Objective Hemangioblastomas of the posterior cranial fossa and spinal cord in adults are excessively vascularized, well-differentiated, and scarce tumors with no metastatic potential. This paper discusses its surgical management and outcome, pointing out their morphological, radiological, and histopathological aspects. This report based on a personal series of six patients and on a literature review. Methods A single-institution personal 6-case series of adult patients diagnosed and operated on by a senior neurosurgeon (KIA) due to posterior cranial fossa or spinal cord hemangioblastoma was analyzed. For easier understanding of hemangioblastoma, we have classified them into four different types. Results The tumors, which were all surgically treated, were located in the posterior cranial fossa in five patients (4 cerebellar, 1 brain stem) and intramedullary in the thoracic spinal cord in one patient. All patients successfully recovered neurologically after a complete tumor resection, having no post-operative neurological deficit or other complications. Conclusion Surgical management of cerebellar and spinal cord hemangioblastoma in adults is highly dependent on its morphological features, as well as on microsurgical technique applied. Since huge differences exist between the cystic/nodular tumor type (Type 1) and the solid type and its two additional variants (Types 2-4), morphology is the most important consideration when deciding surgical approach. Despite significant morphological differences among different subtypes of hemangioblastomas, their histology appears to be relatively similar. Nonetheless, a meticulous and refined surgical technique has to be utilized to achieve a successful outcome.

Spinal dumbbell tumors are defined by a narrowing at the point where they penetrate the intervertebral foramina or dura mater, assuming an hourglass or dumbbell shape. Dumbbell-shaped spinal hemangiomas are extremely rare. We describe a dumbbell spinal tumor (epidural cavernous hemangioma) resected by a 2-stage single-sitting combined approach. We also conduct a substantial literature review of the subject. We present a case of a 78-year-old male who was found to have a homogeneously enhancing, dumbbell-shaped, intraspinal, extradural tumor mass extending into the left chest cavity. The tumor was resected with a single-sitting 2-stage posterior technique: a microsurgical approach, followed by endoscopic resection via a thoracoscopic approach. There are several reports in the literature on the combined approach for dumbbell tumors of the spinal cord. Our case is the first to describe 2-stage combined surgery in 1 sitting for dumbbell hemangioma with the patient in the lateral decubitus position for the thoracoscopic part of the surgery; and the use of a fat pad, which was applied in the neuroforamen via the posterior route, as a marker for resection during the transthoracic procedure.

Background We report a case of isolated metastasis on the anterior clinoid process (ACP) mimicking meningioma. Clinical Presentation A 58-year-old male presented with headaches, right-sided visual disturbances, and blurred and double vision. The cause of double vision was partial weakness of the right III nerve, resulting from compression of the nerve by “hypertrophied” tumor-involved right anterior clinoid. Medical history revealed two primary malignant tumors—male breast cancer and prostate cancer (diagnosed 6 and 18 months prior, respectively). The patient was treated with chemotherapy and showed no signs of active disease, recurrence, or metastasis. Postcontrast head magnetic resonance imaging (MRI) showed extra-axial well-bordered enhancing mass measuring 1.6 × 1.1 × 1 × 1 cm (anteroposterior, transverse, and craniocaudal dimensions) on the ACP, resembling a clinoidal meningioma. Extradural clinoidectomy with tumor resection was performed via right orbitozygomatic pretemporal skull base approach. Visual symptoms improved. Follow-up MRI showed no signs of tumor residual or recurrence. Conclusion This is the first case report of a metastasis of any kind on ACP. Metastasis should be included as a part of the differential diagnosis of lesions of the anterior clinoid. Extradural clinoidectomy is a safe and effective method in the treatment of these tumors.

