Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases.

BACKGROUND: This multi-centre phase II clinical trial is the first prospective evaluation of radioembolisation of patients with colorectal liver metastases (mCRC) who failed previous oxaliplatin- and irinotecan-based systemic chemotherapy regimens. METHODS: Eligible patients had adequate hepatic, haemopoietic and renal function, and an absence of major hepatic vascular anomalies and hepato-pulmonary shunting. Gastroduodenal and right gastric arteries were embolised before hepatic arterial administration of yttrium-90 resin microspheres (median activity, 1.7 GBq; range, 0.9-2.2). RESULTS: Of 50 eligible patients, 38 (76%) had received > or =4 lines of chemotherapy. Most presented with synchronous disease (72%), >4 hepatic metastases (58%), 25-50% replacement of total liver volume (60%) and bilateral spread (70%). Early and intermediate (>48 h) WHO G1-2 adverse events (mostly fever and pain) were observed in 16 and 22% of patients respectively. Two died due to renal failure at 40 days or liver failure at 60 days respectively. By intention-to-treat analysis using Response Evaluation Criteria in Solid Tumours, 1 patient (2%) had a complete response, 11 (22%) partial response, 12 (24%) stable disease, 22 (44%) progressive disease; 4 (8%) were non-evaluable. Median overall survival was 12.6 months (95% CI, 7.0-18.3); 2-year survival was 19.6%. CONCLUSION: Radioembolisation produced meaningful response and disease stabilisation in patients with advanced, unresectable and chemorefractory mCRC.

Count-rate analysis from clinical scans in PET with LSO detectors.

The purpose of optimising the acquisition parameters in positron emission tomography is to improve the quality of the diagnostic images. Optimisation can be done by maximising the noise equivalent count rate (NECR) that in turn depends on the coincidence rate. For each bed position the scanner records coincidences and singles rates. For each patient, the true, random and scattered coincidences as functions of the single count rate(s) are determined by fitting the NEMA (National Electrical Manufacturers Association) 70 cm phantom count rate curves to measured clinical points. This enables analytical calculation of the personalised PNECR [pseudo NECR(s)] curve, linked to the NECR curve. For central bed positions, missing activity of approximately 70% is estimated to get maximum PNECR (PNECR(max)), but the improvement in terms of signal-toz-noise ratio would be approximately 15%. The correlation between patient weight and PNECR(max) is also estimated to determine the optimal scan duration of a single bed position as a function of patient weight at the same PNEC. Normalising the counts at PNECR(max) for the 70 kg patient, the bed duration for a 90 kg patient should be 230 s, which is approximately 30% longer. Although the analysis indicates that the fast scanner electronics allow using higher administered activities, this would involve poor improvement in terms of NECR. Instead, attending to higher bed duration for heavier patients may be more useful.

A multicentric phase II clinical trial on intra-arterial hepatic radiotherapy with 90yttrium SIR-spheres in unresectable, colorectal liver metastases refractory to i.v. chemotherapy: preliminary results on toxicity and response rates.

BACKGROUND: In patients locally progressing after two lines of chemotherapy, some locoregional approaches showed encouraging results in terms of local control of disease. The aim of our study was to evaluate toxicity, clinical response and quality of life in 48 patients with unresectable colorectal liver metastases submitted to selective internal radiotherapy (SIRT). MATERIALS AND METHODS: Up to now 35 patients with unresectable colorectal liver metastases, refractory to two lines of chemotherapy, underwent intra-arterial infusion of resin microspheres with yttrium-90 (SIR-spheres). Pre-treatment evaluation included a CT scan, blood tests, a PET scan and arteriography of celiac trunk, hepatic and superior mesenteric artery; extrahepatic uptakes and pulmonary shunts more than 10% were excluded by a Scinti-scan. The gastroduodenal artery was embolized before the SIR-spheres injection. Other exclusion criteria were liver dysfunction and anatomical vascular anomalies. The clinical response was evaluated by CT-scan following the RECIST criteria. Median follow-up was 4 months. RESULTS: Median number of metastases was 4 (range, 1-15), 38% of cases presenting hepatic involvement < 25%. The median SIRT dose delivered was 1.7 GBq. Median pulmonary shunt was 6%. No operative mortality occurred; early toxicity (within 48 hours) was 20.6%, shown as fever, acute pain and leucocytosis. The late toxicity was 24.1% with chronic pain, jaundice and nausea being the most frequent. All the toxic events were graded 2 or 3 according to the WHO scale. Preliminary results were available in terms of clinical response after 6 weeks: 12.5% had a partial response, 75% a stable disease, while progression of disease, was observed in 12.5% of the patients. CONCLUSION: SIRT is a safe treatment in terms of acute and late toxicity. Intra-arterial microspheres could represent a good therapeutic option for patients with progressing liver metastases only, after two lines of systemic chemotherapy.

