[Indwelling central venous catheters after discontinuation of therapy and risk of infection in children with cancer]. / Permanenza del catetere venoso centrale dopo la sospensione della terapia e rischio infettivo in bambini affetti da neoplasia.

In this retrospective study we report the incidence of CVC-related infections in a pediatric oncology population during the off therapy period. We analysed 128 children with oncologic diseases (solid tumors and leukemia), 78 boys and 50 girls, aged 1 to 21 years, who maintained the CVC in situ at least 6 months after the cessation of chemotherapeutic protocols. Seventy-eight patients had a single lumen Broviac-Hickman CVC, 8 patients had a double lumen Broviac-Hickman and 42 a implantable port device. The permanence of CVC in situ after discontinuation of treatment varied between 6 and 24 months. CVC was removed in 5 patients that presented a CVC-related infection, respectively 6, 6, 6, 7 and 10 months from discontinuation of therapy, in 85 patients because was considered no more necessary. 38 patients are still with CVC in situ; in this group 11 patients relapsed more than 6 months after discontinuation of the therapy and were analysed until the time of relapsed. The result of our study show that the incidence of CVC related infections in patients off therapy is very low. Considering the discomfort that frequent blood withdrawals cause to children and the relapse risk, we think that CVC may be maintained in situ more than 6 months after discontinuation of the therapy without risks for the patients.

[Prognostic factors in neuroblastoma. Usefulness of DNA analysis using flow cytometry on paraffin-embedded material]. / Fattori prognostici nel neuroblastoma. Utilità dell'analisi del DNA mediante citometria a flusso su materiale incluso in paraffina.

Nuclear DNA content was determined on paraffin blocks of 28 neuroblastic tumors retrieved from Surgical Pathology files. In 26 cases cytofluorimetric analysis for DNA content was satisfactory. 8 tumor were diploid, 12 were aneuploid and 6 tetraploid. All but one of the children with diploid neuroblastoma (NB) died after a survival ranging from 14 to 32 months. The only surviving child had a Stage I thoracic ganglioneuroblastoma (GNB) and was alive after 27 months. Conversely 11 of 12 patients with aneuploid tumors were alive with prolonged follow-up. Two children are alive after a period exceeding 146 months. The only exception in this group of aneuploid tumors was a child with Stage IV neuroblastoma of the adrenal gland with pleuro pulmonary metastasis who died after 6 months. In the group with tetraploid tumors 3 patients died (2 children with Stage III and IV died early while the third, with thoracic Stage II GNB, survived for 72 months). Two patients with tetraploid GNB Stage II and III are alive 65 and 72 months after diagnosis respectively. Another child with Stage IV adrenal NB is alive after 14 months but with metastatic spread to bones, bone marrow and lymph nodes. Cox analysis of the cases demonstrated ploidy as an independent prognostic factor. These results are in agreement with other molecular analysis linking near-ploidy of Neuroblastic tumors to poor prognosis. Ploidy, as detected by flow cytometry for nuclear DNA content, may represent an important prognostic factor in Neuroblastic tumors. The advantage of flow cytometry over other techniques of molecular analysis is represented by the simple methodology suitable for fixed and paraffin embedded tissue, even on retrieval material.

[Treatment of metastatic osteosarcoma with verapamil, cyclosporine and chemotherapy. A case report]. / Trattamento dell'osteosarcoma metastatico con verapamile, ciclosporina e chemioterapia. Descrizione di un caso clinico.

