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Purpose: Prostate cancer progression to androgen ablation refractory stage D3 corresponds to cancer cell escape from androgen withdrawal induced apoptosis. Of note, salvage chemotherapy can extend the median survival of approximately 10 months in patients with stage D3. Therefore, novel therapeutic strategies that target the molecular basis of androgen resistance are required. Materials and Methods: The MEDLINE and Current Content databases were used to find studies of the use of estrogens and somatostatin analogues for D3 prostate adenocarcinoma. We also analyzed the rationale and clinical results of our combination therapy using lanreotide and ethinylestradiol. Results: Negative experiences have been reported with somatostatin analogues as monotherapy. On the other hand, the median progression-free survival reported in our experience using lanreotide acetate plus ethinylestradiol clearly surpassed the 10-month survival historically described in stage D3 cases. Conclusions: The use of somatostatin analogues in combination therapy for D3 prostate cancer sustains the novel concept in cancer treatment in which therapies may target not only cancer cells, but also the microenvironment in combination, which can confer protection from apoptosis.

Background Treatment of nephroblastoma (Wilms tumor) has presently achieved a greater than 80% cure rate. Pathologic stage and grade are considered the most reliable prognostic parameters, but other biologic factors are under study in order to improve patient stratification into risk groups. Correlation of elevated levels of the lipogenic enzyme fatty acid synthase (FAS) with aggressiveness of some cancers has drawn attention to this enzyme as a possible marker of poor prognosis. Procedure To determine the predictive strength of FAS expression in Wilms tumor (with particular emphasis on intermediate risk, i.e., non anaplastic tumors, the vast majority of nephroblastomas), we evaluated immunostaining expression in archival specimens from 94 neoplasms. The degree of expression was correlated with stage, grade, clinical course and administration of prenephrectomy chemotherapy. Results Expression of FAS increased in anaplastic tumors (P = 0.043) and higher stages (P = 0.029). FAS expression correlated with OS and DFS at both univariate and multivariate analysis. Comparable results were obtained when analyzing the intermediate risk population separately. Pretreatment resulted in an increased FAS expression, without reaching significance level (P = 0.059). Conclusions Expression of FAS might be an independent prognostic factor, particularly for intermediate-risk patients. The blockade of fatty acid synthesis by inhibition of FAS enzymatic function by means of metabolic analogues might prove a novel target pathway for the treatment of nephroblastoma. Med Pediatr Oncol 2003;40:302–308. © 2003 Wiley-Liss, Inc.

The development of chemoresistance in a variety of cancers seems related to overexpression of the P-glycoprotein (P-gp) drug pump. Nephroblastoma, the most common malignant renal tumor of childhood, usually is responsive to treatment, and prognosis is favorable in most cases. However, the disease in a subset of patients is refractory to treatment, and the disease follows an aggressive course. To study P-gp expression in this tumor and its correlation with outcome, tumor samples from 93 patients were examined by immunohistochemical analysis. P-gp expression was determined separately in both tumor cells and intratumoral capillary endothelium. The likelihood ratio test, the Kaplan-Meier method, and the log-rank test were used to evaluate its association with clinical course, grade, stage, and administration of preoperative chemotherapy. The results for the majority of nephroblastomas were variably positive; in 43 (46%) of them, newly formed capillary endothelial cells also stained positive. While no association of P-gp expression in tumor cells with clinical course, stage, and grade could be demonstrated, positivity in endothelial cells correlated significantly with unfavorable outcome, suggesting that chemoresistance depended on an active blood-tumor barrier. Previous chemotherapy induced P-gp overexpression in tumor cells.

Glomerulocystic kidney disease (GCKD) is a rare congenital condition that is usually reported in infants and young children. Only five cases of acquired GCKD after an acquired renal disease have been reported. Among these, two patients have developed cystic glomerular lesions following hemolytic uremic syndrome (HUS). We report a third case in a 2-year-old patient with this association. Common features between these three cases include atypical HUS, development of GCKD after prolonged peritoneal dialysis treatment, severe hypertension, and normal-sized kidneys without development of macroscopic cysts. Pathology findings in our patient include heavy expression of epidermal growth factor receptor in proximal tubules and evidence of obstruction of the glomerular outflow. We speculate that cystic dilatation of the Bowman's capsule may be secondary to ischemic lesions leading to proximal tubular obstruction.

Using morphometry and image analysis, we investigated 17 patients showing intestinal pseudo-obstruction secondary to intestinal neuronal dysplasia (IND) and 20 controls. In addition to an increase in the number and size of the ganglia and the ganglionic cells, we also noted a significant increase in NO synthase-containing ganglionic cells. We found that this enzyme, responsible for the synthesis of nitrous oxide caused by oxidation of L-argynine aminoacid, is a neurotransmitter able to induce smooth muscle relaxation by activating cyclic AMP. If the increase in NO synthase-producing ganglionic cells is responsible for the increase in nitrous oxide production, one can hypothesize that an overproduction of nitrous oxide plays a role in the pathogenesis of intestinal pseudo-obstruction secondary to neuronal dysplasia. As NO synthase can be blocked, as was demonstrated by giving L-methil-arginine or N-G-nitro-L-argynine, it might be possible to treat intestinal pseudo-obstruction caused by intestinal neuronal dysplasia at the pharmacological level.