Antigranulocyte monoclonal antibody immunoscintigraphy in inflammatory bowel disease in children and young adolescents.

AIM: Diagnostic delay for inflammatory bowel disease (IBD) is frequent, especially in paediatric patients. Scintigraphy with labelled leucocytes has been proposed as a very sensitive diagnostic tool for detecting bowel inflammation. The aim of this study was to evaluate the sensitivity and specificity of immunoscintigraphy in the diagnosis and follow-up of children with IBD and to compare this technique with other diagnostic techniques. METHODS: Sixty-six children with histologically confirmed IBD were enrolled in the study. Twenty-one children in whom IBD was suspected but subsequently not confirmed were used as controls. A total of 138 immunoscintigraphies were performed using 99mTechnetium-labelled monoclonal anti-granulocyte antibodies. Immunoscintigraphy was also compared with other diagnostic techniques. RESULTS: Overall sensitivity of monoclonal antibody immunoscintigraphy (MoAb-IS) in patients with clinically active disease was 94% for Crohn's disease (CD) and 85% for ulcerative colitis (UC). Ultrasonography, endoscopy and radiology were carried out at the same time in 29 patients with CD and in 6 patients with UC: sensitivity of IS was 90% compared with 76% of colonoscopy, 75% for enemas, and 55% for sonography. IS was negative (specificity) in 24% of patients with CD and in 67% of patients with UC during remission, and in 64% of controls with other causes of intestinal inflammation. Diagnostic delay was significantly shorter when compared with a historical cohort of patients. CONCLUSION: Immunoscintigraphy is a highly sensitive detector of intestinal inflammation in young patients with IBD and can be useful for reducing diagnostic delay. However, its specificity is low and all positive cases must be confirmed histologically.

Molecular analyses of sentinel lymph nodes: an open question.

AIMS: To detect micrometastases in the sentinel lymph nodes (SLN) of melanoma patients the authors analysed 52 lymph nodes (47 SLNs and five non-sentinel) and 17 corresponding primary skin melanomas using reverse transcriptase-polymerase chain reaction assays in paraffin-embedded tissues to detect the mRNAs of tyrosinase, MAGE1, MAGE3, MIA, MART-1 and mRNA coding for telomerase catalytic component. RESULTS: Our data show that the use of molecular markers for melanoma micrometastases detection in SLN is still in a very preliminary stage. In comparing the molecular analysis results with the pathological staging we did not find any evident correlation with the expression of the analysed genes in SLN. There are no data for judging the prognostic significance of the detection of circulating tumour cells in patients without clinically recognizable metastases. Despite progress in the field with simultaneous detection of several markers it was assumed that tyrosinase mRNA remains the best target for the detection of metastatic melanoma cells.

Accuracy of technetium-99m sestamibi scintimammography and X-ray mammography in premenopausal women with suspected breast cancer.

The aim of this study was to evaluate the usefulness of technetium-99m sestamibi scintimammography (SSM) and combined use of SSM and X-ray mammography (MG) in premenopausal patients with small (< or =2 cm) suspicious breast lesions. Eighty-seven premenopausal women (median age 47 years, range 32-52) with breast lesions ranging from 4 to 20 mm in greatest diameter (median 12 mm) and detected by MG, underwent SSM prior to open breast biopsy. A planar camera and single-photon emission tomography (SPET) technique were used in 23 (26.4%) and 64 (73.6%) patients, respectively. At histological examination, 72 (82.8%) breast cancers (pT1a=3, pT1b=27, pT1c=42) and 15 (17.2%) benign masses were found. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of MG and SSM were 80.6% vs 80.6%, 60.0% vs 93.3% (P<0.05), 90.6% vs 98.3%, 39.1% vs 50.0% and 77.0% vs 82.8%, respectively. MG + SSM together had a sensitivity of 94.4% (P<0.05 vs SSM alone) and an accuracy of 82.8% for the detection of breast cancer. Tumours undetected by both MG and SSM were significantly (P<0.05) smaller than those correctly diagnosed. Patients with false-negative MG were younger (P<0.05) than those with tumours correctly detected, while SSM sensitivity was independent (P=NS) of age. In conclusion, in premenopausal patients with small breast lesions, the sensitivity of SSM and MG is similar (P=NS), whereas the specificity of SSM is significantly higher (P<0.05) than that of MG. Furthermore, the combination of MG and SSM offers significantly improved sensitivity and accuracy in comparison with the individual techniques, suggesting a complementary role of SSM in the detection of breast cancer in younger patients.