Studies on the use of revertants to overcome MDR have aroused a great interest even if they failed to prove their actual usefulness. A case of 10 years and 6 months old boy is described. He suffered from osteoblastic osteosarcoma and underwent chemotherapy following CNR-NEO3 protocol, wide surgical resection and postoperative chemotherapy. Nineteen months after diagnosis he underwent the removal of a little subpleural nodule in the right lung. Forty-five days later, in the same site, a large local metastasis was observed together with many others secondaries localizations spred in both lungs. Because of the rapid evolution they were considered not suitable for surgical treatment. A cyclosporine and verapamil treatment in association with adryamicin and etoposide was begun with the aim overcoming multidrug resistance. Five treatments were provided. ECG monitoring during verapamil infusion did not show any trouble; mielotoxicity was mild, with no need of transfusions. A lung CT scan at the end of the therapy demonstrated an important decrease of the subpleural metastasis and the vanishing of lung nodules. Another surgical intervention was provided together with 2 postoperative chemotherapy treatments. Twenty-six months later no sign of the disease was observed. Association of verapamil and cyclosporine with chemotherapy allowed to get a good clinical response with a very low toxicity, in a critical situation in which chemotherapy alone did not seem to offer any real possibility.

[Use of cyclosporin and verapamil in association with chemotherapy in the treatment of pediatric patients with advanced-stage neoplasms. A pilot study]. / Impiego della ciclosporina e del verapamile in associazione a chemioterapici nel trattamento di pazienti pediatrici con neoplasia in fase avanzata. Studio pilota.

Multidrug resistance represents one of the most important factors that may lead to a therapeutic failure in some patients affected by malignancies. One of the best known mechanisms is linked to the genic amplification or the overproduction of a membrane glycoprotein, GP170, that is the product of the gene MDR1. The existence of drugs (calcium blockers, cyclosporine, tamoxifen, reserpine, quinidine) able to bind themselves to gp170 and to paralyze its activity in vitro is well known. We studied 20 pediatric patients (median age 9 years) affected by acute lymphoblastic leukemia (ALL), osteosarcoma, neuroblastoma and medulloblastoma, in advanced stage of disease. We employed in all cases the association of cytostatics with verapamil (50-70 mg/m2 i.v.) and cyclosporine (5-8 mg/kg i.v.) with different infusion schedules. In leukemias we administered vincristine (1.5 mg/m2), and daunomycin (40 mg/m2), in solid tumors VP16 (150 mg/m2) and adriamycin (60 mg/m2). Seventy-two therapeutic courses were performed: 39 in ALL, 16 in osteosarcoma, 16 in neuroblastoma and 1 in medulloblastoma. On the whole 5 complete remissions were achieved in ALL patients and 1 in an osteosarcoma patient. We did not observe a significant myelosuppression during treatment, therefore few infectious complications occurred; furthermore electrocardiographic changes have been mild and promptly resolved after temporary discontinuation of verapamil infusion. Our data suggest a synergy of verapamil and cyclosporine in the inhibition of multidrug resistance induced by gp170, without the occurrence of heavy toxicity. The results obtained in ALL patients are encouraging., especially in view of a possible subsequent bone marrow transplantation, while in solid tumors they are not as satisfying.

[Pulmonary complications after bone marrow transplantation]. / Complicanze polmonari dopo trapianto di midollo osseo.

Pulmonary toxicity occurs in approximately 10 to 50% of patients undergoing bone marrow transplantation (BMT). Bacterial pneumonia very commonly affects patients within the first 6 months post-BMT. Etiologic factors include neutropenia and the presence of graft-versus-host disease (GVHD). Pulmonary fungal infections, due to candida and aspergillus, may develop in 16% of patients receiving BMT, with a high mortality rate, being about 80%. A prolonged neutropenia as well as GVHD and associated immunosuppressive treatments are important factors in predisposing a patient to develop fungal pneumonitis. Interstitial pneumonitis occurs in 10-40% of patients; herpes viruses are the most commonly documented cause, with cytomegalovirus (CMV) being the most common pathogen. No causative organism is identified in up to 60% of the cases. It is likely that some of these cases may result from drug or radiation toxicity. Lung shielding and fractionation of the dose have decreased the incidence of interstitial pneumonitis to less than 5%. Patients with GVHD are predisposed to lung infections because of the immunosuppression that accompanies GVHD and its treatment. In addition, GVHD itself appears to have a direct effect on pulmonary epithelium. Cultural and serologic studies as well as radiographic investigations and other diagnostic procedures (ie bronchoalveolar lavage) are needed for appropriate management of pulmonary complications.

