Giulia Ottaviani

The Epidemiology of Osteosarcoma

Osteosarcoma derives from primitive bone-forming mesenchymal cells and is the most common primary bone malignancy. The incidence rates and 95% confidence intervals of osteosarcoma for all races and both sexes are 4.0 (3.5-4.6) for the range 0-14 years and 5.0 (4.6-5.6) for the range 0-19 years per year per million persons. Among childhood cancers, osteosarcoma occurs eighth in general incidence and in the following order: leukemia (30%), brain and other nervous system cancers (22.3%), neuroblastoma (7.3%), Wilms tumor (5.6%), Non-Hodgkin lymphoma (4.5%), rhabdomyosarcoma (3.1%), retinoblastoma (2.8%), osteosarcoma (2.4%), and Ewing sarcoma (1.4%). The incidence rates of childhood and adolescent osteosarcoma with 95% confidence intervals areas follows: Blacks, 6.8/year/million; Hispanics, 6.5/year/million; and Caucasians, 4.6/year/million. Osteosarcoma has a bimodal age distribution, having the first peak during adolescence and the second peak in older adulthood. The first peak is in the 10-14-year-old age group, coinciding with the pubertal growth spurt. This suggests a close relationship between the adolescent growth spurt and osteosarcoma. The second osteosarcoma peak is in adults older than 65 years of age; it is more likely to represent a second malignancy, frequently related to Pagets disease. The incidence of osteosarcoma has always been considered to be higher in males than in females, occurring at a rate of 5.4 per million persons per year in males vs. 4.0 per million in females, with a higher incidence in blacks (6.8 per million persons per year) and Hispanics (6.5 per million), than in whites (4.6 per million). Osteosarcoma commonly occurs in the long bones of the extremities near the metaphyseal growth plates. The most common sites are the femur (42%, with 75% of tumors in the distal femur), the tibia (19%, with 80% of tumors in the proximal tibia), and the humerus (10%, with 90% of tumors in the proximal humerus). Other likely locations are the skull or jaw (8%) and the pelvis (8%). Cancer deaths due to bone and joint malignant neoplasms represent 8.9% of all childhood and adolescent cancer deaths. Death rates for osteosarcoma have been declining by about 1.3% per year. The overall 5-year survival rate for osteosarcoma is 68%, without significant gender difference. The age of the patient is correlated with the survival, with the poorest survival among older patients. Complete surgical excision is important to ensure an optimum outcome. Tumor staging, presence of metastases, local recurrence, chemotherapy regimen, anatomic location, size of the tumor, and percentage of tumor cells destroyed after neoadjuvant chemotherapy have effects on the outcome.

The trigemino-cardiac reflex: An update of the current knowledge

The trigemino-cardiac reflex (TCR) is clinically defined as the sudden onset of parasympathetic activity, sympathetic hypotension, apnea, or gastric hypermotility during central or peripheral stimulation of any of the sensory branches of the trigeminal nerve. Clinically, the TCR has been reported to occur during craniofacial surgery, manipulation of the trigeminal nerve/ganglion and during surgery for lesion in the cerebellopontine angle, cavernous sinus, and the pituitary fossa. Apart from the few clinical reports, the physiologic function of this brainstem reflex has not yet been fully explored. The manifestation of the TCR can vary from bradycardia and hypotension to asystole. From the experimental findings, the TCR represents an expression of a central reflex leading to rapid cerebrovascular vasodilatation generated from excitation of oxygen-sensitive neurons in the rostral ventro-lateral medulla oblongata. By this physiologic response, the systemic and cerebral circulations may be adjusted in a way that augments cerebral perfusion. This review summarizes the current state of knowledge about TCR.

The etiology of osteosarcoma.

Studies to determine the etiology of osteosarcoma involve epidemiologic and environmental factors and genetic impairments. Factors related to patient characteristics include age, gender, ethnicity, growth and height, genetic and familial factors, and preexisting bone abnormalities. Rapidly proliferating cells may be particularly susceptible to oncogenic agents and mitotic errors which lead to neoplastic transformation. Genetic aberrations that accompany osteosarcoma have received increasing recognition as an important factor in its etiology. Osteosarcoma tumor cells exhibit karyotypes with a high degree of complexity which has made it difficult to determine whether any recurrent chromosomal aberrations characterize osteosarcoma. Although extremely rare, osteosarcoma has occasionally been observed in several members of the same family. No other clinical abnormalities in the proband or the affected members were reported. Pathologic examination of the tumors revealed no unusual features. Genetic testing was not available in most of these reports. The patients generally responded to conventional therapy. A genetic predisposition to osteosarcoma is found in patients with hereditary retinoblastoma, characterized by mutation of the retinoblastoma gene RB1 on chromosome 13q14. The Rothmund-Thomson syndrome is an autosomal recessive disorder with a heterogeneous clinical profile. Patients may have a few or multiple clinical features including skin rash, small stature, skeletal dysplasias, sparse or absent scalp hair, eyebrows or eyelashes, juvenile cataracts, and gastrointestinal disturbance including chronic emesis and diarrhea; its molecular basis is the mutation in the RECQL4 gene in a subset of cases. The Li-Fraumeni syndrome is an autosomal dominant disorder characterized by a high risk of developing osteosarcoma and has been found in up to 3% of children with osteosarcoma. It is associated with a germline mutation of the p53, a suppressor gene. The following three criteria must be met for a diagnosis of Li-Fraumeni syndrome: (1) A proband diagnosed with sarcoma when younger than 45 years; (2) A first-degree relative with any cancer diagnosed when younger than 45 years; (3) Another first- or second-degree relative of the same genetic lineage with any cancer diagnosed when younger than 45 years or sarcoma diagnosed at any age. A second recessive p53 oncogene on chromosome 17p13.1 may also play a role in the development and progression of osteosarcoma. Osteosarcoma has also been associated with solitary or multiple osteochondroma, solitary enchondroma or enchondromatosis (Olliers disease), multiple hereditary exostoses, fibrous dysplasia, chronic osteomyelitis, sites of bone infarcts, sites of metallic prostheses and sites of prior internal fixation. Ionizing radiation is a well-documented etiologic factor. Osteosarcoma has also been associated with the use of intravenous radium and Thorotrast. Exposure to alkylating agents may also contribute to its development ,and it is apparently independent of the administration of radiotherapy.