Sestamibi scintimammography in pT1 breast cancer: alternative or complementary to X-ray mammography?

The aim of this study was to compare the results obtained using X-ray mammography (MG) and 99mTc-sestamibi scintimammography (SSM) in patients with breast lesions < or = 2 cm. One hundred and thirty-four women (median age 52 years, range 32-78), who had already been selected for open breast biopsy, underwent both MG and SSM prior to surgery. Final pathology showed 27 (20.1%) benign breast lesions and 107 (79.9%) breast cancers (pT1a=5 [4.7%], pT1b=50 [46.7%], pT1c=52 [48.6%]). The sensitivity, positive predictive value, negative predictive value and accuracy were 81.3%, 97.6%, 55.6% and 83.6% for SSM and 83.2%, 89.9%, 48.6% and 79.1% for MG, respectively. The results were similar (p=NS), but patients with breast cancer (BC) undetected by MG were significantly (p<0.05) younger than those in which the tumor was correctly diagnosed, while the age did not affect SSM sensitivity. SSM was more (p<0.05) specific than MG in BC detection both in the overall group of patients (92.6% vs 63.0%) and in those with < or = 10 mm breast lesions (94.7% vs 63.2%). In conclusion, in patients with suspected BC sized < or = 2 cm, SSM may help in surgical planning because of its high specificity, and should be considered complementary to MG, especially in younger women.

Usefulness of 99m-Tc-sestamibi scintimammography in suspected breast cancer and in axillary lymph node metastases detection.

AIMS: To evaluate the usefulness of 99m-Tc-sestamibi scintimammography (SSM) in the detection of T1-2, N0-1, M0 breast cancer (BC) and axillary node (AN) metastases. PATIENTS AND METHODS: A series of 239 women (median age 55 years) who had already been selected for breast biopsy underwent both mammography (MG) and SSM before surgery. The final diagnosis confirmed in 207 (86.6%) patients, and benign breast lesions in 32 (13.4%). RESULTS: Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of MG and SSM in BC detection were 88.9% vs 87.9%, 62.5% vs 93.8% (P<0.01), 93.9% vs 98.9%, 46.5% vs 54.5%, and 85.4% vs 88.7%, respectively. Age did not affect (P=NS) SSM sensitivity, and in premenopausal patients (n=80 (33.5%)) its specificity was 100%. Overall sensitivity and specificity of SSM for assessing AN involvement were 82.3% and 94.1%, respectively. In patients with <3 AN metastases (n=33 (53.2%)) SSM sensitivity was 69.7%, and only one out of six patients with a single AN metastasis had a positive scan. CONCLUSIONS: In patients with suspicious MG undergoing biopsy, SSM should be considered before surgery because of its high specificity, especially in younger patients. At present, its usefulness in detection of AN metastases is still modest and does not allow a correct pre-operative staging of patients with BC.

Growth hormone decreases muscle glutamine production and stimulates protein synthesis in hypercatabolic patients.

We determined the effects of 24-h recombinant human growth hormone (rhGH) infusion into a femoral artery on leg muscle protein kinetics, amino acid transport, and glutamine metabolism in eight adult hypercatabolic trauma patients. Metabolic pathways were assessed by leg arteriovenous catheterization and muscle biopsies with the use of stable amino acid isotopes. Muscle mRNA levels of selected enzymes were determined by competitive PCR. rhGH infusion significantly accelerated the inward transport rates of phenylalanine and leucine and protein synthesis, whereas the muscle protein degradation rate and cathepsin B and UbB polyubiquitin mRNA levels were not significantly modified by rhGH. rhGH infusion decreased the rate of glutamine de novo synthesis and glutamine precursor availability, total branched-chain amino acid catabolism, and nonprotein glutamate utilization. Thus net glutamine release from muscle into circulation significantly decreased after rhGH administration ( approximately 50%), whereas glutamine synthetase mRNA levels increased after rhGH infusion, possibly to compensate for reduced glutamine precursor availability. We conclude that, after trauma, the anticatabolic action of rhGH is associated with a potentially harmful decrease in muscle glutamine production.