Three children with malabsorption presumably caused by celiac disease had undergone jejunal biopsy. While a histological examination revealed microvacuolization of enterocytes in the absence of celiac lesions, an ultrastructural investigation disclosed numerous chylomicrons and larger lipid vacuoles inside the cytoplasm of enterocytes, mostly in the supranuclear region. No chylomicrons were evident in the interstitium between adjacent enterocytes, as observed in normal subjects. These ultrastructural findings allowed for the diagnosis of "Chylomicron retention disease" (CRD). CRD was described for the first time by Anderson in 1961, and it is included in the group of disorders of biosynthesis and secretion of B apolipoproteins (apoB). This disease, in particular, appears to result from a specific defect involving the secretion of lipoproteins containing apoB-48 from the gut, with the complete absence of post prandial chylomicrons in the sera. CRD needs to be recognized early because of its adverse effects on growth and its potential for neurological and ocular complications, and the ultrastructural identification of chylomicron-size lipid droplets clustered in the enterocytes, with the absence of fat outside the cells, represents the gold standard to identify CRD. together with clinical aspects and laboratory measurements. In this study, we describe the histological and ultrastructural aspects observed in three pediatric cases of CRD.

Osteoclasts from a patient affected by osteopetrosis were examined in vivo and in vitro. Iliac crest biopsy revealed an osteosclerotic pattern, with prominent numbers of osteoclasts noted for hypernuclearity and incomplete adherence to the bone surface. A population comprising tartrate-resistant acid phosphatase (TRAP)-positive, multinucleated and mononuclear cells, and alkaline phosphatase-positive stromal fibroblasts was obtained in vitro from bone marrow. Mononuclear TRAP-positive precursors spontaneously fused in culture to form giant osteoclast-like cells. These cells expressed the osteoclast marker MMP-9 and calcitonin receptor, and lacked the macrophage marker, Fc receptor. Expression and distribution of c-src, c-fms, and CD68, and response to steroid hormones relevant to osteoclast differentiation and function were apparently normal, whereas cell retraction in response to calcitonin was impaired. TRAP-positive multinucleated cells did not form osteoclast-specific adhesion structures (clear zone, podosomes, or actin rings). Bone resorption rate was severely reduced in vitro. Focal adhesions and stress fibers were observed en lieu of podosomes and actin rings. Adhesion structures contained low levels of immunoreactive vitronectin receptor, most of this integrin being retained in cytoplasmic vesicles. These data provide the first characterization of abnormal differentiation and function of human osteopetrotic osteoclast-like cells.

Sinus histiocytosis with massive lymphadenopathy (SHML) (Rosai-Dorfman disease) is a rare self-limited histiocytic disorder of unknown origin, usually present with cervical lymphadenopathy, fever, elevated ESR and haematologic abnormalities. Extranodal lesions may occur as initial manifestations of the disease. In most cases skin lesions are associated with nodal or extranodal localization. A 54-year-old male is reported who, for a period of ten months, presented numerous slowly enlarging, rounded papular lesions on the face, neck, trunk as well as severe cervical lymphadenopathy without general and haematological disturbances. Thereafter a fungating mass developed in the nasal cavity. Histological, histochemical and immunohistochemical tests of skin, mucosal and lymph-node lesions were consistent with a diagnosis of SHML. The immunohistochemical characterization of the cytophagocytic S-100+ macrophages revealed that they were highly positive for the adhesion molecules Vitronectin receptor av/b3, which is used by tissue macrophages for removal of effete cells through phagocytosis.

The atrioventricular node is situated in the lower atrial septum, at the apex of the Koch's triangle. The dimensions of the Koch's triangle are studied in adult humans, while no data exist about them in pediatric age. The knowledge of the dimensions of Koch's triangle in childhood is very important for safe and correct application of radiofrequency energy during transcatheter ablation. The dimensions of Koch's triangle were determined in 69 human pediatric hearts. The median age of the children was 3 months, with a range from 1 day to 14 years, 30 were female and 39 were male. Relations between body weight (extracardiac parameter) and tricuspid valve diameter (intracardiac parameter) were determined in all hearts to show morphometric modifications with growth. The distribution of body weight was not Gaussian and no correlation could be obtained between Koch's triangle dimensions and body weight. However, it was possible to identify that the mean ratio between the cathetus of the Koch's triangle corresponding to the annulus of the tricuspid valve and the tricuspid valve diameter was 0.45 +/- 0.16, with a highly significant correlation coefficient (r = 0.653, P < 0.001). Therefore, by knowing: (1) the diameter of the tricuspid valve, and (2) the constant ratio between the cathetus of the Koch's triangle and the tricuspid valve diameter, it is possible to calculate the length of the segment of the tricuspid annulus along which the transcatheter application of radiofrequency current can be applied to ablate the slow-pathway, thus reducing the risks of damage of the atrioventricular node.

Two siblings presented with a new phenotype consisting of fatal progressive macrocephaly and hypertrophic cardiomyopathy. Onset of symptoms started in both patients at the end of the first month of life with massive brain swelling causing macrocephaly and evolving to extensive brain destruction. Light microscopy of the lesions showed extensive small-vessel proliferation and gliosis. A distinct deficiency of complex I of mitochondrial respiratory chain was established in cultured fibroblasts, skeletal muscle, and heart muscle. Specific lack of complex I protein was demonstrated by two-dimensional gel electrophoresis.

