The insulin-like growth factor system and cancer.

Traumatic spinal cord injury (SCI) has devastating consequences for the physical, social and vocational well-being of patients. The demographic of SCIs is shifting such that an increasing proportion of older individuals are being affected. Pathophysiologically, the initial mechanical trauma (the primary injury) permeabilizes neurons and glia and initiates a secondary injury cascade that leads to progressive cell death and spinal cord damage over the subsequent weeks. Over time, the lesion remodels and is composed of cystic cavitations and a glial scar, both of which potently inhibit regeneration. Several animal models and complementary behavioural tests of SCI have been developed to mimic this pathological process and form the basis for the development of preclinical and translational neuroprotective and neuroregenerative strategies. Diagnosis requires a thorough patient history, standardized neurological physical examination and radiographic imaging of the spinal cord. Following diagnosis, several interventions need to be rapidly applied, including haemodynamic monitoring in the intensive care unit, early surgical decompression, blood pressure augmentation and, potentially, the administration of methylprednisolone. Managing the complications of SCI, such as bowel and bladder dysfunction, the formation of pressure sores and infections, is key to address all facets of the patient's injury experience.

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Traumatic spinal cord injury

Method of monitoring or diagnosing disease conditions, including disease of the prostate, that involve measuring a combination of tumor markers and at least one component of the IGF axis. The invention is exemplified with prostate cancer and benign prostatic hyperplasia, the tumor marker prostate specific antigen, and the insulin-like growth factors and their binding proteins.

Insulin-like growth factor system and cancer

The recent completion of the first draft of the human genome sequence and advances in technologies for genomic analysis are generating tremendous opportunities for epidemiologic studies to evaluate the role of genetic variants in human disease. Many methodological issues apply to the investigation of variation in the frequency of allelic variants of human genes, of the possibility that these influence disease risk, and of assessment of the magnitude of the associated risk. Based on a Human Genome Epidemiology workshop, a checklist for reporting and appraising studies of genotype prevalence and studies of gene-disease associations was developed. This focuses on selection of study subjects, analytic validity of genotyping, population stratification, and statistical issues. Use of the checklist should facilitate the integration of evidence from these studies. The relation between the checklist and grading schemes that have been proposed for the evaluation of observational studies is discussed. Although the limitations of grading schemes are recognized, a robust approach is proposed. Other issues in the synthesis of evidence that are particularly relevant to studies of genotype prevalence and gene-disease association are discussed, notably identification of studies, publication bias, criteria for causal inference, and the appropriateness of quantitative synthesis.

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Reporting, Appraising, and Integrating Data on Genotype Prevalence and Gene-Disease Associations

Insulin-like growth factors (IGFs) are important mediators of growth, development, and survival, are synthesized by almost any tissue in the body, and their action is modulated by a complex network of molecules, including binding proteins, proteases and receptors, which all comprise the IGF system. Evidence from in vitro and animal studies suggests that overexpression of IGFs by cancer cells and/or the nearby stroma as well as the type IGF-I receptor by the cancer cells may play a significant role in establishing a transformed phenotype in an increasing number of malignancies. More specifically, IGFs may promote cell cycle progression and inhibition of apoptosis either by directly associating with other growth factors or indirectly by interacting with other molecular systems which have an established role in carcinogenesis and cancer promotion, such as the steroid hormones and integrins. In addition, a growing number of epidemiologic studies suggest that increased serum levels of IGFs and/or altered levels of their binding proteins are associated with increased risk for developing several malignancies. These data indicate that IGF dysregulation should now be considered as an important independent factor for cancer risk, and a potential target for novel antineoplastic therapies and/or preventative strategies in high-risk groups.

The role of the IGF system in cancer: from basic to clinical studies and clinical applications.

Neurogenic bladder dysfunction due to spinal cord injury poses a significant threat to the well-being of patients. Incontinence, renal impairment, urinary tract infection, stones, and poor quality of life are some complications of this condition. The majority of patients will require management to ensure low pressure reservoir function of the bladder, complete emptying, and dryness. Management typically begins with anticholinergic medications and clean intermittent catheterization. Patients who fail this treatment because of inefficacy or intolerability are candidates for a spectrum of more invasive procedures. Endoscopic managements to relieve the bladder outlet resistance include sphincterotomy, botulinum toxin injection, and stent insertion. In contrast, patients with incompetent sphincters are candidates for transobturator tape insertion, sling surgery, or artificial sphincter implantation. Coordinated bladder emptying is possible with neuromodulation in selected patients. Bladder augmentation, usually with an intestinal segment, and urinary diversion are the last resort. Tissue engineering is promising in experimental settings; however, its role in clinical bladder management is still evolving. In this review, we summarize the current literature pertaining to the pathology and management of neurogenic bladder dysfunction in patients with spinal cord injury.

