Craniopharyngioma is a rare neoplasm in the rat, and few cases have been described. These lesions are thought to originate from squamous cell remnants of Rathke's pouch, an evagination of primitive stomatodeum. This neoplasm is usually locally invasive, and neither cranial nor extracranial metastases have been described. A spontaneously occurring malignant, metastasizing craniopharyngioma arising from the neurohypophysis was detected in a 2-year-old male albino rat. The infiltrative growth was observed in the wall of the vessels of the circle of Willis, in the perivascular space of Virchow and Robin, in the submeningeal space near the hypothalamus, through the fissura chorioidea, in the medulla oblongata, and along the optic nerve into the periocular region. Metastases were detected in the thalamus and hippocampus. The diagnosis was made on the basis of microscopic, immunocytochemical and ultrastructural findings.

There is a substantial research gap regarding analgesic interventions for children and adolescents with chronic pain. Most clinical trials in the field focus on the evaluation of non-pharmacological interventions and are of low methodological quality. There is also a specific lack of trials involving infants and children and adolescents with long-lasting diseases.

The complex hematopoietic effects of placental growth factor (PlGF) prompted us to test in mice and nonhuman primates the mobilization of peripheral blood progenitor cells (PBPCs) elicited by recombinant mouse PlGF-2 (rmPlGF-2) and recombinant human PlGF-1 (rhPlGF-1). PBPC mobilization was evaluated by assaying colonyforming cells (CFCs), high-proliferative potential-CFCs (HPP-CFCs), and long-term culture-initiating cells (LTCICs). In mice, both rmPlGF-2 and rhPlGF-1 used as single agents failed to mobilize PBPCs, whereas the combination of rhPlGF-1 and granulocyte colony-stimulating factor (rhG-CSF) increased CFCs and LTC-ICs per milliliter of blood by four-and eightfold, respectively, as compared with rhG-CSF alone. rhPlGF-1 plus rhG-CSF significantly increased matrix metalloproteinase-9 plasma levels over rhG-CSF alone, suggesting a mechanistic explanation for rhPlGF-1/rhG-CSF synergism. In rhesus monkeys, rhPlGF-1 alone had no mobilization effect, whereas rhPlGF-1 (260 g/kg per day) plus rhG-CSF (100 g/kg per day) increased rhG-CSF-elicited mobilization of CFCs, HPP-CFCs, and LTC-ICs per milliliter of blood by 5-, 7-, and 15-fold, respectively. No specific toxicity was associated with the administration of rhPlGF-1 alone or in combination. In conclusion, our data demonstrate that rhPlGF-1 significantly increases rhG-CSF-elicited hematopoietic mobilization and provide a preclinical rationale for evaluating rhPlGF-1 in the clinical setting. STEM CELLS 2007;25:252-261

We investigated, morphologically and immunohistochemically, 74 medullary adrenal tumors, including 64 pheochromocytomas (14 malignant and 50 benign), 9 ganglioneuromas, and 1 malignant schwannoma. The tumors were detected in 2-year-old Wistar and Sprague-Dawley rats from carcinogenicity studies. Morphologically, benign pheochromocytomas were characterized by monomorphic, small, basophilic cells with almost absence of mitoses. Malignant pheochromocytomas presented a low grade of pleomorphism, higher rate of mitoses, necrosis, infiltrative growth and in 1 case metastases in the lung. Ganglioneuromas were characterized by ganglion and neuron-like cells embedded in an eosinophilic matrix containing neurites, Schwann cells, and scant fibrovascular elements. All pheochromocytomas were strongly immunoreactive for tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. Subpopulations of chromaffin cells expressed chromogranin A (CGA) positivity. Matrix and Schwann cells were positive for S-100 and for glial fibrillary acidic protein (GFAP). In focal areas of the tumors, ganglion cells and axons were positive for neurofilament proteins (NFP) and synaptophysin. Ganglion cells exhibited peripherin and beta-tubulin. Proliferative activity of the tumors was assessed by immunostaining the endogenous cell proliferation associated-antigen Ki-67 and the proliferating cell nuclear antigen (PCNA). As expected, cell proliferation indices were much higher in malignant pheochromocytomas than in benign, yet ganglioneuromas remained immunonegative. Considering that Ki-67 antigen is more specific for cell proliferation, it should be regarded as marker of choice for supporting the differential diagnosis between benign and malignant pheochromocytomas.

No abstract

We investigated, morphologically and immunohistochemically, 74 medullary adrenal tumors, including 64 pheochromocytomas (14 malignant and 50 benign), 9 ganglioneuromas, and 1 malignant schwannoma. The tumors were detected in 2-year-old Wistar and Sprague-Dawley rats from carcinogenicity studies. Morphologically, benign pheochromocytomas were characterized by monomorphic, small, basophilic cells with almost absence of mitoses. Malignant pheochromocytomas presented a low grade of pleomorphism, higher rate of mitoses, necrosis, infiltrative growth and in 1 case metastases in the lung. Ganglioneuromas were characterized by ganglion and neuron-like cells embedded in an eosinophilic matrix containing neurites, Schwann cells, and scant fibrovascular elements. All pheochromocytomas were strongly immunoreactive for tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. Subpopulations of chromaffin cells expressed chromogranin A (CGA) positivity. Matrix and Schwann cells were positive for S-100 and for glial fibrillary acidic protein (GFAP). In focal areas of the tumors, ganglion cells and axons were positive for neurofilament proteins (NFP) and synaptophysin. Ganglion cells exhibited peripherin and ß-tubulin. Proliferative activity of the tumors was assessed by immunostaining the endogenous cell proliferation associated-antigen Ki-67 and the proliferating cell nuclear antigen (PCNA). As expected, cell proliferation indeces were much higher in malignant pheochromocytomas than in benign, yet ganglioneuromas remained immunonegative. Considering that Ki-67 antigen is more specific for cell proliferation, it should be regarded as marker of choice for supporting the differential diagnosis between benign and malignant pheochromocytomas.

Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family which signals through VEGF receptor-1. In mice, administration of an adenoviral vector expressing human PlGF accelerates bone marrow recovery following myelosuppression and mobilizes PBPCs. By injecting either murine or human PlGF alone, we failed to detect any PBPC mobilization in mice, whereas the combined injection of PlGF plus G-CSF resulted in a 2- to 4-fold increase of PBPCs. Due to the relevant clinical impact of any procedure capable of improving PBPC mobilization, we tested the mobilizing activity of PlGF (Geymonat S.p.A., Anagni, Italy) as an adjunct to G-CSF in a nonhuman primate model. A cohort of Rhesus Monkeys (n = 4) was initially mobilized with G-CSF alone (100 μg/kg/day, SC, for 5 days) (cycle 1), and after a 6-week wash-out period, received a second mobilization therapy consisting of PlGF (130 μg/kg, IV, for 5 days) plus G-CSF (cycle 2). After an additional 6-week wash-out period, a third mobilization cycle consisting of PlGF (260 μg/kg, IV, for 5 days) plus G-CSF (cycle 3) was administered. Hematopoietic mobilization was evaluated by white blood cell counts (WBCs), committed colony-forming cells (CFCs), high-proliferative potential CFCs (HPP-CFCs), and long-term culture-initiating cells (LTC-ICs). Mobilization parameters were analyzed daily during treatment (days 1 to 5), and 3 and 5 days post-cessation of therapy. As compared to baseline values, a 5-day administration of G-CSF alone induced an average 5-fold increment of the mean (±SD) WBC counts (8,708±2,458 vs 43,523±13,790, P ≤.005). As compared to G-CSF alone, the peak values of WBCs were slightly increased by adding PlGF at 130 μg/kg (60,040±9,508) or 260 μg/kg (49,048±7,120). As compared to pretreatment values, the absolute numbers of circulating CFCs per ml blood were increased on average by 85-, 335-, and 358-fold under G-CSF (11,406±4,093, P ≤.005), G-CSF/PlGF 130 μg/kg (46,283±8,287, P ≤.005), and G-CSF/PlGF 260 μg/kg (60,777±8,563, P ≤.005), respectively. At cycles 2 and 3, the peak levels of CFCs were increased by 4- and 5-fold over cycle 1 (G-CSF alone). As compared to pretreatment values, the absolute numbers of circulating HPP-CFCs per ml blood were increase on average by 17-, 158, and 284-fold after under G-CSF (1,593±405, P ≤.005), G-CSF/PlGF 130 μg/kg (8,557±1,142, P ≤.005), and G-CSF/PlGF 260 μg/kg (12,205±2,172, P ≤.005), respectively. At cycles 2 and 3, the levels of day-5 HPP-CFCs were increased by 5- and 8-fold over cycle 1. Under G-CSF alone, the absolute numbers of circulating LTC-ICs were increased by 53-fold as compared to baseline values (211±41 vs 4±7, P≤.005). The combined G-CSF/PlGF (130 μg/kg) treatment increased LTC-ICs by 389-fold as compared to pretreatment values (3,115±988 vs 8±5, P≤.005), with a 15-fold increase over G-CSF alone. In conclusion, our data demonstrate that in nonhuman primates PlGF strongly synergizes with G-CSF for the mobilization of primitive and committed PBPCs.

Spontaneously occurring and chemically induced pheochromocytomas are rare in mice. That the mouse pheochromocytoma is a more appropriate animal model than that of the rat for study of human medullary adrenal tumors has been suggested. The expression of phenylethanolamine-N-methyltransferase (PNMT), the enzyme responsible for production of epinephrine from norepinephrine, is common to both mouse and human pheochromocytomas. This investigation assessed the expression of the immunohistochemical markers PNMT, tyrosine hydroxylase (TH), and chromogranin A (CGA) in spontaneously occurring and chemically induced pheochromocytomas in the B6C3F1 mouse. Spontaneous tumors were derived from control animals from 10 different studies and the pheochromocytomas from treated groups from 4 different studies. All tumors were positive for maximal TH expression. A highly significant difference in PNMT expression (p < 0.01) occurred between spontaneously occurring pheochromocytomas classified as benign or "malignant" by the criteria of toxicologic pathology. Chemically induced tumors showed intermediate PNMT staining. A marked reduction in CGA expression occurred in pheochromocytomas induced by technical grade pentachlorophenol, compared to the other three chemicals and the spontaneously occurring tumors. These findings suggest that immunohistochemistry is a reliable tool in investigating the functional capabilities of pheochromocytomas in mice. PNMT expression is a tightly regulated component of the chromaffin cell phenotype and appears to be readily lost in mouse pheochromocytomas, particularly those with aggressive characteristics.