Myofibroblastoma (MF) is an uncommon, usually benign, mesenchymal tumor infrequently described in soft tissues. We report here on the clinicopathologic findings of a soft tissue MF (STMF) presenting in the neck of a 90-year-old man as a slowly growing and non-painful nodule, 4 cm in greatest diameter. Histology revealed a circumscribed lesion constituted of monomorphous bipolar spindle cells arranged in swirling fascicles with intervening broad bands of hyalinized collagen and well formed “amianthoid” fibers. Immunohistochemistry showed the spindle cells to be immunoreactive for vimentin, smooth muscle actin and muscle specific actin and, focally, for desmin; im-munostaining for cytokeratin, epithelial membrane antigen, S-100 protein, factor VIII-related antigen, and CD34 was negative. Based on the present case and on those previously reported in the literature, STMF is characterized by: 1) exclusive incidence in the male sex; 2) variable immunoreactivity of the neoplastic cells for desmin, probably reflecting an origin from a peculiar subset of myofibroblasts, or, alternatively, a further myoid differentiation; 3) variable abundance of (hyalinized) collagen; 4) presence of amianthoid fibers. The combination of desmin immunoreactivity, frequently observed in MF of the breast, and amianthoid fibers, the main feature of MF of the lymph nodes, has never been observed in soft tissue MF. It is important to recognize STMF as a specific clinicopathologic entity to avoid confusion with other types of spindle cell proliferation and to differentiate it from other types of myofibromatosis.

A two-month-old infant developed a vascular tumor of the right flank which, upon biopsy, proved to be a spindle cell hemangioendothelioma. The increased capillary bed characterizing the neoplasm caused a severe thrombocytopenia together with a consumption coagulopathy (Kasabach-Merritt syndrome). The patient, who was dependent on platelet transfusions, improved quickly after interferon α-2a was given at the dosage of 3,000,000 U/m2, with resolution of the Kasabach-Merritt syndrome after three weeks and a 75% decrease of the tumor volume within three months of treatment. Med. Pediatr. Oncol. 28:358–361, 1997. © 1997 Wiley-Liss, Inc.

In neuroblastoma, high levels of mRNA for p14h trkA and p75 LNGFR neurotrophin receptors are predictive of favorable outcome. Their evaluation by Northern blot, however, requires substantial amounts of tissue and this prevents their routine evaluation as well as the possibility for multicenter studies to be easily carried out. In an attempt to overcome these limitations, the feasibility and reliability of determining both neurotrophin receptors on cryostat sections by immunohistochemistry were assessed, and these findings were compared to those obtained from Northern blot analysis. Primary tumor samples from 28 untreated patients at all stages were evaluated by using H10 anti-p140 trkA and ME20.4 anti-p75 LNGFR mAbs. Although weak, positiveimmunostaining was found in 9 of 28 tumors for p140 trkA and in 5 of 28 tumors for p75 LNGFR . As compared to Northern blot, the concordance rate was 79% (22 of 28 cases) for p140 trkA (p < 0.05) and 71% (20 of 28 cases) for p75 LNGFR (p < 0.05). No case negative for Northern blot was found to be positive with immunohistochemistry. Since only high mRNA levels for both receptors have been shown to be clinically relevant, their immunohistochemical detection, although less sensitive than Northern blot, can be just as sufficient and reliable as a prognostic tool, and possibly with a better cost-benefit ratio.

BACKGROUND Inflammatory myofibroblastic tumor or inflammatory pseudotumor is an uncommon lesion reported in various organs and believed to be a non-neoplastic reactive inflammatory condition. The concept of benign lesion has been recently challenged from both clinical demonstration of recurrence and cytogenetic evidence of acquired clonal chromosomal abnormality. Because DNA aneuploidy can be a useful marker for neoplasia, we analyzed nuclear DNA content of these lesions using flow cytometry. METHODS In this study, inflammatory myofibroblastic tumors from nine children were examined retrospectively by evaluating clinicopathologic features and ploidy. DNA ploidy status was analyzed by flow cytometry in nuclei isolated from paraffin-embedded tumor tissues. RESULTS Three of the nine patients had local recurrence or distant metastases. Flow cytometric DNA analysis revealed five of the nine cases were diploid and four hyperdiploid (DNA indices 1.14, 1.16, 1.19, and 1.33). All lesions had a low S-phase fraction. Samples from the three subjects with clinical recurrence were all hyperdiploid. CONCLUSIONS The present data indicate that flow cytometry identifies aneuploidy (hyperdiploidy) in approximately half of the cases of inflammatory myofibroblastic tumors. This feature appears to reflect a more aggressive biologic behavior. In addition to the reported cytogenetic abnormalities, our data suggest that inflammatory myofibroblastic tumor, generally considered a benign reactive inflammatory process, may evolve as a distinct, potentially malignant, lesion. Therefore, flow cytometric DNA analysis is a suitable tool to provide the clinician with both diagnostic and prognostic information and to individuate the most feasible therapeutic approach. Cancer 1996;77:778-84.

We report on a morphologic variant of multiple myeloma, identified in a 39-year-old man, with osteolytic lesions in two ribs and three lumbar vertebrae. Serum electrophoresis was normal and immunofixation of serum and urine was negative. Histologic examination of a resected rib revealed a homogeneous population of neoplastic plasma cells with granular and eosinophilic cytoplasm. Immunohistochemical stains showed monoclonality for λ light chain and negativity for all heavy chains. At the ultrastructural level, the cytoplasm of the neoplastic plasma cells was almost totally occupied by round and elongated mitochondria, pushing the rough endoplasmic reticulum to the periphery. To the best of our knowledge, only two similar cases have been reported in the literature so far. The usefulness of obtaining a clinicopathologic correlation for the behaviour of this extremely rare variant of multiple myeloma is discussed.