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Neurogenic bladder in spinal cord injury patients.

Finasteride, a competitive and specific inhibitor of 5alpha-reductase, is widely used in the treatment of symptomatic benign prostatic hyperplasia. We demonstrate here that finasteride, when administered in an in vivo experimental system, caused ventral prostate regression. Intraprostatic dihydrotestosterone levels decreased, whereas testosterone levels increased in a dose-dependent manner following finasteride treatment. Finasteride also inhibited the expression of insulin-like growth factor (IGF)-I and IGF-I receptor genes in the ventral prostate. Finasteride significantly increased IGF binding protein-3 and slightly decreased IGF binding protein-2, -4, and -5 gene expression. Because IGFs are potent mitogens for prostate epithelial cells, this newly described activity of finasteride may contribute to its antiproliferative properties, particularly with regard to the inhibition of prostate growth seen clinically and in animal models.

https://cancerres.aacrjournals.org/content/canres/58/2/215.full.pdf

Reduction of Ventral Prostate Weight by Finasteride Is Associated with Suppression of Insulin-like Growth Factor I (IGF-I) and IGF-I Receptor Genes and with an Increase in IGF Binding Protein 3

Pheochromocytoma in children and adolescents: a clinical spectrum.

Renal angiomyolipoma (RAML), though a rare benign tumor, may impose a significant morbidity or even mortality due to its unique characteristics and the complications subsequent to its treatment. The classic tumor variant is composed of smooth muscular, vascular, and fatty components. The most straightforward diagnosis is when the fat component is abundant and gives a characteristic appearance on different imaging studies. In fat-poor lesions, however, the diagnosis is difficult and presumed a renal cell carcinoma. Yet, some variants of RAML, though rare, express an aggressive behavior leading to metastasis and mortality. The challenge lies in the early detection of benign variants and identifying aggressive lesions for proper management. Another challenge is when the vascular tissue component predominates and poses a risk of hemorrhage that may extend to the retroperitoneum in a massive life-threatening condition. The predicament here is to identify the characteristics of tumors at risk of bleeding and provide a prophylactic treatment. According to the clinical presentation, different treatment modalities, prophylactic or therapeutic, are available that span the spectrum of observation, embolization, or surgery. Renal impairment may result from extensive tumor burden or as a complication of the management itself. Improvement of diagnostic techniques, super-selective embolization, nephron-sparing surgery, and late treatment with the mammalian target of rapamycin inhibitors have provided more effective and safe management strategies. In this review, we examine the evidence pertaining to the risks imposed by RAML to the patients and identify merits and hazards associated with different treatment modalities.

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The Risks of Renal Angiomyolipoma: Reviewing the Evidence

Background: Microdissection testicular sperm extraction (microTESE) has become the standard of care for sperm retrieval in non-obstructive azoospermia (NOA) patients. Understanding the significant determinants of microTESE outcomes may result in improvements in sperm retrieval rates and provide better-informed clinical decisions. Methods: This is a clinical retrospective study conducted through chart review of 421 NOA patients who underwent microTESE between August 2009 and July 2015 in a tertiary-care referral hospital. Clinical, biochemical and histopathological characteristics were collected. Normal serum testosterone level was defined as testosterone >9.9 nmol/L. Multiple logistic regression was used to identify determinants of microTESE in the studied population. A P Results: Sperms were successfully retrieved in 39.4% of cases. The average testosterone level was 11.51±7.40 and 11.67±6.42 in patients with successful and unsuccessful microTESE, respectively (P=0.820). No significant association was found between serum testosterone level and sperm motility and amount. Of all variables, histological subtype remained to be the most significant determinant of microTESE outcomes in the examined population, with hypospermatogenesis having over a 3-fold higher odd of successful microTESE than sertoli-cell only. Conclusions: Serum testosterone level appears to have no significant association with microTESE outcomes in NOA. The underlying histological pattern is a significant determinant of the procedure’s success.

/pdf/serum-testosterone-levels-and-other-determinants-of-sperm-4bq1uri3fk.pdf

Raouf M. Seyam

Papers

Neurogenic bladder in spinal cord injury patients.

Reduction of Ventral Prostate Weight by Finasteride Is Associated with Suppression of Insulin-like Growth Factor I (IGF-I) and IGF-I Receptor Genes and with an Increase in IGF Binding Protein 3

Pheochromocytoma in children and adolescents: a clinical spectrum.

The Risks of Renal Angiomyolipoma: Reviewing the Evidence

Serum testosterone levels and other determinants of sperm retrieval in microdissection testicular sperm extraction.