Current management practices for hyponatremia (HN) are incompletely understood. The HN Registry has recorded diagnostic measures, utilization, efficacy, and outcomes of therapy for eu- or ...hypervolemic HN. To better understand current practices, we analyzed data from 3087 adjudicated adult patients in the registry with serum sodium concentration of 130 mEq/l or less from 225 sites in the United States and European Union. Common initial monotherapy treatments were fluid restriction (35%), administration of isotonic (15%) or hypertonic saline (2%), and tolvaptan (5%); 17% received no active agent. Median (interquartile range) mEq/l serum sodium increases during the first day were as follows: no treatment, 1.0 (0.0–4.0); fluid restriction, 2.0 (0.0–4.0); isotonic saline, 3.0 (0.0–5.0); hypertonic saline, 5.0 (1.0–9.0); and tolvaptan, 4.0 (2.0–9.0). Adjusting for initial serum sodium concentration with logistic regression, the relative likelihoods for correction by 5 mEq/l or more (referent, fluid restriction) were 1.60 for hypertonic saline and 2.55 for tolvaptan. At discharge, serum sodium concentration was under 135 mEq/l in 78% of patients and 130 mEq/l or less in 49%. Overly rapid correction occurred in 7.9%. Thus, initial HN treatment often uses maneuvers of limited efficacy. Despite an association with poor outcomes and availability of effective therapy, most patients with HN are discharged from hospital still hyponatremic. Studies to assess short- and long-term benefits of correction of HN with effective therapies are needed.
Several decades of basic and clinical research have demonstrated that
there is an association between the insulin-like growth factors (IGFs)
and neoplasia. We begin with a brief discussion of the ...function and
regulation of expression of the IGFs, their receptors and the
IGF-binding proteins (IGFBPs). A number of investigational
interventional strategies targeting the GH or IGFs are then reviewed.
Finally, we have assembled the available scientific knowledge about
this relationship for each of the major tumor types. The tumors have
been grouped together by organ system and for each of the major tumors,
various key elements of the relationship between IGFs and tumor growth
are discussed. Specifically these include the presence or absence of
autocrine IGF-I and IGF-II production; presence or absence of IGF-I and
IGF-II receptor expression; the expression and functions of the IGFBPs;
in vitro and in vivo experiments
involving therapeutic interventions; and available results from
clinical trials evaluating the effect of GH/IGF axis down-regulation in
various malignancies.
Patients with acromegaly are currently treated with surgery, radiation therapy, and drugs to reduce hypersecretion of growth hormone, but the treatments may be ineffective and have adverse effects. ...Pegvisomant is a genetically engineered growth hormone-receptor antagonist that blocks the action of growth hormone.
We conducted a 12-week, randomized, double-blind study of three daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo, given subcutaneously, in 112 patients with acromegaly.
The mean (+/-SD) serum concentration of insulin-like growth factor I (IGF-I) decreased from base line by 4.0+/-16.8 percent in the placebo group, 26.7+/-27.9 percent in the group that received 10 mg of pegvisomant per day, 50.1+/-26.7 percent in the group that received 15 mg of pegvisomant per day, and 62.5+/-21.3 percent in the group that received 20 mg of pegvisomant per day (P<0.001 for the comparison of each pegvisomant group with placebo), and the concentrations became normal in 10 percent, 54 percent, 81 percent, and 89 percent of patients, respectively (P<0.001 for each comparison with placebo). Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in ring size, soft-tissue swelling, the degree of excessive perspiration, and fatigue. The score fortotal symptoms and signs of acromegaly decreased significantly in all groups receiving pegvisomant (P< or =0.05). The incidence of adverse effects was similar in all groups.
On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone-receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement.
The authors have previously demonstrated that modulation of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis can significantly affect meningioma growth in vitro. These studies were ...performed to evaluate the efficacy of GH receptor blockade in vivo.
Primary cultures from 15 meningioma tumors obtained in humans were xenografted into athymic mice. Approximately 1.5 million cells from each of the 15 tumors were implanted into the flanks of two female mice, one pair for each tumor. One animal from each of the 15 pairs was then treated with the GH receptor antagonist pegvisomant and the other with vehicle alone for 8 weeks. The tumor volume was measured using digital calipers three times per week. The mean tumor volume at the initiation of injections was 284 +/- 18.8 mm3 in the vehicle group and 291.1 +/- 20 mm3 in the pegvisomant group. After 8 weeks of treatment, the mean volume of tumors in the pegvisomant group was 198.3 +/- 18.9 mm3 compared with 350.1 +/- 23.5 mm3 for the vehicle group (p < 0.001). The serum IGF-I concentration in the vehicle group was 319 +/- 12.9 microg/L compared with 257 +/- 9.7 in the pegvisomant group (p < 0.02). A small but significant decrease was observed in circulating IGF binding protein (IGFBP)-3 levels, whereas slight increases occurred with respect to serum IGFBP-1 and IGFBP-4 levels. In the placebo group the tumor weight was 0.092 +/- 0.01 g compared with 0.057 +/- 0.01 g in the pegvisomant group (p < 0.02). The IGF-I and IGF-II concentrations were measured in the tumors by using a tissue extraction method. These human-specific immunoassays demonstrated that there was no autocrine production of IGF-I in any of the tumors, either in the pegvisomant or vehicle group. The IGF-I levels were highly variable (0-38.2 ng/g tissue) and did not differ significantly between treatment groups.