We report on a 4-year-old boy with recurrent giant-cell fibroblastoma of the right nasal genal region. Histologic examination revealed that both lesions were constituted of spindle and stellate cells and a minor amount of multinucleated giant cells in a myxoid stroma containing cisternal-like spaces. Immunohistochemical examination revealed positivity for vimentin in both cellular components. Ultrastructural examination showed, in some spindle and multinucleated cells, two kinds of intracellular crystalline inclusions, located, respectively, in the cisternae of the rough endoplasmic reticulum and, apparently free, in the cytoplasm. To the best of our knowledge, this case, unusual for its location, is the first example of giant-cell fibroblastoma bearing intracellular crystalline inclusions.

A 43-year-old man underwent surgical removal of L4-L5 nerve root tumor which bulged to the extra and intradural spaces and extended as a dumbbell through the intervertebral foramen. Histological examination showed pleomorphic tumor cells with heavy melanin pigmentation. Most of the tumor cells were immunohistochemically positive for vimentin, S-100 protein and HMB-45 antigen; basic myelin protein was detectable in single tumor cells. Electron-microscopy revealed melanosomes in different stages of differentiation and some characteristics of Schwann cells, such as redundant basal lamina production. Taken together the tumor showed features of histological malignancy and incomplete schwannian differentiation with considerable overlap between melanoma and malignant melanotic schwannoma.

Background Congenital-infantile fibrosarcoma is a rare tumor of the pediatric age. It involves subjects under 5 years of age, and more than 200 cases have been reported in the literature. Methods The authors present the clinicopathologic findings of 2 cases and review the literature. Results Of our 2 patients, the first was a 2-years and 6-months-old female and the second a newborn male. The female presented a tumor in the retroperitoneum without recurrences or metastasis after 17 months, and the male on left foor with a recurrence after 3 months. Histologically, the tumors were mainly composed of spindle-shaped cells. Immunohistochemically, in both cases, neoplastic cells were positive for vimentin; focal positivity for muscular specific actin was present in the tumor of the female. Ultrastructurally, tumors were composed of mesenchymal cells with fibroblastic and myofibroblastic features. Flow cytometric analysis of the retroperitoneal tumor showed an aneuploid population of neoplastic cells. Conclusions Congenital-infantile fibrosarcoma should be considered a borderline tumor; its biologic behavior is better than that of adult fibrosarcoma. Histologic diagnosis is not easy; the microscopic picture may be confused with fibromatosis or with malignant mesenchymal neoplasms. Only a follow-up of many years can confirm the benignancy or malignancy of any individual tumor, even though clinico-pathologic features may be distinctive enough to permit its recognition.

Alkenes were reacted with diphenyl diselenide in presence of ceric ammonium nitrate in methanol, affording β-methoxyalkyl phenyl selenides in good yields.

From 1985 to 1992, 1068 cardiac transplants have been performed in the Italian units. The immediate causes of death of 142 of the 148 orthotopic cardiac transplantation recipients who died within the first 6 postoperative months were surveyed. Deaths were grouped into three periods: perioperative (⩽1 month, 68.3%), early (>1 ⩽3 months, 23.2%), and advanced (>3 ⩽6 months, 8.5%). Acute graft failure (arising from the ischemic damage to the donor heart, from surgical problems, from severe pulmonary hypertension, or from multiorgan failure) accounted for 49% of perioperative deaths and, along with noncardiac emergencies (23% of perioperative deaths), was significantly more frequent in this period than in the subsequent ones. The dissection of thoracic arteries was responsible for 4% of postoperative deaths, occurring exclusively among patients transplanted for ischemic or valvular heart disease. In the early and advanced periods, untreatable acute rejection (13%) and fatal infections (38%), mostly saprophytic, were significantly more frequent. Ischemic heart damage secondary to graft vasculopathy already caused 26% of deaths between the fourth and sixth months after transplantation. Some diseases, such as acute rejection, had the same frequency as both underlying disease and immediate cause of death. On the contrary, graft failure is more common as primary disease, leading to death also through noncardiac complications and saprophytic infections. Bacterial infections have the same frequency as both prime and immediate cause of death, viral infections are more common as primary disease, and the opposite is true for saprophytic infections.

Amidoalkyl radicals, generated from amides by Mn(OAc)3 in acetic acid react with phenyl substituted alkenes to generate five-membered lactones or lactams. Ultrasound at ambient temperature significantly accelerates these single electron transfer reactions even when compared with conventional conditions under reflux or simple mechanical stirring. In some cases sonication leads to unusual products.

Ten cirrhotic patients with ultrasonically discernible focal liver masses underwent fine cutting needle biopsy. Specimens were obtained from the focal lesions under ultrasound guidance and histologically diagnosed as regenerative nodules. An image analyzer was then used to determine the cytoplasmic area, nuclear area, and nuclear/cytoplasmic ratio for 100 randomly selected cells from each specimen. Data were then compared with data for specimens of normal liver tissue and data from patients with alcoholic or posthepatic cirrhosis or well-differentiated hepatocellular carcinoma (HCC). The morphometric parameters for the group of regenerative nodule specimens fell within an intermediate range between those for HCC and the nondysplastic samples, strongly suggesting a preneoplastic nature. Nine of the 10 regenerative lesions showed liver cell dysplasia, and 3 of these patients developed HCC during follow-up. Ultrasonically discernible focal masses in a cirrhotic liver should be considered preneoplastic, if not neoplastic lesions and treated aggressively to prevent their progression to outright malignancy.