Glioma-Initiating Cells (GICs) are thought to be responsible for tumor initiation, progression and recurrence in glioblastoma (GBM). In previous studies, we reported the constitutive phosphorylation of the STAT3 transcription factor in GICs derived from GBM patient-derived xenografts, and that STAT3 played a critical role in GBM tumorigenesis. In this study, we show that CRISPR/Cas9-mediated deletion of STAT3 in an established GBM cell line markedly inhibited tumorigenesis by intracranial injection but had little effect on cell proliferation in vitro. Tumorigenesis was rescued by the enforced expression of wild-type STAT3 in cells lacking STAT3. In contrast, GICs were highly addicted to STAT3 and upon STAT3 deletion GICs were non-viable. Moreover, we found that STAT3 was constitutively activated in GICs by phosphorylation on both tyrosine (Y705) and serine (S727) residues. Therefore, to study STAT3 function in GICs we established an inducible system to knockdown STAT3 expression (iSTAT3-KD). Using this approach, we demonstrated that Y705-STAT3 phosphorylation was critical and indispensable for GIC-induced tumor formation. Both phosphorylation sites in STAT3 promoted GIC proliferation in vitro. We further showed that S727-STAT3 phosphorylation was Y705-dependent. Targeted microarray and RNA sequencing revealed that STAT3 activated cell-cycle regulator genes, and downregulated genes involved in the interferon response, the hypoxia response, the TGFβ pathway, and remodeling of the extracellular matrix. Since STAT3 is an important oncogenic driver of GBM, the identification of these STAT3 regulated pathways in GICs will inform the development of better targeted therapies against STAT3 in GBM and other cancers.

BACKGROUND:Rathke cleft cysts (RCCs) and pituitary adenomas (PAs) are thought to have a common embryonic ancestry; however, PAs with a concomitant RCC inside the sella turcica are rarely observed. Ectopic pituitary tumors are also rare.CASE DESCRIPTION:We present the case of a 65-year-old woman with an ectopic RCC in the sphenoid sinus and outside the sella turcica concomitant with an adrenocorticotropic hormone (ACTH)-staining, clinically silent PA. The patient had headache but no endocrine or visual disturbances. Preoperative magnetic resonance imaging revealed infrasellar cystic lesion in the sphenoid sinus with erosion of the clivus and intact sellar floor. The patient underwent gross total microsurgical resection through the transnasal route with an uneventful postoperative course.CONCLUSIONS:To our knowledge, this is the first reported ectopic RCC located outside the sella turcica with a concomitant ACTH-staining PA. This also appears to be the first ACTH-staining adenoma concomitant with RCC reported in the literature, regardless of location, not presenting with Cushing disease. This case shows that we can now include pituitary adenoma with or without a concomitant RCC in the differential diagnosis of processes in the sphenoid sinus. As both PAs and RCCs are benign sellar lesions, surgical management of a concomitant occurrence of these tumors mainly depends on the size of the lesions and their clinical manifestations. For patients with PA and concomitant RCC, surgical resection should be considered, as there is an approximatrely 20% recurrence rate of the cyst after resection and the possibility of future clival erosion, if left untreated.

Skin is the largest body organ forming a metabolically active barrier between external and internal environments. The metabolic barrier is composed of cytochromes P450 (CYPs) that regulate its homeostasis through activation or inactivation of biologically relevant molecules. In this review we focus our attention on local steroidogenic and secosteroidogenic systems in relation to skin cancer, e.g., prevention, attenuation of tumor progression and therapy. The local steroidogenic system is composed of locally expressed CYPs involved in local production of androgens, estrogens, gluco- and mineralo-corticosteroids from cholesterol (initiated by CYP11A1) or from steroid precursors delivered to the skin, and of their metabolism and/or inactivation. Cutaneous 7-hydroxylases (CYP7A1, CYP7B1 and CYP39) potentially can produce 7-hydroxy/oxy-steroids/sterols with modifying effects on local tumorigenesis. CYP11A1 also transforms 7-dehydrocholesterol (7DHC)→22(OH)7DHC→20,22(OH)2-7DHC→7-dehydropregnenolone, which can be further metabolized to other 5,7- steroidal dienes. These 5,7-dienal intermediates are converted by ultraviolet radiation B (UVB) into secosteroids which show pro-differentiation and anti-cancer properties. Finally, the skin is the site of activation of vitamin D3 through two alternative pathways. The classical one involves sequential hydroxylation at positions 25 and 1 to produce active 1,25(OH)2D3, which is further inactivated through hydroxylation at C24. The novel pathway is initiated by CYP11A1 with predominant production of 20(OH)D3 which is further metabolized to biologically active but non-calcemic D3-hydroxyderivatives. Classical and non-classical (novel) vitamin D analogs show pro-differentiation, anti-proliferative and anticancer properties. In addition, melatonin is metabolized by local CYPs. In conclusion cutaneously expressed CYPs have significant effects on skin physiology and pathology trough regulation of its chemical milieu.