In an in vivo tumor model, downregulation of the GH/IGF-I axis significantly reduces meningioma growth and, in some instances, causes tumor regression. Because the concentrations of IGF-II in tumor did not vary with pegvisomant treatment and there was no autocrine IGF-I production by the tumors, the mechanism of the antitumor effect is most likely a decrease of IGF-I in the circulation and/or surrounding host tissues. Because the authors have previously demonstrated that the GH receptor is ubiquitously expressed in meningiomas, direct blockade of the GH receptor on the tumors may also be contributing to inhibitory actions.
We have identified several estrogen receptor (ER) mRNA isoforms in rat pituitary and characterized their regulation by gonadal steroids. The ER mRNAs correspond to splice variants in which either ...exon 4, exons 3 and 4, or exons 5 and 6 are deleted. A previously isolated pituitary-specific truncated mRNA, TERP-1, containing a unique 5′-end and exons 5 through 8 of the full-length ER, was also studied. The exon deletion variants were expressed in males and females, in pituitary, uterus, testes, heart, hypothalamus, and liver. An antibody to the ER C-terminus bound to full-length (64 kDa) and smaller (50–55 kDa and 40–45 kDa) ER proteins in uterus and pituitary and a pituitary-specific ER of 20–24 kDa corresponding to TERP-1. Estrogen (E) treatment in vivo stimulated full-length ER 2–3-fold, and TERP-1 7–10-fold, but had no effect on any exon deletion variant. Progesterone treatment, alone or with E, had no consistent effect on any ER mRNA form. TERP-1 mRNA was also dramatically and specifically modulated during the estrous cycle, increasing ≈500-fold between the morning of diestrous and the afternoon of proestrus. Thus, ER mRNA variants exist in estrogen-responsive tissues; the pituitary contains at least one tissue-specific ER which is regulated by steroids and which may contribute to changes in regulated biological activity.
A 5.2-kb mRNA band that contains estrogen receptor (ER) sequence and exhibits sex- and tissue-specific expression has been identified in rat pituitary via Northern analysis; this band is composed of ...at least two distinctive ER mRNA isoforms. This mRNA is expressed in high levels in female pituitary but is absent in male pituitary and uterus, whereas the mRNA encoding the full-length receptor (6.2 kb) is expressed in all the aforementioned tissues. Estradiol treatment potently induces the expression of the 5.2-kb band in the male pituitary. Oligonucleotide hybridization and ribonuclease-protection experiments indicate that the pituitary ER variant is missing exons 1-4. Two corresponding cDNA clones, truncated estrogen receptor product 1 and 2 (TERP-1 and TERP-2), were isolated by using the anchored PCR. Both sequences contain a 31-bp segment of specific sequence upstream of exon 5; TERP-2, however, contains an additional 66 bp of specific sequence between the 31-bp segment and exon 5. On Northern analysis, probes complementary to the 31-bp segment of specific sequence hybridize only to the 5.2-kb band. Immunoblotting identified several proteins in rat pituitary that could represent the translation products of these or related transcripts. In summary, several ER isoforms have been identified that exhibit both tissue-specific expression and marked estrogen regulation and differ from full-length receptor by virtue of sequence upstream of the exon 4/5 boundary. Physiologically, the putative proteins encoded by these or similar isoforms might be important modulators of the tissue-and promoter-specific effects of estradiol.
Acromegaly: a new therapy Friend, Keith E
Cancer control,
2002 May-Jun, Volume:
9, Issue:
3
Journal Article
Peer reviewed
Open access
The treatment of acromegaly can be challenging. Despite a multimodality approach (surgery,radiation, dopamine agonists, somatostatin analogs), many patients do not achieve normalization of serum ...insulin-like growth factor I (IGF-I) concentrations.
The author discusses the characteristics and indications of pegvisomant therapy for patients with acromegaly and compares the use of this newly developed GH receptor antagonist with other pharmacological agents such as somatostatin and dopamine agonists.
