Pathology and genetics of tumours of the urinary system and male genital organs

https://www.farm.ucl.ac.be/FARM2129/2008-2009/Tulkens/anemie-neutropenie/Veronese-Pegylation-Drug-Discovery-Today-2005-10-1451-1458.pdf

PEGylation, successful approach to drug delivery.

Once a rarely used subset of medical treatments, protein therapeutics have increased dramatically in number and frequency of use since the introduction of the first recombinant protein therapeutic--human insulin--25 years ago. Protein therapeutics already have a significant role in almost every field of medicine, but this role is still only in its infancy. This article overviews some of the key characteristics of protein therapeutics, summarizes the more than 130 protein therapeutics used currently and suggests a new classification of these proteins according to their pharmacological action.

Protein therapeutics: a summary and pharmacological classification

The insulin-like growth factor 1 (IGF1) signalling pathway has important roles in regulating cellular proliferation and apoptosis. Converging results from epidemiological research and in vivo carcinogenesis models indicate that high levels of circulating IGF1 are associated with increased risk of several common cancers. Ongoing research seeks to clarify the mechanisms underlying these observations and to determine the extent to which IGF physiology influences patterns of cancer incidence. Various therapeutic strategies that target the IGF1 receptor have demonstrated impressive antineoplastic activity in laboratory models, and clinical trials of several novel drug candidates are planned.

Insulin-like growth factors and neoplasia.

Background. The declining activity of the growth hormone-insulin-like growth factor I (IGF-I) axis with advancing age may contribute to the decrease in lean body mass and the increase in mass of adipose tissue that occur with aging. Methods. To test this hypothesis, we studied 21 healthy men from 61 to 81 years old who had plasma IGF-I concentrations of less than 350 U per liter during a six-month base-line period and a six-month treatment period that followed. During the treatment period, 12 men (group 1) received approximately 0.03 mg of biosynthetic human growth hormone per kilogram of body weight subcutaneously three times a week, and 9 men (group 2) received no treatment. Plasma IGF-I levels were measured monthly. At the end of each period we measured lean body mass, the mass of adipose tissue, skin thickness (epidermis plus dermis), and bone density at nine skeletal sites. In group 1, the mean plasma IGF-I level rose into the youthful range of 500 to 1500 U per liter during treatment, where...

Effects of Human Growth Hormone in Men over 60 Years Old

Background: Antiestrogens are effective in the treatment of estrogen receptor (ER) positive breast carcinoma. The use of antiestrogen therapy in pituitary adenomas, however, has not been explored. This study attempted to identify a population who may benefit from antiestrogen therapy.

Estrogen receptors in prolactinomas: a clinico-pathological study.

Medical therapy plays an important role in the management of patients with acromegaly and is commonly used adjunctively after surgical resection of the pituitary tumor. Generally, surgery alone provides a 50 to 70% rate of cure; however, the outcome depends on the experience and ability of the surgeon and the characteristics of the tumor. The role of postsurgical medical therapy is to achieve long-term biochemical control of the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis. In some patients, medical therapies may be implemented sooner as primary or preoperative therapy. Somatostatin analogs have been the mainstay of medical therapy for acromegaly. The somatostatin analog octreotide produces normalization of IGF-I in approximately 50% of patients but is associated with gastrointestinal adverse effects, including the development of gallstones. Octreotide requires thrice-daily subcutaneous administration. Long-acting formulations of somatostatin analogs (octreotide LAR, lanreotide) are at least as effective and as well tolerated as short-acting octreotide. Unfortunately, some patients are suboptimally responsive to or become intolerant of these agents. Pegvisomant belongs to a new class of agents known as GH-receptor antagonists. This novel agent competitively binds to the GH receptor, blocking IGF-I production. Pegvisomant is highly effective in achieving normal IGF-I concentrations and in reducing signs and symptoms of acromegaly, even in patients resistant to previous treatments. Pegvisomant has been proved safe and well tolerated and has no effect on gallbladder motility. GH levels remain elevated. Transient elevations in liver enzyme levels require monitoring but rarely necessitate termination of therapy. Normalizing IGF-I concentrations with pegvisomant also may have a beneficial effect on carbohydrate metabolism and cardiovascular risk.