Adverse effects of prenatal tobacco smoke exposure on biological parameters of the developing brainstem.

We aimed to study the consequences of chronic exposure to tobacco smoke in utero on the morphological and functional maturation of the brainstem by comparing stillbirths of smoker mothers versus nonsmoker mothers. A total of 42 stillbirths, aged 25-40 gestational weeks, underwent autopsy according to our guidelines (). The brainstem was studied on serial sections and by immunohistochemistry to assay the expression of the EN2 gene, somatostatin (SS) and the tyrosine hydroxylase enzyme (TH). We observed a significant correlation between maternal smoking and sudden intrauterine unexplained death (SIUD), hypoplasia of the ArcN, no immunostaining of the EN2 in the arcuate nucleus (ArcN), and of TH in the locus coeruleus (LC) (P < 0.05). An increased incidence of maternal smoking was also observed in fetuses with SS negativity in the hypoglossus nucleus (HypoglN). Exposure in utero to maternal smoking may strongly interfere with brain biological parameters, giving rise not only to structural developmental abnormalities of the arcuate nucleus, but also to a decrease of noradrenergic activity in the LC, of EN2 gene expression in the ArcN and of SS in the HypoglN.

Techniques and criteria in pathologic and forensic-medical diagnostics in sudden unexpected infant and perinatal death.

For each case of sudden infant and perinatal death, a full review of clinical and epidemiologic data and a complete necropsy study were performed according to the necropsy protocol devised by the Institute of Pathology, University of Milan, Milan, Italy (available at: http://users.unimi.it/~pathol/sids_e.html). Histopathologic examination of unexpected late fetal and neonatal death and SIDS cases allowed us to identify frequent alterations, mainly congenital, of the autonomic nervous system, modulating respiratory, cardiovascular, arousal, and upper digestive activities. The data and arguments presented herein provide a brief survey tending to open, rather than conclude, a far-reaching subject and to motivate medicolegal specialists and pathologists to perform more in-depth study.

Sudden Infant Death Syndrome (SIDS): a study of cardiac conduction system.

The theory that Sudden Infant Death Syndrome (SIDS) may be related to lethal cardiac arrhythmias or heart block due to structural abnormalities of the conduction system is attractive and still of particular interest. We analyze 69 autopsied cases of SIDS (46 males and 23 females, infants ranging in age from 3 to 365 days) and 24 age-matched cases of explained death (ED) as controls (16 males and 8 females), infants who died from extracardiac cause (cerebral and respiratory). SIDS and ED groups were divided into three subgroups according to the age: (A) from 3 to 60 days; (B) from 61 to 120 days; (C) from 121 to 365 days. Histological observations were focused on the cardiac conduction system (CCS) which was examined on serial sections with the technique devised by one of the present authors (L. Rossi). The following findings were observed: resorptive degeneration (97.10% of SIDS, 75% of ED), His bundle dispersion (33. 33% of SIDS, 16.66% of ED), Mahaim fibers (21.73% of SIDS, 8.3% of ED), cartilaginous meta-hyperplasia (5.79% of SIDS, 4.16% of ED), persistent fetal dispersion (24.63% of SIDS, 16.66% of ED), intramural right bundle (20.29% of SIDS, 25% of ED), left sided His bundle (20.29% of SIDS and 8.3% of ED), hemorrhage of the atrio-ventricular junction (15.94% of SIDS), septation of the bifurcation (13.04% of SIDS), atrio-ventricular node (AVN) dispersion (7.24% of SIDS), sino-atrial node hypoplasia (5.79% of SIDS), Zahn node (1.45% of SIDS), His bundle hypoplasia (1.45% of SIDS), intramural left bundle (1.45% of SIDS), AVN dualism (2.89% of SIDS), and His bundle dualism (2.89% of SIDS, 4.16% of ED). Only the presence of resorptive degeneration was significantly higher in SIDS than in ED cases (p = 0.004). Regarding the subgroups, the only significant difference was the higher presence of intramural right bundle in SIDS-A than in SIDS-B (p = 0.01). Despite the non-specificity of most of these findings, we believe that these changes, associated with particular conditions and/or neurovegetative stimuli, could cause potentially malignant arrhythmias. These data suggest the need for an accurate approach and examination of the cardiac conduction system in all cases of sudden death in infancy

