Normal anatomy of the developing fetal brain. Ex vivo anatomical-magnetic resonance imaging correlation

Fetal brain Magnetic Resonance Imaging (MRI) is a new technique of growing interest, with a high potential to detect prenatal central nervous system abnormalities. This requires an accurate knowledge of the normal morphological sequence of brain development. In this paper we studied the cortical development of post-mortem normal fetal brains, correlating MRI estimations of fetal age with in vitro anatomical and anthropometric measurements.

Ten post-mortem fetal heads were submitted to MRI. Maturational state of sulci and gyri and gray-white matter differentiation were analysed in the MRIs and by dissection of the brains. The findings were correlated with the previously estimated ages of the fetuses, which varied between 17 and 38 weeks. Consistency between methods was assessed employing intraclass correlation coefficient and Bland–Altman plots, with a 95% confidence interval. Estimations of fetal age obtained by MRI were very similar to those achieved by anthropometric measurements or by considering anatomical parameters. Gyral development proved to be more precise than gray-white matter differentiation for this purpose.

Fetal MRI proved to be as reliable as the macroscopic anatomical examination for depicting normal cortical developmental sequence and age, suggesting that this technique may be a suitable option for achieving precise information about the morphology of human brains along the gestational period.     

Bone marrow stromal cells attenuate injury-induced changes in galanin,NPY and NPY Y1-receptor expression after a sciatic nerve constriction

Single ligature nerve constriction (SLNC) of the rat sciatic nerve triggers neuropathic pain-related behaviors and induces changes in neuropeptide expression in primary afferent neurons. Bone marrow stromal cells (MSCs) injected into the lumbar 4 (L4) dorsal root ganglia (DRGs) of animals subjected to a sciatic nerve SLNC selectively migrate to the other ipsilateral lumbar DRGs (L3, L5 and L6) and prevent mechanical and thermal allodynia. In this study, we have evaluated the effect of MSC administration on the expression of the neuropeptides galanin and NPY, as well as the NPY Y₁-receptor (Y₁R) in DRG neurons. Animals were subjected to a sciatic nerve SLNC either alone or followed by the administration of MSCs, phosphate-buffered saline (PBS) or bone marrow non-adherent mononuclear cells (BNMCs), directly into the ipsilateral L4 DRG. Seven days after injury, the ipsilateral and contralateral L4–5 DRGs were dissected out and processed for standard immunohistochemistry, using specific antibodies. As previously reported, SLNC induced an ipsilateral increase in the number of galanin and NPY immunoreactive neurons and a decrease in Y₁R-positive DRG neurons. The intraganglionic injection of PBS or BNMCs did not modify this pattern of expression. In contrast, MSC administration partially prevented the injury-induced changes in galanin, NPY and Y₁R expression. The large number of Y₁R-immunoreactive neurons together with high levels of NPY expression in animals injected with MSCs could explain, at least in part, the analgesic effects exerted by these cells. Our results support MSC participation in the modulation of neuropathic pain and give insight into one of the possible mechanisms involved.     

Expression of neurotensin and its receptors in pituitary adenomas

The neurotensin (NT) produced in the hypothalamus and in pituitary gonadotrophs and thyrotrophs participates in neuroendocrine regulation. Recently, the involvement of this peptide in normal and neoplastic cell proliferation has been postulated. In the present study, we evaluated the expression of NT and its receptors (NTR1, 2 and 3) in a series of 50 pituitary adenomas [11 growth hormone (GH)-, eight prolactin (PRL)-, four adrenocorticotrophic hormone (ACTH)- and 27 nonfunctioning adenomas]. NT mRNA expression was significantly higher in functioning compared to nonfunctioning adenomas and with normal pituitary. Nonfunctioning pituitary adenomas showed lower expression of NT mRNA than normal pituitary. In the immunohistochemical study of functioning adenomas, NT was colocalised with GH, PRL and ACTH secreting cells. In nonfunctioning adenomas, the NT immunoreactivity intensity was variable among the samples. NTR3 mRNA expression was observed in all examined samples and was higher in the adenomas, both functioning and nonfunctioning, compared to normal pituitary. By contrast, NTR1 and NTR2 mRNA were not detected in either pituitary adenomas or normal tissue. The higher expression of NTR3, as well as the expression of NT by tumoural corticotrophs, lactotrophs and somatotrophs, which are cells types that do not express this peptide in the normal pituitary, suggests that NT autocrine and/or paracrine stimulation mediated by NTR3 may be a mechanism associated with the tumourigenesis of functioning adenomas.     