Role of medical therapy in the management of acromegaly

The usual first treatment for Cushing’s disease is surgical removal of the pituitary adenoma. In patients in whom surgery is unsuccessful or who decline an operation, radiation to the pituitary offers the possibility of remission. No form of radiation delivery results in immediate control of cortisol production. Thus, until radiation treatment becomes effective, medical therapy to lower cortisol production is indicated. The time to remission with radiation therapy cannot be predicted, medical therapy should be discontinued every 6 months to assess response to radiation treatment; a normal 24 h urine free cortisol being the optimal outcome. There are no prospective studies comparing the results among the different types of radiation delivery. The type of radiation delivery depends on several factors, including the availability of different treatment modalities and the size of the target area (focused high dose radiation with the Gamma knife is not suitable for a large lesion close to the optic nerves or optic chiasm). All types of radiation delivery cause loss of normal pituitary function and patients should be monitored regularly (every 6 months) for development of new hypopituitarism and appropriate hormone replacement(s). Complications of radiation therapy may include adverse effects on vision, normal brain tissue, and with older methods of fractionated radiation delivery, vasculopathy with an increased risk of cerebrovascular disease. Current use of more targeted methods of delivery will hopefully reduce this risk. If pituitary surgery is unsuccessful and the patient undergoes bilateral adrenalectomy, without pituitary radiation, there is a substantial risk, approximately 50% of patients, of development of Nelson’s syndrome (growth of pituitary adenoma, increase in serum ACTH, hyperpigmentation). There is a role for pituitary radiation in the treatment of patients with Cushing’s disease, most commonly as adjunctive therapy after unsuccessful pituitary surgery. Regular medical monitoring is necessary to determine the effectiveness of radiation therapy and development of new pituitary hormone deficiency.

Cushing's disease: radiation therapy.

Objective Gamma Knife radiosurgery (GKRS) provides a safe and effective management option for patients with all types of pituitary adenomas. The long-term adverse effects of targeted radiation to the hypothalamic-pituitary axis in relationship to radiation dose remain unclear. In this retrospective review, the authors investigated the role of differential radiation doses in predicting long-term clinical outcomes and pituitary function after GKRS for pituitary adenomas. Methods A cohort of 236 patients with pituitary tumors (41.5% nonfunctioning, 58.5% functioning adenomas) was treated with GKRS between 1998 and 2015. Point dosimetric measurements, with no minimum volume, to 14 consistent points along the hypothalamus bilaterally, pituitary stalk, and normal pituitary were made. Statistical analyses were performed to determine the impact of doses to critical structures on clinical, radiological, and endocrine outcomes. Results With a median follow-up duration of 42.9 months, 18.6% of patients developed new loss of pituitary function. The median time to endocrinopathy was 21 months (range 2-157 months). The median dose was 2.1 Gy to the hypothalamus, 9.1 Gy to the pituitary stalk, and 15.3 Gy to the normal pituitary. Increasing age (p = 0.015, HR 0.98) and ratio of maximum dose to the pituitary stalk over the normal pituitary gland (p = 0.013, HR 0.22) were independent predictors of new or worsening hypopituitarism in the multivariate analysis. Sex, margin dose, treatment volume, nonfunctioning adenoma status, or ratio between doses to the pituitary stalk and hypothalamus were not significant predictors. Conclusions GKRS offers a low rate of delayed pituitary insufficiency for pituitary adenomas. Doses to the hypothalamus are low and generally do not portend endocrine deficits. Patients who are treated with a high dose to the pituitary stalk relative to the normal gland are at higher risk of post-GKRS endocrinopathy. Point dosimetry to specific neuroanatomical structures revealed that a ratio of stalk-to-gland radiation dose of 0.8 or more significantly increased the risk of endocrinopathy following GKRS. Improvement in the gradient index toward the stalk and normal gland may help preserve endocrine function.

Radiation dose to neuroanatomical structures of pituitary adenomas and the effect of Gamma Knife radiosurgery on pituitary function.

Prior to the discovery of insulin, linear growth failure was common among children with IDDM (1). And descriptive studies of growth velocity in the early insulin era identified significant subsets of children with marked growth failure (2). An extreme example of stunted growth, the Mauriac Syndrome—characterized by obesity, hepatomegaly and delayed puberty—was described and successfully treated with appropriate insulin administration and, more specifically, newer longer-acting insulin preparations (3). Today, children with this syndrome rarely are seen. Since the introduction of insulin therapy in IDDM more than 60 years ago, marked changes in the species, purity, duration of action, and mode of delivery have occurred, and improved methods for monitoring disease activity have been developed. Growth failure is not a common finding in pediatric diabetes clinics today; instead, it is seen only in the exceptional child with chronic underinsulinization and/or IDDM-associated acquired hypothyroidism. Studies of intermediary metabolism and glucose counterregulation, however, have identified marked abnormalities in the hypothalamic-pituitarygrowth axis in children with IDDM, even in those who are growing normally. Such findings suggest that even today's more modest levels of hyperglycemia and/or underinsulinization could be associated with potentially serious consequences for children in the future, including the development and progression of diabetic retinopathy. In this report, we review current knowledge concerning the pathophysiology of the growth axis in IDDM children and the mechanisms responsible for the abnormalities observed. In addition, we review studies of children with alterations in linear growth prior to the onset of clinical diabetes mellitus.

Mary Lee Vance

Papers

Estrogen receptors in prolactinomas: a clinico-pathological study.

Role of medical therapy in the management of acromegaly

Cushing's disease: radiation therapy.

Radiation dose to neuroanatomical structures of pituitary adenomas and the effect of Gamma Knife radiosurgery on pituitary function.

Growth and the Child with Diabetes Mellitus