We present a undescribed condition in a girl who died at 8 years of hypertrophic cardiomyopathy. Muscle and endomyocardial biopsies disclosed a selective loss of thick filaments ultrastructurally. In muscle biopsy histochemical abnormalities of myofibrillar AT-Pase were confined to type 1 fibres. Gel electrophoresis of muscle homogenate showed no qualitative abnormalities of slow and fast myosin heavy chains (MHC) and light chains, and the amount of the different myosin isozymes was in agreement with histochemical myofibrillar ATPase findings. The pathogenetic mechanisms have not been elucidated in this case but we suspect an abnormality of the beta-cardiac MHC gene, the only gene expressed in the heart and in type 1 skeletal muscle fibres.

A 58-year-old man had a biopsy taken in November 1998 and was diagnosed as having prostatic adenocarcinoma of Gleason score 5 (3+2); his serum PSA was 86.7 ng/mL. A DRE revealed a palpable nodule of increased consistency on the left lobe of the prostate; TRUS showed a hypoechoic area 1.5 cm in diameter in the peripheral zone of the left lobe of the prostate, with no evidence of capsular or seminal vesicle in®ltration. CT of the abdomen and pelvis showed no lymphadenopathy, and the bone scan and chest X-rays were normal. Laboratory tests showed a signi®cant reduction in haemoglobin (94 g/L, normal 132±170), platelet count (89 000; normal 150 000±450 000) and neutrophils (33.8%, normal 55±70). In November 1998 the patient underwent an iliac bone marrow biopsy and the histology showed tumour cell clusters; immunohistochemical staining for PSA was positive at the tumour cell sites. Histological sections from the prostate biopsy were assessed for chromogranin A expression by immunohistochemistry [1], and more than one focus with extensive staining for chromogranin A was detectable in the tumour cells (.Fig. 1). Moreover, high

Amidoalkyl radicals, generated from amides by Mn(OAc)3 in acetic acid react with phenyl substituted alkenes to generate five-membered lactones or lactams. Ultrasound at ambient temperature significantly accelerates these single electron transfer reactions even when compared with conventional conditions under reflux or simple mechanical stirring. In some cases sonication leads to unusual products.

Diastematomyelia is a structural anomaly which concerns primarily the spine and secondarily the nervous structures contained in it. A case of early prenatal diagnosis (20th week) by ultrasound of diastematomyelia with associated diplomyelia in a diabetic woman is reported. Radiological and pathological examination of the fetus after therapeutic abortion confirmed the diagnosis.

One hundred forty-three biopsies of Kaposi's sarcoma (KS) from 96 patients were assessed histopathologically, and mitoses were counted. Ninety-seven samples from 66 patients were analyzed by flow cytometry. Six of 97 (5.8%) KS lesions were DNA aneuploid with a clustering around a DNA index of 1.5 (range, 1.4 to 1.6). The median percentage of S-phase plus G2-phase cells (%S + G2) was 16.7%. Increasing mitotic counts and %S + G2 were seen with progression of the phase and pattern of disease. Nodular KS and spindle cell predominant KS had the highest mitotic counts and %S + G2, with nodular KS larger than 4 mm having a higher mitotic count than those smaller than 4 mm. These findings suggest a low level of DNA aneuploidy in KS and important changes in the level of cell proliferation with the phase and pattern of the disease. However, flow cytometry does not solve the dilemma of whether KS is a hyperplastic or neoplastic process.

A careful overview of the classical appearances of Kaposi's sarcoma (KS) as well as of its variants were reviewed from the clinical and pathological point of view. The growth phases (stages) and the cellular patterns were histopathologically compared with emphasis on the developmental progression of disease as well as mitotic activity. Other morphological aspects were also assessed such as the features of the early phases and the incidence of hyaline bodies. One hundred and forty-three lesions from 96 patients mostly of the Italian sporadic type were investigated. A complete list of those entities which should be considered in differential diagnosis is shown and the dilemma of whether KS is a neoplasia or a hyperplasia is discussed.

A10-YEAR-OLD FEMALE patient was diagnosed radiologically with osteopetrosis at the age of 2 months. The patient is the second child of apparently healthy nonconsanguineous parents. Her 12-year-old brother was unaffected. The father’s history was negative. The mother’s history revealed the presence of two first grade cousins with Wilson’s syndrome, and the only brother died from sudden infant death syndrome during sleep at the age of 12 months.

Virus cell-to-cell spread has been reported for many different viruses and may contribute to pathogenesis of viral disease. The role played by cell-to-cell contact in hepatitis C virus (HCV) transmission was studied in vitro by cell co-cultivation experiments. A human lymphoblastoid B-cell line, infected persistently with HCV in vitro (TO.FEHCV), was used as HCV donor [Serafino et al., 2003]; recipient cells were the human hepatoma HepG2 cell line. Both cell types were co-cultured for 48 hr to allow the cell-to-cell contacts. The hepatoma HepG2 cells are not permissive to free-virus infection, but they were infected successfully using TO.FEHCV cells as source of virus. The kinetics of viral RNA synthesis and the percentage of infected cells were compared in cell-mediated-and cell-free-viral infection. After co-cultivation, a consistent proportion of hepatoma cells replicated HCV and stably expressed viral antigens. Virus produced was infectious as demonstrated by the ability to reinfect fresh B-cells. This cell model shows that permissiveness to HCV infection can be achieved in vitro in non-permissive hepatoma cells by direct cell-to-cell contacts with infected human B-cells. This mechanism of virus spread may also play a pathogenic role in vivo. J. Med. Virol. 78:192–201, 2006. © 2005 Wiley-Liss, Inc.