Primary pigmented micronodular disease of the adrenals.

Primary pigmented micronodular disease is a peculiar form of ACTH-independent Cushing's syndrome characterized by the familial occurrence, the frequent association with malformations and the pathological adrenocortical picture consisting in micronodules with cellular deposition of lipofuscinic pigment. We describe here a case occurring in a 14-year-old girl.

Growth hormone responses to pyridostigmine in normal adults and in normal and short children.

There is evidence indicating that the cholinergic system positively modulates GH release probably by inhibiting somatostatinergic tone. In the present study, the effects of cholinergic enhancement by pyridostigmine, (PD), a cholinesterases inhibitor, on GH release in normal adults (n = 14) (NA) and in both normal (n = 5) (NC) and short children (n = 19) (SC) with familial short stature (n = 7) or constitutional growth delay (n = 12) were studied. In SC the insulin hypoglycaemia (IH)-induced GH increase was also studied. In both NC and SC 60 mg orally PD induced a significant GH increase with mean peak at 90 min (mean +/- SEM 11.0 +/- 2.2 ng/ml in NC and 11.2 +/- 2.3 ng/ml in SC). The GH areas under response curve (AUC) were 379.3 +/- 76.6 and 327.8 +/- 43.2 ng/ml/h in NC and SC respectively. In NA 120 mg orally PD induced a significant GH increase with mean peak at 120 min (5.1 +/- 1.1 ng/ml) which was significantly lower (P less than 0.05) than that observed in both NC and SC. This statistical difference was strengthened by evaluating AUC (NA:205.6 +/- 33.7 ng/ml/h, P less than 0.05 vs NC and SC). The correlation of drug dosage with body area ruled out that this difference could be related to the different PD dose in adults and children. In SC, IH induced a GH increase significantly lower than that observed after PD (GH peak 7.8 +/- 0.6 vs 16.4 +/- 1.9 ng/ml P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Enhancement of cholinergic tone by pyridostigmine promotes both basal and growth hormone (GH)-releasing hormone-induced GH secretion in children of short stature.

Increased cholinergic tone induced by pyridostigmine (PD) increases basal plasma GH levels and potentiates the GH response to GHRH in normal adults. In this study the effects of PD (60 mg, orally) on both basal and GHRH (1 microgram/kg)-induced GH secretion in seven children with familial short stature (FSS), six with GH deficiency (GHD) and 10 with constitutional growth delay (CGD) were studied and compared with results obtained by stimulation with insulin-induced hypoglycemia (IH) and GHRH alone. The mean peak plasma GH levels were variable, but individual values were frequently low in all groups after both IH [FSS, 9.7 +/- 1.3 (+/- SEM) ng/mL; GHD, 1.6 +/- 0.4 ng/mL; CGD, 7.0 +/- 0.8 ng/mL] and GHRH (FSS, 23.8 +/- 6.6 ng/mL; GHD, 11.1 +/- 5.8 ng/mL; CGD, 15.1 +/- 4.5 ng/mL) administration. PD induced GH responses (FSS, 14.5 +/- 1.6 ng/mL; GHD, 3.8 +/- 0.8 ng/mL; CGD, 18.3 +/- 3.2 ng/mL) that in many children in the FSS and CGD groups were higher than those after IH and GHRH treatment. PD clearly increased the GH response to GHRH in all children [FSS, 69.5 +/- 9.4 ng/mL (P less than 0.01 vs. other stimuli); GHD, 18.0 +/- 7.5 ng/mL; CGD, 50.0 +/- 8.5 ng/mL (P less than 0.01 vs. other stimuli)]. We conclude that in children with short stature, as in adults, enhancement of cholinergic tone increases both basal and GHRH-induced GH secretion, and that PD plus GHRH is the best provocative stimulus for evaluating the somatotroph response.