[An occult pancreatic insulinoma: radio-guided surgery with 111-In-octreotide. A case report and review of the literature on pre- and intraoperative diagnosis]. / Insulinoma pancreatico occulto: chirurgia radio-guidata con 111-In-octreotide. Case report e revisione della letteratura in tema di diagnosi pre ed intraoperatoria.

INTRODUCTION: Pancreatic insulinoma is a small, rare neoplasm; its radical therapy is surgical enucleation or resection. Although clinical diagnosis is simple, instrumental and radiological localization is still difficult (occult insulinoma: 10-20%). MATERIAL AND METHODS: The authors present the case of a 71-year-old patient suffering from relapsing vertigo syndrome, derangement and transient lypothymia after strong physical activity. ECG, encephalic and abdominal C.T., eco-color-Doppler of epiaortic vessels failed to identify any pathological features. Laboratory tests only revealed that basal glycemia was always lower than normal. Insulinoma was strongly suspected following the outcome of dosages of insulin and C-peptide in the serum and was confirmed after a supervised fast test (72 h). Once the biochemical diagnosis had been reached an abdominal eco, C.T., a selective and superselective angiography and echo-endoscopy were carried out to locate the tumor site but results were negative. Only somatostatin-receptor scintigraphy with 111 In-octreotide detected a catchment area (diameter: 3 cm) to the right of the hypochondrium, anterior to the kidney and caudal to the left hepatic lobe. RESULTS: During laparotomy a hand-held gamma detecting probe (C-Trak) was used to detect in situ tumour binding of the radiolabelled octreotide and a neoplasm was identified and enucleated from the pancreatic head (diameter: 7 mm), undistinguishable from the surrounding parenchyma. Postoperative signal checks of the surgical field and of the neoplasm revealed, in the first, the absence of captation and, in the second, maximal captation. Histological findings confirmed the nature of the neoplasm: an insulinoma with a ring pattern. Two years after surgery the patient is in good health, with no signs of relapse. CONCLUSIONS: Radio-guided surgery with labelled octreotide makes it possible to pinpoint small insulinomas, locate occult neoplasm, verify the completeness of surgical excision in the field and in the surgical piece, by comparing the different captation of labelled octreotide and check neoplasm multicentricity and any metastases.

Artifacts, anatomical and physiological variants, and unrelated diseases that might cause false-positive whole-body 131-I scans in patients with thyroid cancer.

The whole body 131-I scan remains an important component in the postoperative treatment of patients with well-differentiated thyroid cancer. Because normal thyroid tissue remnants and residual or metastatic foci of well-differentiated thyroid cancer have the unique ability to concentrate, organify, and store 131-I, the whole body scan provides a depiction of those tissues that can be ablated with therapeutic doses of 131-I. Over time, it has become obvious that the whole body scan may also reveal foci of 131-i uptake owing to a wide variety of other causes. We provide a detailed pathophysiological classification of the artifacts, anatomic and physiological variants, and nonthyroidal diseases that may give rise to false-positive whole body scans in postoperative patients with thyroid cancer. These include ectopic foci of normal thyroid tissue; nonthyroidal physiological sites (eg, choroid plexus, salivary glands, gastric mucosa, urinary tract); contamination by physiological sections; ectopic gastric mucosa; other gastrointestinal abnormalities; urinary tract abnormalities; mammary abnormalities; serous cavities and cysts; inflammation and infection; nonthyroidal neoplasms; and currently unexplained causes. This article also provides a detailed review of the widely scattered English language literature in which these phenomena were originally described.

Usefulness of screening program for celiac disease in autoimmune thyroiditis.