The discovery of corticotropin-releasing factor (CRF) or CRH defining the upper regulatory arm of the hypothalamic-pituitary-adrenal (HPA) axis, along with the identification of the corresponding receptors (CRFRs 1 and 2), represents a milestone in our understanding of central mechanisms regulating body and local homeostasis. We focused on the CRF-led signaling systems in the skin and offer a model for regulation of peripheral homeostasis based on the interaction of CRF and the structurally related urocortins with corresponding receptors and the resulting direct or indirect phenotypic effects that include regulation of epidermal barrier function, skin immune, pigmentary, adnexal, and dermal functions necessary to maintain local and systemic homeostasis. The regulatory modes of action include the classical CRF-led cutaneous equivalent of the central HPA axis, the expression and function of CRF and related peptides, and the stimulation of pro-opiomelanocortin peptides or cytokines. The key regulatory role is assigned to the CRFR-1α receptor, with other isoforms having modulatory effects. CRF can be released from sensory nerves and immune cells in response to emotional and environmental stressors. The expression sequence of peptides includes urocortin/CRF→pro-opiomelanocortin→ACTH, MSH, and β-endorphin. Expression of these peptides and of CRFR-1α is environmentally regulated, and their dysfunction can lead to skin and systemic diseases. Environmentally stressed skin can activate both the central and local HPA axis through either sensory nerves or humoral factors to turn on homeostatic responses counteracting cutaneous and systemic environmental damage. CRF and CRFR-1 may constitute novel targets through the use of specific agonists or antagonists, especially for therapy of skin diseases that worsen with stress, such as atopic dermatitis and psoriasis.

Hypoxia-inducible factor-1α (HIF-1α) is a highly oxygen sensitive bHLH protein that is part of the heterodimeric HIF-1 transcription factor. Under hypoxic stress, HIF-1 activity is induced to control expression of multiple downstream target genes, including vascular endothelial growth factor (VEGF). The normal epidermis exists in a constant mild hypoxic microenvironment and constitutively expresses HIF-1α and HIF-2α. Expression of HIF-1α and/or HIF-2α has been suggested to correlate with the increased malignant potential of melanocytes, therefore, failures of melanoma therapies may be partially linked to high HIF activity. Notably, melanomas that have the V600E BRAF mutation exhibit increased HIF-1α expression. We have utilized a bioinformatics approach to identify putative hypoxia response elements (HREs) in a set of genes known to participate in the process of melanogenesis (includingTRPM1, SLC45A2, HRAS, C-KIT, PMEL and CRH). While some of the mechanistic links between these genes and the HIF pathway have been previously explored, others await further investigation. Although agents targeting HIF activity have been proposed as novel treatment modalities for melanoma, there are currently no clinical trials in progress to test their efficacy in melanoma.

The skin has developed a hierarchy of systems that encompasses the skin immune and local steroidogenic activities in order to protect the body against the external environment and biological factors and to maintain local homeostasis. Most recently it has been established that skin cells contain the entire biochemical apparatus necessary for production of glucocorticoids, androgens and estrogens either from precursors of systemic origin or, alternatively, through the conversion of cholesterol to pregnenolone and its subsequent transformation to biologically active steroids. Examples of these products are corticosterone, cortisol, testosterone, dihydrotesterone and estradiol. Their local production can be regulated by locally produced corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) or cytokines. Furthermore the production of glucocorticoids is affected by ultraviolet B radiation. The level of production and nature of the final steroid products are dependent on the cell type or cutaneous compartment, e.g., epidermis, dermis, adnexal structures or adipose tissue. Locally produced glucocorticoids, androgens and estrogens affect functions of the epidermis and adnexal structures as well as local immune activity. Malfunction of these steroidogenic activities can lead to inflammatory disorders or autoimmune diseases. The cutaneous steroidogenic system can also have systemic effects, which are emphasized by significant skin contribution to circulating androgens and/or estrogens. Furthermore, local activity of CYP11A1 can produce novel 7Δ-steroids and secosteroids that are biologically active. Therefore, modulation of local steroidogenic activity may serve as a new therapeutic approach for treatment of inflammatory disorders, autoimmune processes or other skin disorders. In conclusion, the skin can be defined as an independent steroidogenic organ, whose activity can affect its functions and the development of local or systemic inflammatory or autoimmune diseases. This article is part of a Special Issue entitled 'CSR 2013'.

