21-1 levels were 1.9, 4.8 and 14.4 ng/ml, respectively. Preoperative CYFRA 21-1 levels were lower in the 11 patients who achieved a pathologic complete response at second-look compared with those who had clinically or surgically detectable persistent disease after first-line chemotherapy (median, range 1.9, 0.6-9.2 ng/ml versus 10.2, 0.1-51.4 ng/ml, P = 0.007). The pathologic complete response rate was significantly greater in patients with low preoperative CYFRA 21-1 levels compared with those with elevated CYFRA 21-1 levels at any cut-off limit for the antigen (1.9, 4.8 and 14.4 ng/ml). However, Cox regression analysis failed to detect a significant association between preoperative CYFRA 21-1 assay and survival. As for the follow-up of advanced ovarian cancer patients, CYFRA 21-1 levels were higher in the 42 samples drawn from patients with clinically detectable disease compared with the 48 specimens collected from patients with no clinical evidence of disease (median, range = 1.15, 0.3-40.7 ng/ml versus 0.4, 0.1-9.1 ng/ml, P < 0.0001). In conclusion, preoperative serum CYFRA 21-1 assay appears to be predictive of response to chemotherapy, but not prognostic of survival, for patients with advanced ovarian cancer. Moreover, the serial measurement of CYFRA 21-1 levels might have a potential clinical relevance for the assessment of disease status in patients followed after surgery and chemotherapy.

A new human chromogranin 'A' immunoradiometric assay for the diagnosis of neuroendocrine tumours.

We investigated whether plasma chromogranin A (CgA), measured by a new immunoradiometric assay, may be a sensitive and specific marker of phaeochromocytoma and of other neuroendocrine tumours. This study involved 121 patients of whom 20 with phaeochromocytoma, 28 with other neuroendocrine tumours (19 gastroenteropancreatic tumors, 3 medullary thyroid and 6 small cell lung carcinomas), 25 with solid nonfunctioning adrenocortical tumours and 48 with essential hypertension. In addition, 130 normal subjects were taken as controls. Plasma catecholamines were measured by using high-performance liquid chromatography, and CgA by a two-site sandwich immunoradiometric assay involving monoclonal antibodies raised against the unprocessed central domain (145-245) of human CgA. Plasma CgA in controls (49.0 +/- 3.1 ng ml(-1), mean +/- SE) and in essential hypertensives (50.8 +/- 3.5 ng ml(-1)) was lower (P< 0.0001) than in adrenocortical tumours (91.8 +/- 13.2 ng ml(-1)), in phaeochromocytomas (254 +/- 49 ng ml(-1)) and in patients with other neuroendocrine tumours (469 +/- 84 ng ml(-1)). Plasma CgA and catecholamines identified 13 and 18 out of 20 phaeochromocytomas with sensitivity of 65% and 90%, respectively. Combined measurement of both markers improved sensitivity up to 100%. In the other neuroendocrine tumours, CgA was abnormal in 23/28 cases (sensitivity 82%) and in 6 it was the only circulating marker of disease. In gastroenteropancreatic tumours, CgA measurement identified all cases (sensitivity 100%). Specificity of CgA in patients with essential hypertension was 98%. In conclusion, CgA determination showed high sensitivity in identifying gastroenteropancreatic tumours and, in association with catecholamines, in detecting patients with phaeochromocytoma. CgA sometimes appeared to be the only circulating marker of disease. Since the specificity of CgA proved to be excellent, this assay may be useful for diagnosis both of functioning and non-functioning neuroendocrine tumours.

Octreotide acetate long-acting release in patients with metastatic neuroendocrine tumors pretreated with lanreotide.