In bladder exstrophy and to a lesser extent in epispadias the muscular tissue in the bladder wall may often be replaced by collagen. The aim of our study was to assess the relative changes of smooth muscle versus connective tissue in patients with the exstrophy-epispadias complex.Nine full thickness detrusor biopsies from children with the exstrophy-epispadias complex were analyzed. Biopsies were stained with the Masson trichrome method to differentiate muscular tissue from collagen. At x50 magnification using image software for computerized morphometry the areas of smooth muscle and collagen were measured and expressed as a percent. As controls, detrusor biopsies from 8 children with unilateral obstructive megaureter or ectopic ureter were analyzed using the same method.The average rates of smooth muscle in children with the exstrophy-epispadias complex were 7, 19.3 and 31.5%, respectively, in newborns, and before and after bladder neck reconstruction. In controls the rate averaged 56.5%.The ratio of smooth muscle-to-connective tissue increases from the newborn period to puberty in the exstrophy-epispadias complex. After staged reconstruction is completed this ratio remains below normal, although it is increased. Such a change may represent a histological marker of the inadequate volume increase of some of these bladders.

Desmoplastic small round cell tumor (DSRCT) is a neoplasia that occurs mainly in childhood and involves abdominal or peritoneal sites, coexpressing ectodermal and mesenchimal immunophenotypic markers, and is endowed with an impressive stromal desmoplasia that tends to decrease on tumor relapse. To date, over 150 cases have been collected in the literature. Its presumed neuroectodermal histogenesis has been challenged by cytogenetic findings different from those usually associated with neoplasms of neuroectodermal origin. The authors report a case bearing clinical and histologic aspects of typical desmoplastic retroperitoneal small cell tumor, with intense and diffuse nuclear immunopositivity for WT1, but lacking divergent immunophenotype. Ultrastructural investigation revealed that desmoplasia could result from fibrillary synthesis by neoplastic cells.

PURPOSE. Fatty acid synthase (FAS) performs the anabolic conversion of dietary carbohydrate or protein to fatty acids. Many common human cancers express high levels of FAS, and its differential expression between normal and neoplastic tissues has led to the consideration of FAS as a target for anticancer therapy. To investigate the potential of targeting FAS in the treatment of retinoblastoma, we first determined whether FAS was activated in this human tumor. Moreover, correlation of FAS expression with tumor aggressiveness was determined. METHODS. FAS reactivity was evaluated by immunohistochemistry in 66 retinoblastoma specimens from 65 patients. Degree of tumor differentiation, choroid invasion, optic nerve infiltration, mitotic rate, and necrosis extension were estimated. FAS expression was correlated with all these tumor characteristics by means of parametric and nonparametric statistical analyses. RESULTS. Eighty-two percent of tumors were FAS positive. Stronger FAS expression correlated with more advanced choroid (P 0.001) and optic nerve (P 0.016) invasion, high mitotic index (P 0.001), and less differentiated histology (P 0.047). Correlation with extension of necrosis was not statistically significant. Unaffected retina was negative. CONCLUSIONS. The data suggest that expression of FAS and fatty acid synthesis support an essential functional aspect of retinoblastoma cells, perhaps cell growth or survival. FAS activation may serve as a novel target for systemic and local antineoplastic therapy and, because it increases with tumor aggressiveness, its inhibition could represent an alternative treatment strategy in advanced and resistant retinoblastomas. (Invest Ophthalmol Vis Sci. 2003;44:2399 ‐2403) DOI:10.1167/iovs.02-0934

Treatment of nephroblastoma (Wilms tumor) has presently achieved a greater than 80% cure rate. Pathologic stage and grade are considered the most reliable prognostic parameters, but other biologic factors are under study in order to improve patient stratification into risk groups. Correlation of elevated levels of the lipogenic enzyme fatty acid synthase (FAS) with aggressiveness of some cancers has drawn attention to this enzyme as a possible marker of poor prognosis.To determine the predictive strength of FAS expression in Wilms tumor (with particular emphasis on intermediate risk, i.e., non anaplastic tumors, the vast majority of nephroblastomas), we evaluated immunostaining expression in archival specimens from 94 neoplasms. The degree of expression was correlated with stage, grade, clinical course and administration of prenephrectomy chemotherapy.Expression of FAS increased in anaplastic tumors (P = 0.043) and higher stages (P = 0.029). FAS expression correlated with OS and DFS at both univariate and multivariate analysis. Comparable results were obtained when analyzing the intermediate risk population separately. Pretreatment resulted in an increased FAS expression, without reaching significance level (P = 0.059).Expression of FAS might be an independent prognostic factor, particularly for intermediate-risk patients. The blockade of fatty acid synthesis by inhibition of FAS enzymatic function by means of metabolic analogues might prove a novel target pathway for the treatment of nephroblastoma.

We describe here the clinicopathological findings in a child with congenital nephrotic syndrome (CNS) non-responsive to medical therapy who developed acquired cystic kidney disease (ACKD) in both native kidneys after long-term peritoneal dialysis. This case indicates that CNS is a further pathologic condition related to the development of ACKD.