Corticotropin-Releasing Factor (CRF), a 41 amino acid long hypothalamic neuropeptide discovered by Vale and Rivier (Spiess et al. 1981; Vale et al. 1981), and related urocortin (Urc1-3) are brain neuropeptides that regulate behavioral, autonomic, endocrine, reproductive, metabolic, and immune functions (Grammatopoulos and Chrousos 2002; Hillhouse et al. 2002; Perrin and Vale 1999). In peripheral tissues, they act as local immunomodulators with predominantly proinflammatory actions (Hasse et al. 2007; Slominski 2003b; Slominski et al. 2006c; Theoharides and Cochrane 2004) as well as they directly regulate cardiovascular, gastrointestinal, reproductive, and gestational activities (Hillhouse et al. 2002). These neuropeptides exert their regulatory activities via interaction with CRF receptors, CRF1 and CRF2, which were cloned and initially characterized by Vale's group and others (Grammatopoulos and Chrousos 2002; Hillhouse and Grammatopoulos 2006; Hillhouse et al. 2002; Perrin and Vale 1999; Slominski et al. 2001).

Endocannabinoids (ECS) constitute lipid mediators (amides, esters, and ethers of long chain polyunsaturated fatty acids) which act similarly to the exogenous Δ9 tetrahydrocannabinol (THC; the main psychoactive ingredient of the plant Cannabis sativa) and are produced in humans and animals (Maccarrone et al. 2003; Rahn and Hohmann 2009). The cutaneous ECS system is fully functional due to the expression of ECS and their receptors as well as ECS-degrading enzymes. All the components of the skin ECS system were shown to modulate the proliferation, differentiation, growth, and apoptosis of various skin cell types as well as tumorigenesis and local cytokine production (reviewed by Biro et al. 2009; Kupczyk et al. 2009; Toth et al. 2011). ECS are synthesized “on demand” by receptor-stimulated cleavage of membrane lipid precursors and are not stored in synaptic vesicles which distinguishes them from typical neurotransmitters. ECS reuptake may be facilitated by a transporter that has not been cloned yet; however, pharmacological inhibitors of ECS transport have nonetheless been developed (Guindon and Hohmann 2009). The lipophilic nature of ECS allows them to activate various enzymes in cytosol and membraneous compartments (Kupczyk et al. 2009).

Melatonin production is highly conserved in nature through different species including bacteria, unicellular eukaryotes, algae, plants invertebrates, and vertebrates (Hardeland et al. 2011; Reiter 1991; Slominski et al. 2008a; Tan et al. 2002; Yu and Reiter 1993). In mammals, melatonin is produced in the pineal gland (Reiter 1991) as well as in brain, retina, Harderian gland, ciliary body, lens, thymus, airway epithelium, bone marrow, immune cells, gonads, placenta, gastrointestinal tract, and skin (Bubenik 2002; Carrillo-Vico et al. 2004; Hardeland et al. 2011; Kanda and Watanabe 2007; Pandi-Perumal et al. 2006; Slominski et al. 2005a, 2008a; Watson 1994; Zmijewski et al. 2009b), and perhaps other organs. Circulating melatonin predominantly derives from the pineal gland by diffusion into the circulation, although entry from other extra-pineal sites of production is also possible.