Effects of a new long-acting form of bromocriptine on tumorous hyperprolactinemia.

Recently, a new long-acting form of bromocriptine (Parlodel LA, Sandoz) has been developed and it has already been found to be effective in lowering plasma PRL levels in normal volunteers and postpartum women. This work reports the clinical, hormonal and radiological effects of a single 50 mg dose of long-acting bromocriptine in 10 patients with tumorous hyperprolactinemia (2 microprolactinomas, 6 macroprolactinomas, 1 acromegaly and 1 nonsecreting macroadenoma). A rapid and long-lasting (28 days) normalization of PRL levels was observed in patients with microprolactinoma, acromegaly and nonsecreting adenoma. None of the 6 patients with macroprolactinoma underwent normalization of plasma PRL, but the latter was markedly reduced (61-80% of basal levels). A second injection of the drug in 5 macroprolactinoma patients induced a further reduction of plasma PRL levels in 2 of them. No changes in the tumor size were observed either after the first or the second injection of long-acting bromocriptine in any of the patients. This injectable form of bromocriptine induced nausea and/or mild hypotension lasting a few h in 4 of the 10 patients and was better tolerated than the oral form as regards both the duration and intensity of the side effects. Thus, as this drug has proved to be efficacious and well tolerated by the patients, this long-acting form of bromocriptine may be a valid therapeutical approach for initiating medical treatment of patients with prolactinoma.

Long term treatment with oral single administration of bromocriptine in patients with hyperprolactinemia.

In the treatment of hyperprolactinemia bromocriptine is generally administered in 3 daily doses during the day. Due to the limited compliance of patients under this long term regimen, in 16 hyperprolactinemic patients we investigated the efficacy and tolerability of the treatment with this dopaminergic drug administered as a single evening dose. This dose was the same which the patients had been assuming previously on a tid basis. Chronic treatment (4-12 months) with an oral single evening dose of bromocriptine is able to control plasma PRL at least as well as the traditional tid regimen (2.8-21.6 ng/ml vs 1.2-31.8 ng/ml). Furthermore, during this single dose regimen the side effects were of lesser intensity and extent. Since the compliance of the patients with the single dose regimen was very good and the efficacy the same in reducing plasma PRL and controlling the clinical manifestations with a lower rate of side effects, we suggest to extend this regimen to all patients with hyperprolactinemia treated with bromocriptine after successful reduction of plasma PRL levels is obtained.

Potentiation of cholinergic tone by pyridostigmine bromide re-instates and potentiates the growth hormone responsiveness to intermittent administration of growth hormone-releasing factor in man.

It is known that in normal subjects repeated administration of the growth hormone-releasing factor (GRF) induces a state of partial refractoriness of the somatotropes to GRF. Studies were conducted to verify whether the cholinergic system plays a role in the mechanism(s) underlying the reduced GH responsiveness to the neuropeptide. In five healthy men, the GH response to three consecutive injections of GRF (50 micrograms iv), administered at 2 h intervals, was considerably blunted after the second and third GRF bolus. Administration of the inhibitor of cholinesterase, pyridostigmine bromide (120 mg orally) 30 min before the second GRF bolus, not only restored but greatly potentiated the GH responsiveness to the second GRF bolus. The GH response to the third GRF bolus was not apparently influenced by pre-treatment with pyridostigmine. These data reinforce the view that cholinergic neurotransmission plays an important role in the control of GH secretion in human.

Comparison between pituitary computed tomographic findings and tests of hypothalamo-pituitary function in 72 patients with hyperprolactinaemia.