Study of the Brainstem, Particularly the Arcuate Nucleus, in Sudden Infant Death Syndrome (SIDS) and Sudden Intrauterine Unexplained Death (SIUD)

Complete examination of the brainstem involves transverse serial 5-&mgr;m sections made throughout the entire brainstem. The number of serial sections varies from 360 in sudden intrauterine unexplained death (SIUD) to 600 in term fetuses to over 1400 sections in sudden infant death syndrome (SIDS) victims. The procedure is not applicable in all histopathological laboratories, owing to the need for additional technical personnel. The simplified procedure allows a remarkable reduction of the number of sections. The brainstem is divided into 3 blocks. The first, cranial block, extends from the border between the medulla oblongata and pons up to the upper pole of the olivary nucleus. The second, intermediate block, corresponding to the submedian area of the inferior olivary nucleus, has as reference point the obex and extends 2 to 3 mm above and below the obex itself. The third, caudal block, includes the lower pole of the inferior olivary nucleus and the lower adjacent area of the medulla oblongata. Examinations of the brainstems from 106 SIDS victims, 30 controls, and 51 stillborns underlined a remarkable variability, particularly of the arcuate nucleus. The simplified examination of the brainstem makes it possible to evaluate the structures, examining 3 specific levels, defined by morphologic reference points.

Psychosocial and functional outcomes in long-term survivors of osteosarcoma: a comparison of limb-salvage surgery and amputation.

Traditionally, physicians have believed that limb‐salvage surgery has functional and cosmetic advantages over amputation, yet the literature is equivocal. Therefore, we sought to compare the psychosocial and functional outcomes in osteosarcoma survivors after limb‐salvage surgery and amputation. We hypothesized there to be neither psychosocial nor functional outcome differences between groups.

Guidelines for neuropathologic diagnostics of perinatal unexpected loss and sudden infant death syndrome (SIDS): a technical protocol.

In light of the growing information on the pathophysiology and clinical aspects of unexpected perinatal loss and sudden infant death syndrome (SIDS), a novel approach to the inherent problems by pathologists has become necessary. Herein, we propose an up-to-date protocol for accurate examination of the central autonomic nervous system and of the cardiac conduction system, which can encompass morphological and/or functional abnormalities of reliable epicritical value in unexplained perinatal loss and SIDS, particularly in those cases (still quite numerous) lacking adequate clinical documentation. Anatomo-pathologic examination of the central autonomic nervous system includes an in-depth study on histological serial sections of the brainstem, cerebellum, and spinal cord, where the main structures participating in control of the vital functions are located. For the histological study of the cardiac conductions system, serial sections were obtained from two blocks, including the sino-atrial node and the atrio-ventricular system, respectively. This type of updated investigation is yielding important arguments for a broader discussion of the pathogenesis of unexpected stillbirth, early neonatal death, and SIDS, besides allowing a more complete forensic-medical documentation of individual cases.

Preliminary Study on the Cytoarchitecture of the Human Parabrachial/Kölliker-Fuse Complex, with Reference to Sudden Infant Death Syndrome and Sudden Intrauterine Unexplained Death

The parabrachial/Kölliker-Fuse complex has been defined, in different animal species, to lie in the dorsolateral part of the pontine tegmentum and to be subdivided into three well-defined regions: the medial parabrachial nucleus, the lateral parabrachial nucleus, and the Kölliker-Fuse nucleus. Experimental studies have shown that the parabrachial/Kölliker-Fuse complex is involved in a variety of functional activities and above all plays an important role in respiratory modulation. In human brainstem, the cytoarchitecture and physiology of this complex have not yet been fully characterized. The aim of the present study was to examine fetal and infant human brainstems in order to define the precise morphology of the three nuclei of the parabrachial/Kölliker-Fuse complex, and to determine whether this nervous center shows morphologic alterations in sudden infant death syndrome (SIDS) and in sudden intrauterine unexplained death (SIUD). In serial sections of 31 brainstems of subjects aged from 32 gestational wk to 10 months of life, we studied, by morphologic and morphometric analyses, the cytoarchitecture and the extension of the three nuclei of the parabrachial/Kölliker-Fuse complex. All the morphometric parameters were very similar in SIUD and SIDS cases to those of the respective control group, as shown by the absence of significant statistical differences between the two fetus and infant groups. We observed that the features of both the lateral and the medial parabrachial nuclei are largely consistent with those reported in experimental studies. In contrast, the Kölliker-Fuse nucleus appears to be more developed in human beings than in other animal species, showing a greater extension and a more complex structure, as well as subdivision into two subnuclei (compactus and dissipatus).