The work of Hans Selye was fundamental in defining the hypothalamic–pituitary–adrenal (HPA) axis as the body’s important coordinator of responses to systemic stress (Selye 1936; Seyle 1976). The HPA functional structure has been completed by determining that hypothalamic corticotropin-releasing factor (CRF) acts as the regulator of the production of ACTH and β-endorphin in the anterior pituitary (Spiess et al. 1981; Vale et al. 1981). The HPA pathway (Fig. 7.1) is triggered by various stress factors which activate production of CRF in the paraventricular nucleus (PVN) (Chrousos 1995; Chrousos and Gold 1992; Owens and Nemeroff 1991). In pituitary CRF binds to CRF type 1 receptors (CRF1) (Aguilera et al. 2001; Hillhouse and Grammatopoulos 2006; Perrin and Vale 1999) increasing production and secretion of the proopiomelanocortin (POMC)-derived peptides, i.e., ACTH, MSH, and β-endorphin (Hillhouse and Grammatopoulos 2006; Pritchard and White 2007; Smith and Funder 1988). The arginine vasopressin (AVP) produced by the PVN can also act synergistically with CRF in activating the HPA axis (Chrousos 1995; Itoi et al. 2004). In the adrenal cortex ACTH, by interacting with the MC2 receptors (MC2-R), stimulates production and secretion of cortisol in humans or corticosterone in rodents. These corticosteroids counteract the effects of stressors by mobilization of energy reserves, buffering tissue damages, and suppressing immune system. Moreover, corticosteroids via feedback mechanisms inhibit the HPA axis through the suppression of CRF and POMC production. The HPA axis is also controlled by cytokines, tissue modifiers, and growth factors, which can be either produced in the brain or by peripheral tissues including cells of the immune system. Thus, there are various ways of controlling stress responses at the level of hypothalamus or pituitary that bypass the central brain coordinating centers (c.f. in Besedovsky and Rey 2007; Blalock and Smith 2007; Chesnokova and Melmed 2002) (Fig. 7.1).

Skin, the body's largest organ, is strategically located at the interface with the external environment where it detects, integrates, and responds to a diverse range of stressors including solar radiation. It has already been established that the skin is an important peripheral neuro-endocrine-immune organ that is tightly networked to central regulatory systems. These capabilities contribute to the maintenance of peripheral homeostasis. Specifically, epidermal and dermal cells produce and respond to classical stress neurotransmitters, neuropeptides, and hormones. Such production is stimulated by ultraviolet radiation (UVR), biological factors (infectious and noninfectious), and other physical and chemical agents. Examples of local biologically active products are cytokines, biogenic amines (catecholamines, histamine, serotonin, and N-acetyl-serotonin), melatonin, acetylocholine, neuropeptides including pituitary (proopiomelanocortin-derived ACTH, beta-endorphin or MSH peptides, thyroid-stimulating hormone) and hypothalamic (corticotropin-releasing factor and related urocortins, thyroid-releasing hormone) hormones as well as enkephalins and dynorphins, thyroid hormones, steroids (glucocorticoids, mineralocorticoids, sex hormones, 7-delta steroids), secosteroids, opioids, and endocannabinoids. The production of these molecules is hierarchical, organized along the algorithms of classical neuroendocrine axes such as hypothalamic-pituitary-adrenal axis (HPA), hypothalamic-thyroid axis (HPT), serotoninergic, melatoninergic, catecholaminergic, cholinergic, steroid/secosteroidogenic, opioid, and endocannbinoid systems. Dysregulation of these axes or of communication between them may lead to skin and/ or systemic diseases. These local neuroendocrine networks are also addressed at restricting maximally the effect of noxious environmental agents to preserve local and consequently global homeostasis. Moreover, the skin-derived factors/systems can also activate cutaneous nerve endings to alert the brain on changes in the epidermal or dermal environments, or alternatively to activate other coordinating centers by direct (spinal cord) neurotransmission without brain involvement. Furthermore, rapid and reciprocal communications between epidermal and dermal and adnexal compartments are also mediated by neurotransmission including antidromic modes of conduction. In conclusion, skin cells and skin as an organ coordinate and/or regulate not only peripheral but also global homeostasis.