We determined the prevalence of celiac disease in subjects with autoimmune thyroiditis compared with sick and healthy subjects. The screening was performed with IgA-class endomysium antibody, by indirect immunofluorescence using human umbilical cord as the antigenic substrate. Six of the 172 patients with autoimmune thyroiditis were found to be anti-endomysium positive (3.4%) and five of these underwent intestinal biopsy, which showed total villous atrophy. By contrast, 3 (0.75%) of 396 patients with nongastroenterologic malignancies and 10 (0.25%) of 4000 blood donors were found to have celiac disease. The prevalence of autoimmune diseases was significantly higher in patients with both celiac disease and autoimmune thyroiditis than in patients with autoimmune thyroiditis alone (P = 0.01). This study confirms that celiac disease is increased among patients with autoimmune thyroiditis. We suggest that these patients may benefit from screening for celiac disease so as to eliminate symptoms and limit the risk of developing other autoimmune disorders.

Parathyroid scintigraphy.

Parathyroid scintigraphy, first proposed in the seventies, has developed an irreplaceable role in the preoperative location of enlarged parathyroid tissues. The contribution of Ferlin, who in the early eighties proposed the use of the potassium analogue 201Thallium and subtraction scintigraphy to obviate thyroid tissue interference was especially important. At the present time, this imaging modality, is widely accepted for the preoperative localization of parathyroid adenomas owing to its high accuracy and reproducibility. Various modified acquisition and processing protocols have been reported and 201Thallium still continues to be used, but other radiopharmaceuticals, such as 99mTc-methoxyisobutyl isonitrile (99mTc-MIBI) and 99mTc-tetrofosmin are now often preferred, especially because of the more favourable physical properties of the Technetium labelling. In some cases, thyroid subtraction scintigraphy can be replaced by dual phase 99mTc-methoxyisobutyl isonitrile acquisition. There is also an increasing interest in SPECT studies, which have the potential to more accurately locate the sites of adenomas and allow for detection of smaller lesions, which further increases total sensitivity and accuracy of the technique.

Female "varicocele": two cases diagnosed by labeled red blood cell angioscintigraphy and treated by percutaneous phlebography and embolization.

Varicocele, a varicosity of the gonadal venous plexus, is a well-recognized disorder occurring in up to 10% of men. In women, an analogous varicosity of the salpingo-ovarian plexus is rare. This may be explained, in part, by the lack of obvious findings on clinical examination in women compared with men and the need, until recently, to use invasive venographic methods to confirm the diagnosis. Two cases of "female varicocele" diagnosed by means of echo Doppler and Tc-99m red blood cell scintigraphy and their cure by percutaneous phlebographic occlusion of the ovarian venous varicosity are described.

[Profound venous thrombosis and popliteal cyst: problems of differential diagnosis relative to the use of phleboscintigraphy. Description of a clinical case]. / Trombosi venosa profonda e cisti poplitea: problematiche di diagnosi differenziale relativamente all'utilizzo della fleboscintigrafia. Descrizione di un caso clinico.

The following is the case report of M. G. a 68-year-old male carrier of polcythemia vera, a pathology in which the risk of thrombosis is increased. The patient presented clinically suspected deep venous thrombosis and a phleboscintigraphy confirmed the diagnosis. A real-time B-mode ultrasonography performed later instead demonstrated a popliteal cyst. The case report focuses on diagnostic methods in deep venous thrombosis and particular attention is paid to the role of phleboscintigraphy, of impedance plethysmography and of real time B-mode ultrasonography.

An unusual adrenal metastasis secondary to Hürthle cell carcinoma of the thyroid.

A 66-year-old woman with Hürthle cell thyroid carcinoma associated with a right adrenal gland metastasis suspected on a postradioiodine therapy scan, is reported. Histology specimens confirmed the suspicion. Adrenal metastases have never been reported previously in this kind of tumor. On radionuclide imaging, there was marked I-131 uptake in the tumor remnant and its metastases, and the tumor spread through both lymphatic and hematogenous routes, as shown by lymph node, bone, and lung metastases.

Nifedipine can preserve renal function in patients undergoing aortic surgery with infrarenal crossclamping.