Treatment of nephroblastoma (Wilms' tumor) has presently achieved a 90% survival rate. Stage and grade are considered the most reliable prognostic parameters, but other biological factors are under study in order to improve patient stratification. Deoxyribonucleic acid (DNA) ploidy has been suggested to be useful in this setting. We retrospectively studied 79 patient with nephroblastoma (58 pretreated with chemotherapy and 21 not pretreated) by means of flow cytometry. DNA content and synthetic phase values were correlated with pathologic features and outcome. DNA modifications induced by chemotherapy were investigated. Sixty-nine tumors were diploid and 10 aneuploid. DNA content did not correlate with clinical course and was not modified by pretreatment. Aneuploid tumors were restricted to lower stages. Mean S-phase rate was lower and did not vary according to histology in pretreated tumors, while it was higher and increased with grade (p = 0.007) in previously untreated tumors. The fraction of cells in synthetic activity was related to outcome: Patients whose tumors displayed higher S-phase rates had a more favorable clinical course. Ploidy did not appear to be of prognostic significance. S-phase rate decreased after chemotherapy (p = 0.0002) and was related to survival. The worse outcome of pretreated patients might be attributed to a minor sensitivity to postoperative treatment: Preoperative chemotherapy would decrease the cell proliferation and might select resistant cellular clones of (possible) neoplastic residues.

The case of a 61-year-old woman with Whipple's disease-associated sicca complex is reported. Tropheryma whipplei infection was diagnosed by histological and ultrastructural examination of the jejunal mucosa and sequence analysis of the bacterial 16S ribosomal DNA. The role of vitamin A malabsorption in sicca complex secondary to Whipple's disease is discussed.

It has been suggested that an atypical course of primary infection by EBV and the reactivation of EBV infection in transplanted patients may induce hepatitis. We explored the possibility to dissect the infectious activity from the ability to promote B lymphocyte proliferation in vivo by injecting in nu/nu mice a low number (2 x 10(6)-0.05 x 10(6)) of cells from CE a normal human bone marrow-derived B cell line. This line carries an endogenous EBV in episomal and linear forms. Twenty nu/nu mice were inoculated subcutaneously with the B cell line CE and a matched group with the cell line RAG obtained by EBV in vitro infection of normal human peripheral blood. The mice injected with the CE line did not develop a lymphoproliferative disease, but 5 of them displayed typical histopathological lesions of chronic hepatitis without involvement of other organs. Similar results were obtained in 2 out of 20 animals in the RAG group. A close association between liver lesions and a previous EBV infection, by putative circulating B lymphoblastoid cells releasing their EBV, was established by PCR and by in situ hybridization with BamHI "W" DNA probe. This latter probe detected the presence of about 15% of positive cells only in affected livers. In addition, the rare detection in some hepatocytes of "A" type Cowdry bodies would suggest the occurrence of continuous EBV replication although at a very low level. These data show that we succeeded in dissecting the infectious from the proliferative activity of the endogenous EBV carrier CE cell line. This provides in addition a promising model for chronic EBV-associated hepatitis.

Purpose: The aim of this study was to perform a clinicopathologic evaluation of a single pediatric institution renal tumor series. Most patients were treated within the frame of 3 consecutive SIOP trials, which included preoperative chemotherapy as their main feature. Methods: Medical records and diagnoses of 111 patients were reviewed. The association of pathologic features with outcome was investigated by means of the Kaplan-Meier method, the Cox model, and a logistic multivariate analysis. Comparison among different trial results was carried out. Results: In 98 patients (88%), nephroblastoma was diagnosed, followed by 6 adult-type renal tumors, 3 cystic nephromas, 2 mesoblastic nephromas, and 2 clear cell sarcomas. For nephroblastoma, a statistically significant correlation between grade and both disease-free survival rate and 5-year survival rate, and between stage and overall survival rate was shown. Lymph node involvement, local relapse, nephrogenic rests, and older age at presentation appeared to be less important prognostic factors. Tumor spillage was very sensitive to chemo or radiotherapy. No significant difference in outcome was observed among different trials. Conclusions: Wilms' tumor was the most frequent neoplasm and resulted in a 5-year cure rate of 90%. Clinical course was influenced mainly by diffuse anaplasia and, to a minor extent, by lymph node involvement. Because some tumors followed an unpredictable course, it is likely that also other biological factors played a significant role. J Pediatr Surg 36:1522-1527. Copyright © 2001 by W.B. Saunders Company.

The term "neuronal ceroid lipofuscinosis" (NCL) describes a complex of inherited neurodegenerative conditions associated with storage of lipopigments in brain tissue. In 1989 Dyken proposed a classification of NCL based on the age, clinical symptoms, and ultrastructural aspects of the lipopigments. At the ultrastructural level it is possible to distinguish 5 different patterns of osmiophilic lipopigments: usual lipofuscin, fingerprint deposits, granular profiles, curvilinear bodies, and microtubular aggregates. The concept that each ultrastructural pattern was the counterpart of a specific clinical type has been proved not to be true. Advances in molecular genetic techniques have allowed the identification of defective genes and their protein products in several NCL clinical forms. Ceroid lipofuscin deposits may be ultrastructurally observed not only in neuronal cells, but also in several other sites, such as trophoblastic cells, thus permitting prenatal diagnosis. In spite of recent advances in immunohistochemical identification of biochemical markers, the ultrastructural identification of lipofuscinic pigments remains the gold standard to identify NCL, together with clinical aspects and respective gene defects. This study describes the ultrastructural aspects observed in 8 cases of NCL syndromes (3 juvenile, 3 infantile, 1 late infantile, and 1 congenital clinical form). In these patients, genetic analysis was also performed.