To verify the diagnostic capacity of some dynamic tests of the prolactin (Prl) secretion, the findings obtained by high-resolution computed tomography (CT) were compared with results obtained from tests using nomifensine (NOM) domperidone (DOM) and thyrotrophin-releasing hormone (TRH) in 72 patients with pathological hyperprolactinaemia. None of the patients with tumours had a positive Prl response to NOM or to DOM administration; however, a positive response to these tests was present in only 24 and 41%, respectively, of the patients with normal CT picture. The results of TRH testing were similar to those obtained with DOM. Different neuroendocrine patterns were disclosed by comparing pituitary Prl and thyrotrophin (TSH) responses to DOM: 1) some subjects had a reduced Prl response together with an exaggerated or normal TSH response to DOM; they comprised patients with tumour, empty sella, and normal CT picture; 2) other patients with normal CT picture had a positive Prl and a normal TSH response to DOM. These results demonstrate that a negative Prl response to NOM and DOM characterizes all patients with adenoma; however, the tumour-like responses in patients with no visible tumours seem to reduce the diagnostic value of these tests, unless the latter may predate the radiological appearance of an adenoma. On the other hand, a positive Prl and a normal TSH response to DOM exclude the presence of a pituitary tumour. This diagnostic finding is strengthened by the positive response also to NOM. Whatever may be the diagnostic validity of dynamic tests, they provide sound information on the functional state of dopamine neurotransmission.

Cholinergic involvement in the growth hormone releasing hormone-induced growth hormone release: studies in normal and acromegalic subjects.

To throw light onto the mechanism(s) by which the cholinergic system influences growth hormone (GH) release, the effects of two muscarinic receptor blockers, pirenzepine and atropine, and of an acetylcholinesterase inhibitor, pyridostigmine bromide, on the GH response to GHRH-44 were studied in 19 normal volunteers. Moreover, the effects of pirenzepine administration on plasma GH levels both in basal conditions and after stimulation by GHRH-44 and TRH were studied in 9 acromegalics. Both pirenzepine (0.6 mg/kg i.v., 5 min before GHRH) and atropine (1 mg i.m., 15 min before GHRH) blunted the GH response to GHRH (1 microgram/kg i.v. bolus) (area under the response curve, AUC: 81.3 +/- 17.3 vs. 481.2 +/- 211.3 ng/ml/h for pirenzepine and 100.2 +/- 27.0 vs. 364.7 +/- 81.0 ng/ml/h for atropine; p less than 0.01). Pyridostigmine (120 mg orally, 30 min before GHRH) induced a variable but significant (p less than 0.02) rise in basal plasma GH levels and, furthermore, an unequivocal potentiation of the GH response to GHRH (AUC: 1044.6 +/- 245.3 vs. 481.2 +/- 211.3 ng/ml/h; p less than 0.01). In all but one acromegalics 0.6 mg/kg i.v. pirenzepine was unable to modify the basal GH levels whilst it showed a variable inhibitory effect on the GH response to GHRH. The GH response to TRH (200 micrograms i.v. bolus) was instead unmodified by pirenzepine. In conclusion, muscarinic receptor blockade inhibits while cholinergic potentiation seems to positively modulate the GH response to GHRH. Therefore, the cholinergic system seems to positively modulate the GHRH effect on somatotrophs.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathophysiological doses of glucagon cause a transient increase of the hepatic vein potassium concentration in man.

In order to evaluate whether glucagon-induced hyperkalemia is due to mobilization of potassium from the splanchnic region, we measured potassium changes in the hepatic veins following a glucagon injection into the ascending aorta. Twenty-seven subjects undergoing routine cardiac catheterization for diagnostic purposes were studied. Hepatic venous and aortic blood samples were withdrawn simultaneously under basal condition and 30, 60, 120, 180, 300, 600 s after a bolus injection of either saline, glucagon (100 ng/kg body weight) or glucagon +somatostatin (100 micrograms). After the intra-aortic injection, plasma glucagon in the hepatic veins reached levels comparable to those observed under pathophysiological conditions. Plasma potassium increased promptly with a peak at 60 s (delta max: 0.79 +/- 0.12 mmol/l, mean +/- SEM; p less than 0.01). The glucose increment peaked at 300 s (delta max: 2.36 +/- 0.20 mmol/l, mean +/- SEM; p less than 0.01). Potassium increment was potentiated by the addition of somatostatin, despite the abolition of insulin and C-peptide rises (potassium delta max: 0.56 +/- 0.10 mmol/l; p less than 0.05). In conclusion, these data demonstrate that glucagon induces a transient mobilization of potassium from the splanchnic region in man. This effect of glucagon on potassium is not antagonized by glucagon-induced insulin secretion.