Sixteen patients diagnosed with an aneurysm of abdominal aorta or Leriche disease underwent elective aortic surgery involving crossclamping of infrarenal aorta (ICC). These patients were randomized into two equal groups and 8 patients were infused with nifedipine starting from the isolation of aorta until the end of surgery (group A) while another 8 patients were infused with low-dose dopamine (group B) over the same surgical course. Plasma endothelin (ET) was measured before the induction of anesthesia, at the beginning and at the end of the clamp period and at the end of the operation. Intraoperatively, creatinine clearance and urinary excretion of PGE2, 6-keto PGF1 alpha and TxB2 were also determined before, during and after aortic crossclamping. Preoperative GFR as well as preinduction cardiac index (CI) and pulmonary capillary wedge pressure (PCWP) of the two groups did not differ. During cross-clamping plasma ET rose significantly in both groups. However, after clamp removal, plasma ET decreased in group A while it remained elevated in group B. Urinary excretion of TxB2, PGE2 and 6-keto PGF1 alpha increased during clamp in both groups, but the ratio of PGE2 + 6-keto PGF1 alpha/TxB2 during and after clamp was significantly higher in group A than in B. Postclamp creatinine clearance decreased in group B, and increased in group A; postoperative value of GFR was unchanged in group A and decreased significantly in group B. In conclusion, infusion of nifedipine, in contrast to dopamine, prevented the decrease of GFR in patients undergoing aortic surgery. This effect could be mediated by a nifedipine modulation of ET vascular synthesis and/or a preferential renal synthesis of vasodilating prostanoids.

A case of bronchial carcinoid: diagnosis and follow-up with 111In-DTPA-octreotide.

Scintigraphy with radiolabelled analogue of somatostatin is highly sensitive in detecting carcinoid tumors especially if performed with Single Photon Computed Tomography (SPECT). In this report we describe our experience with 111In-DTPA-Octreotide in a female patient affected by a small asymptomatic intrabronchial carcinoid demonstrated by CT scan and bronchial endoscopy performed after recurrent left pneumonias. Planar views and SPECT images, using 111In-DTPA-Octreotide, were collected before and four hours after the first endoscopic laser resection. All groups of SPECT images were positive in the left parahilar region but at a different degree. Scans performed after resection showed a low degree of uptake which was considered to be probably secondary to local swelling; CT scan was negative. Follow up endoscopic biopsy repeated at six months, showed a relapse always in the same site; CT scan of the thorax was again negative. 111In-DTPA-Octreotide images obtained at twelve months were positive always in the left parahilar region, CT scan was negative but another biopsy was not possible. Therefore it was suspected a relapse of the carcinoid which was probably growing only through the bronchial wall without spreading towards the bronchial lumen and/or the lung parenchima. In this occasion, it was also thought that images collected four hours after resection could be positive not only for swelling but for a relapse as well. In every scintigraphic session, SPECT images presented higher quality than planar. This case suggests that 111In-DTPA-Octreotide SPECT is a non-invasive diagnostic technique which could be applied as a follow-up tool especially to patients with no-secreting carcinoid neoplasm and/or with negative or doubtful endoscopic and radiological investigations.

Direct in vivo assessment of parathyroid hormone-calcium relationship curve in renal patients.

Secondary hyperparathyroidism (SHP) is a well documented finding even in the early stages of chronic renal failure (CRF). A sigmoidal relationship, fitting a four parameter model, links PTH secretion rate and calcium concentration changes. To our knowledge, PTH secretory parameters have only been studied in uremic patients who are in dialysis treatment. As a result of these studies, a possible role for derangement in setpoint values (that is, the serum calcium concentration corresponding to the mid-range value on the sigmoidal curve) has been suggested in the pathogenesis of SHP in CRF. Our study was undertaken to gain insight into the calcium-PTH relationship curve in the first course of CRF and to assess whether a change in any of the secretory parameters is related to the beginning of SHP. We studied 27 male renal patients with a variable degree of renal function (creatinine clearance 12 to 164 ml/min) and 9 control subjects. In all patients and controls the following parameters were evaluated: (1) basal 1,25(OH)2 vitamin D, 25(OH)vitamin D, calcitonin (CT), intact PTH; (2) GFR by Cr51EDTA clearance; (3) the sigmoidal PTH-ionized calcium relation curve, by means of a hypocalcemic stimulating test (Na2-EDTA 37 mg/kg body weight/2 hr) and a hypercalcemic test (Ca gluconate giving 8 mg/kg of body weight/2 hr of Ca element), performed on two consecutive days.(ABSTRACT TRUNCATED AT 250 WORDS)