Patients with bisphosphonates-associated osteonecrosis of the jaw have reduced circulating endothelial cells

Osteonecrosis of the jaws (ONJ) associated with the use of bisphosphonates is a newly described entity. To elucidate the mechanism leading to ONJ and to test the hypothesis that in patients with ONJ the bisphosphonates may interfere with endothelial cell proliferation, using flow cytometric analysis we evaluated the number of circulating endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) in eight patients with bisphosphonate treatment and osteonecrosis, eight multiple myeloma (MM) patients with bisphosphonates treatment without ONJ and five normal subjects. MM patients showed an increase of CD34+ cells with respect the control subjects and ONJ subjects. EPCs and CECs were higher in MM patients compared to controls and ONJ patients. ONJ patients showed a decrease of EPCs compared to control subjects while CECs were similar to the controls group. Our results seem to show the possibility that bisphosphonates could have a antiangiogenic effect and a suppressive effect on CECs of patients with ONJ.     

High-dose therapy and autologous peripheral blood stem cells transplantation followed by a very low reduced intensity regimen with fludarabine + cyclophosphamide and allograft improve complete remission rate in de novo multiple myeloma patients

The recent development of reduced intensity conditioning and allotransplantation (RICT) has opened a new way to assure engraftment of donor cells while reducing early transplant-related mortality. We evaluated the combination of high-dose therapy and autologous peripheral blood stem cells transplantation (APBSCT) followed by RICT to extend the benefit of allografting procedures in de novo multiple myeloma (MM) patients. Fifteen subjects with stage III MM (median age 51 years, range 40-57) received high dose melphalan (200 mg/m(2)) followed by APBSCT previously collected after cyclophosphamide (4 g/m(2)) and granulocyte colony-stimulating factor (G-CSF). After 3-4 months from APBSCT, the patients underwent RICT, consisting of fludarabine 30 mg/m(2) + cyclophosphamide 300 mg/m(2) on days -4, -3, and -2. Acute graft-versus-host disease (GVHD) occurred in 2 patients; 6 patients developed chronic GVHD; 4 patients developed CMV antigenemia and were treated pre-emptively with ganciclovir. No transplant related mortality was shown. Response was simultaneously measured by both electrophoresis (EP) and immunofixation (IF); when IF was negative, patients were classified in complete remission (CR) and when it remained positive, near CR (nCR). After a median follow up of 44 months post APBSCT, 100 and 43% of patients are still alive and progression-free, respectively. Overall, the CR + nCR rate after dose-reduced allograft was enhanced from 26.7 to 73.3%. A correlation not statistically significant between GVHD and remission was found. In conclusion, an up-front tandem strategy with a very low reduced intensity-conditioning regimen for allografting following autografting is feasible and induces high CR/nCR rate in MM.     

Early detection of recurrences in the follow-up of primary breast cancer in an asymptomatic or symptomatic phase