Prolactin and TSH responses to both domperidone and TRH in normal and hyperprolactinaemic women after dopamine synthesis blockade.

A study of the effect of alpha-methyl-1-tryosine (metyrosine) blockade (2 g/d for 2 d) of dopamine (DA) synthesis on the PRL and TSH response to domperidone (DOM) and TRH in normal women and subjects with pathological hyperprolactinaemia is reported. In the normal subjects, there was a marked increase in basal PRL (51.7 +/- 11.1 vs 5.7 +/- 1.0 ng/ml) and the PRL and TSH responses to DOM were abolished. The PRL response to TRH was also reduced. In the hyperprolactinaemic subjects, metyrosine had no effect on basal PRL nor on the virtually non-existent PRL response to DOM, whereas it abolished the exaggerated TSH response. The conclusion is drawn that the response of both PRL and TSH to DA receptor blockers is really dependent upon DA inhibitory tone. A fall in this tone can also be postulated as responsible for the hyporesponsiveness of PRL to DOM frequently observed in pathological hyperprolactinaemia. In addition, the fact that metyrosine also abolished the exaggerated TSH response to DOM shows that the latter is totally dependent on enhanced DA inhibition of the thyrotrophs. Lastly, the reduced PRL response to TRH after metyrosine indicates that DA partly determines the ability of the lactotrophs to respond to TRH.

Effect of metoclopramide, domperidone and apomorphine on GH secretion in children and adolescents.

The way in which the dopaminergic system controls GH secretion in infancy and adolescence was investigated by studying the effects on GH of a specific dopaminergic agonist apomorphine, and two antagonists, metoclopramide (MC), which can and domperidone (DOM), which cannot cross the blood-brain-barrier, (BBB), in 14 males and 6 females aged 8-17 years. Treatment with both antagonists was followed by a marked increase in Prl, whereas only MC stimulated GH secretion, suggesting that this action must occur inside the BBB if it is linked to antidopaminergic properties. GH secretion was also stimulated by apomorphine, which acts at the central level. The paradox posed by the presence of a central effect on GH secretion derived from both an agonist and an antagonist of the dopaminergic receptors is discussed.

Effect of naloxone on gonadotropin secretion before and after testosterone in Klinefelter's syndrome.

A study was performed on eight subjects with Klinefelter's syndrome to assess the relation between gonadal hormones and opioid inhibition of gonadotropin secretion through comparison of their gonadotropin response to naloxone (NAL) (0.3 mg/kg; 1/3 bolus iv. at time 0 and 2/3 iv. for 120 min) before and after testosterone propionate (TP) 100 mg/day im. for 5 days. Under basal conditions, NAL failed to induce a significant change in LH levels. After TP, however, despite unchanged basal LH levels (mean +/- S.E.M.: 27.0 +/- 3.4 vs 21.2 +/- 3.21 microU/ml), LH significantly increased in response to NAL. FSH did not respond to NAL either before or after TP administration, though FSH levels were significantly reduced by TP. These findings suggest that in man, as in animals, gonadal hormones regulate opioid inhibition of LH secretion. The negative feedback of testosterone and its ability to activate opioid inhibiting tone may be dissociated, in keeping with the view that gonadal hormones control gonadotropin secretion through the activation of distinct, albeit concomitant, mechanisms.