Summary Myofibroblasts are spindle cells having ultrastructural features in common with smooth muscle cells and fibroblasts. In the last few years, tumours have been described in which myofibroblasts represent not only a reactive mechanism but also a true neoplastic component. They constitute new nosologic entities which might be termed “myofibroblastic tumours”. Tumours with benign and, rarely, malignant behaviour are reported to belong to this group of lesions. Recently, a third tumour type with borderline biological course, named “inflammatory myofibroblastic tumour” (IMT), has been identified, a condition that has been regarded as a benign and reactive disorder for a long time. Only in recent reports has been demonstrated that, in spite of an apparently benign morphological pattern, some cases of IMT have a malignant course. In this connection, DNA analysis by flow cytometry is a valuable diagnostic tool, because it allows identification of the ploidy status, a procedure that is often useful for predicting the nature and the biological behaviour of the lesion. In this study, 11 cases of myofibroblastic tumours were examined retrospectively by evaluating clinicopathological features and DNA ploidy status by flow cytometry. The diagnosis of myofibroblastic tumour was confirmed by performing histology, immunohistochemistry, and electron microscopy in all patients. In detail, these 11 cases were composed of 1 benign myofibroblastoma, 1 myofibrosarcoma and 9 IMTs. Among these myofibroblastic tumours, all those with local recurrence or distant metastases (one myofibrosarcoma and three IMT) showed an aneuploid cell population demonstrable by flow cytometric analysis, whereas the other cases with benign course (one benign myofibroblastoma and six IMT) exhibited an euploid DNA content. These data suggest the following: a) Besides the rare myofibroblastomas and myofibrosarcomas, IMTs represent a larger group of lesions with potentially different biological and clinical course. b) DNA flow cytometric analysis is a reliable tool that supports histopathological examination in characterizing those cases of IMT that, though being malignant, mimic benign lesions. Consequently, it establishes the basis for a different therapeutic approach according to the euploid or aneuploid DNA content.

A girl affected by a restrictive cardiomyopathy with neuromuscular involvement is described. Morphological examination showed a pattern of multicore myopathy and with electron microscopy a sarcoplasmic accumulation of electron dense granular and filamentous material was demonstrated both in skeletal muscle and heart. This peculiar electron dense material corresponded to increased desmin in muscle and cardiac fibres and was demonstrated immunohistochemically.

Objective To determine the accuracy of comparative cytologic and frozen section intraoperative diagnosis in neuropathology and the relevance of diagnostic accuracy during both craniotomic and stereotactic biopsies and to provide further data on rare and/or diagnostically controversial lesions. Study design Both cytologic and frozen section preparations were employed in the intraoperative diagnosis of 85 consecutive central and peripheral nervous system lesions obtained from classical surgery (70 samples, 4 of which were intramedullary) and stereotactic biopsies (15 samples). Results Combining cytologic and frozen section details allowed a fair diagnosis in 81 cases (95.29%), confirmed on paraffin sections. In the remaining cases intraoperative misdiagnosis was due to technical-staining defects (1 case); absence of tumor differentiation, resolved only by ultrastructural examination (2 cases); and marked tumor heterogeneity, resolved by wide tissue sampling and immunohistochemistry (1 case). Conclusion Besides providing a general description of cytologic and frozen section criteria useful in intraoperative diagnostic neuropathology and adding further details about some problematic and/or rare entities, our work confirmed: (1) the usefulness of comparative cytologic and frozen section examination in the intraoperative diagnosis of central nervous system lesions, (2) the relevance of the accuracy of intraoperative diagnosis during both craniotomy and stereotaxis, including intramedullary samples; and (3) the importance of fair "conduct" in intraoperative neuropathology, always comparatively considering morphologic and clinicoradiologic data.

In order to directly ascertain the presence of HCV virus infection in livers of patients with HCV chronic hepatitis, we investigated, by transmission electron microscopy (TEM), liver biopsies from 2 adults and 4 children for the presence of virus-like particles (VLPs). The plasmas of these HCV-positive patients were HCV-RNA-positive, with high ALT values. In liver tissue samples examined, we were able to detect plus and minus strands of HCV RNA by strand-specific RT-PCR. Aggregates or single VLPs of about 45 nm in diameter were detectable in variable amounts in endoplasmic cisternae and in hepatocyte cytoplasms of infected patients. These results emphasize the relevance of performing TEM assays to confirm the diagnosis of HCV infection.

Hypertrophic cardiomyopathy (HCM) is an idiopathic cardiac disease which is predominantly genetic in origin and transmitted as an autosomally dominant trait [1, 2]. The mutated genes code for altered contractile myofibrillar proteins, leading to deformed myocytes and histological evidence of extensive myocell disorganization, namely the disarray typical of hypertrophie cardiomyopathy (HCM). In the natural history of HCM endstage heart failure is relatively infrequent and associated with a pattern of left ventricular systolic impairment with cavity dilatation, which occurrs in about 10% of patients [3, 4], with a yearly incidence of 1.5% [5]. End-stage disease may coexist with premature sudden death in family members carrying the same genetic abnormality [6]. This pattern is characterized by a particularly poor prognosis, so that heart transplantation has been advocated in this subgroup of patients.