Therapy with pegvisomant allows serum IGF-I concentrations to be normalized in up to 97% of patients with acromegaly, including those who have failed other treatment modalities. With this agent,circulating GH levels increase as a result of the drop in IGF-I levels. The rise is rapid (within 2 weeks) and does not appear to be progressive over time.
Published studies have shown pegvisomant to have efficacy in the treatment of acromegaly. As it appears to be well tolerated and safe, this novel compound may be an important therapeutic option for patients with acromegaly. Additional study of this novel agent and its mode of action is warranted.
Although human meningioma cells have been heterotopically implanted in nude mice, introducing these cells into intracranial locations seems more likely to reproduce normal patterns of tumor growth. ...To provide an orthotopic xenograft model of meningioma, the authors implanted a controlled quantity of meningioma cells at subdural and intracerebral sites in athymic mice.
Malignant (one tumor), atypical (two tumors), or benign (three tumors) meningiomas were placed into primary cell cultures. Cells (10(6)/10 microl) from these cultures and from an immortalized malignant meningioma cell line, IOMM-Lee, were injected with stereotactic guidance into the frontal white matter or subdural space of athymic mice. Survival curves were plotted for mice receiving tumor cells of each histological type and according to injection site. Other mice were killed at intervals and their heads were sectioned whole. Hematoxylin and eosin staining of these sections revealed the extent of tumor growth.
The median length of survival for mice with malignant, atypical, or benign tumors was 19, 42, or longer than 84 days, respectively. Atypical and malignant tumors were invasive, but did not metastasize extracranially. Malignant tumors uniformly showed leptomeningeal dissemination and those implanted intracerebrally grew locally and spread noncontiguously to the ventricles, choroid plexus, convexities, and skull base. Tumors formed in only 50% of mice injected with benign meningioma cells, whereas injection of more aggressive cells was uniformly successful at tumor production. The three types of human meningiomas grown intracranially in athymic mice maintained their relative positions in the spectrum of malignancy. However, atypical meningiomas became more aggressive after xenografting and acquired malignant features, implying that there had been immune constraint in the original host. Tumor cells injected into brain parenchyma migrated to more optimal environments and grew best there. This model provides insights into the biology of meningiomas and may be useful for testing new therapies.
Pegvisomant is a new growth hormone receptor antagonist that improves symptoms and normalises insulin-like growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to ...12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days.
Treatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and are excluded from the efficacy analysis.
Mean serum IGF-1 concentrations fell by at least 50%: 467 μg/L (SE 24), 526 μg/L (29), and 523 μg/L (40) in patients treated for 6, 12 and 18 months, respectively (p<0·001), whereas growth hormone increased by 12·5 μg/L (2·1), 12·5 μg/L (3·0), and 14·2 μg/L (5·7) (p<0·001). Of the patients treated for 12 months or more, 87 of 90 (97%) achieved a normal serum IGF-1 concentration. In patients withdrawn from pegvisomant (n=45), serum growth hormone concentrations were 8·0 μg/L (2·5) at baseline, rose to 15·2 μg/L (2·4) on drug, and fell back within 30 days of withdrawal to 8·3 μg/L (2·7). Antibodies to growth hormone were detected in 27 (16·9%) of patients, but no tachyphylaxis was seen. Serum insulin and glucose concentrations were significantly decreased (p<0·05). Two patients experienced progressive growth of their pituitary tumours, and two other patients had increased alanine and asparate aminotransferase concentrations requiring withdrawal from treatment. Mean pituitary tumour volume in 131 patients followed for a mean of 11·46 months (0·70) decreased by 0·033 cm
3(0·057; p=0·353).
Pegvisomant is an effective medical treatment for acromegaly.
Surgical navigation systems (frameless stereotaxy) have been used in addition to or instead of fluoroscopy during transsphenoidal surgery. This study compares the intraoperative localization by an ...optical tracking system (Elekta Viewscope) with fluoroscopy. Viewscope and fluoroscope sagittal images were compared by the establishment of a Cartesian coordinate system based on anatomical landmarks and by the spatial localization of surgically relevant points for 20 patients. The Viewscope was found to have a total deviation of 3.0 +/- 0.6 mm (mean +/- SD) compared to fluoroscopy (p < 0.01). Much of the error resulted from the registration process, which according to the Viewscope software had an expected error of 3.1 +/- 0.8 mm for this series of patients, and from the probe-to-system correlation (error of 1.0 +/- 0.3 mm). Although frameless stereotactic systems give the surgeon useful trajectory data with three-dimensional visualizations, they remain somewhat inaccurate. The multiplanar abilities of the Viewscope provide an additional but not mandatory advantage to the simplicity and accuracy of fluoroscopy during this type of surgery.