BACKGROUND: In the present study we investigated the efficacy and tolerability of i.m. octreotide acetate (octreotide LAR) in patients with metastatic neuroendocrine tumors (NETs) previously treated and failed on i.m. lanreotide. PATIENTS AND METHODS: Fifteen patients (8 females, 7 males, median age 67 years, range 28-81 years) with metastatic NETs (8 endocrine pancreatic tumors, 7 midgut carcinoids) were enrolled in the study. All patients were in progressive disease (objective: 11 patients, symptomatic: 10 patients, biochemical: 11 patients) after treatment with slow release lanreotide, 30 mg every 14 days for a median time of 8 months (range 3-19 months). All patients had measurable disease; 12 patients had elevated serum and/or urine markers and 11 were symptomatic. Octreotide scintigraphy was positive in 13 of 15 patients. Octreotide LAR was administered as i.m. injection at the dose of 20 mg every four weeks until disease progression. RESULTS: An objective partial response (PR) was documented in one patient (7%), no change (NC) in six (40%), and progressive disease (PD) in eight patients (53%). The PR was observed in one patient with non-functioning endocrine pancreatic tumor with progressive liver and lymph node metastases after 16 months of i.m. lanreotide therapy. The median duration of disease stabilization was 7.5 months (range 6-12+ months). The overall biochemical response rate was 41%, including CRs (33%) and PRs (8%); biochemical responses were observed in carcinoids as well as in endocrine pancreatic tumors; the median duration of response was 5 months for CRs and 7.5 months for PRs. The overall symptomatic response rate was 82%. The median duration of response for diarrhoea, abdominal pain, or both was 6.5 months (range 3-12+ months). Improvement in performance status (PS) was obtained in 5 of 11 patients with PS of 1 at study entry. Median duration of octreotide LAR treatment was seven months (range 3-12+ months). No serious adverse events were reported; mild side effects were reported in 26% of patients. CONCLUSIONS: Octreotide LAR 20 mg shows significant efficacy in terms of objective response rate (PR + SD), biochemical and symptomatic control in patients with metastatic NETs of the GEP system pretreated and progressing on slow release lanreotide.

Long-acting depot lanreotide in the treatment of patients with advanced neuroendocrine tumors.

Long-acting depot forms of somatostatin analogs administered by intramuscular injections are now available for the treatment of neuroendocrine tumors (NETs). In the present study, we investigated the efficacy and tolerability of a slow-release form of lanreotide in patients with advanced NETs. From July 1996 to January 1999, 25 patients with advanced NETs (12 carcinoids, 13 endocrine pancreatic tumors) were enrolled in the study. Thirteen patients were pretreated with subcutaneous octreotide, chemotherapy, or hepatic metastasis alcoholization. All the patients had measurable disease. Seventeen patients were symptomatic and 20 patients had elevated serum and/or urine markers. Octreotide scintigraphy was positive in 23 of 25 patients. Lanreotide was administered as intramuscular injections at the dose of 30 mg every 2 weeks until there was objective, biochemical, or symptomatic tumor progression. Objective partial responses (PRs) were documented in 2 patients (8%), whereas 10 patients (40%) had tumor stabilization. The PRs were observed in patients with midgut carcinoids, of whom one was pretreated with subcutaneous octreotide. The response duration was 21+ and 24+ months in responding patients; the median duration of disease stabilization was 8.5 months (range, 4-21+). The overall biochemical response rate was 42%, including 2 complete responses (CRs) (10.5%) and 6 PRs (31.5%); all biochemical responses were observed mostly in patients with carcinoid tumors; the duration of response was 18+ and 30+ months for CRs; the median duration of biochemical response was 7 months (range, 4-18+) for PRs. The overall symptomatic response rate was 70% with a median duration of 7.5, 18, and 18+ months for diarrhea, abdominal pain, and flushing, respectively. Median duration of lanreotide treatment was 10 months (range, 2-30+). No significant side effects were reported. Depot lanreotide 30 mg shows significant efficacy in terms of objective response rate and in biochemical and symptomatic control, in pretreated patients as well as nonpretreated patients with advanced NETs. Tolerability is good, with good patient compliance.