AIMS AND BACKGROUND: Periodic follow-up after primary treatment for breast cancer is a common procedure for the early detection of recurrent disease in the asymptomatic state. Anyway, there is no clinical evidence that treatment of metastases may improve the prognosis if applied in the asymptomatic state. The aim of the present study was to investigate the modality of detection of the first relapse in the asymptomatic vs the symptomatic state. METHODS: We retrospectively analyzed 717 breast cancer patients who had been consecutively referred to the Parma Oncology Division during the period 1986 to December 1988. Recurrences were detected in the course of periodic follow-up. RESULTS: A total of 211 of the 408 patients evaluated had a first relapse with a median follow-up of 94.7 months. Local and distant recurrences were 49% and 47%, respectively. Bone recurrences represented 24% of the total first recurrences, then chest wall recurrences in 23%, local regional nodes in 13%, lung in 7%, liver in 4%, and brain in 2%. The distribution of the studied patients according to recurrence site and asymptomatic or symptomatic state was different: 69% of asymptomatic patients (110) had a local recurrence vs 31% of symptomatic patients (101). A difference in survival was recorded in favor of cases detected in the asymptomatic state (P <0.001). CONCLUSIONS: The present study suggests that an early detection of local recurrence might have a favorable impact on the prognosis of patients followed after primary treatment for breast cancer. It should be considered that any difference in survival could also be explained by several "biases" and that breast cancer follow-up is still an area of investigation open to discussion in which many questions remain to be clarified.     

Molecular profile and clinical variables in BRCA1-positive breast cancers. A population-based study

PURPOSE: To evaluate the clinical features of breast cancer patients with genetic susceptibility to this disease and to investigate the contribution of BRCA1 germline mutations to the phenotype of these tumors. PATIENTS AND METHODS: We reviewed the clinical and pathological records of 102 women with suspected inherited susceptibility to breast cancer consecutively seen at the Genetic Oncology Service of Parma, Italy. Sixty-two patients with a high probability of harboring a germline, cancer-predisposing mutation were tested for BRCA1 mutations. Exon 11 was screened using the protein truncation test and detected mutations were confirmed by direct sequencing (DS). All other exons were analyzed by DS. RESULTS: Among the 62 patients with a completed mutation analysis, 48 (77.4%) had wild-type BRCA1, six (9.6%) had variants of unclear significance, eight (13%) had deleterious mutations. BRCA1-associated breast cancers (BABC) were significantly less likely to be diagnosed at stage I than breast cancers in women without mutations (12.5% vs 51%; P = 0.045), more likely to have a high proliferation rate (100% vs 24%, P < 0.001), and more likely to be histological grade 3 (100% vs 14%, P < 0.001), estrogen and progesterone receptor negative (87.5% vs 13%, P < 0.001; 75% vs 23%, P = 0.004), and p53 positive (87.5% vs 30%, P = 0.023). All tumors with BRCA1 mutations were HER-2/neu negative compared with 57% of the non-BRCA1 tumors (P = 0.04). There were no significant differences between BABC and non-BABC in 20-year relapse-free survival, 20-year event-free survival, and 20-year overall survival. CONCLUSION: In this population-based study, BABC seems to present with adverse molecular features when compared with non-BABC, although the prognosis appears to be similar.     

Prevalence and characteristics of epilepsy in the Aeolian islands

PURPOSE: To estimate the prevalence and define the clinical characteristics of epileptic disorders in the 13,431 residents of the Sicilian Aeolian archipelago, on June 1, 1999. METHODS: All established or suspected cases were identified by the neurologists of our working group from available medical information sources. Possible epilepsy cases were then evaluated by the epileptologists by using a standardized questionnaire. The patients were further reviewed by the whole research team to confirm the clinical diagnosis. For a more detailed syndromic definition, some patients underwent EEG or neuroradiologic investigations or both. RESULTS: The crude point prevalence rate of active epilepsy was 3.13 (95% confidence interval, 2.2-4.2). The prevalence rate age-adjusted to the 2001 Italian population was 3.01. Females had a slightly higher prevalence rate than did males. The highest age-specific prevalence was found in patients aged 5 to 14 years (5.05) and in those aged 65 to 74 years (5.41). Partial seizures with or without secondary generalization were more common (61.7%) than were generalized seizures. Eighty-three percent of cases had symptomatic or cryptogenic localization-related epilepsies, and 8.5% had idiopathic (generalized or partial) epilepsies. Epilepsy was unclassified in 8.5% of cases. CONCLUSIONS: The prevalence of active epilepsy in the Aeolian islands is lower than that in other developed areas, including northern Italy, but is similar to that in Sicily. Partial seizures were the most common type, and localization-related symptomatic epilepsies were the largest syndromic category.