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Imaging surgical epilepsy in children.

INTRODUCTION: Epilepsy surgery rests heavily upon magnetic resonance imaging (MRI). Technical developments have brought significantly improved efficacy of MR imaging in detecting and assessing surgical epileptogenic lesions, while more clinical experience has brought better definition of the pathological groups. DISCUSSION: MRI is fairly efficient in identifying developmental, epilepsy-associated tumors such as ganglioglioma (with its variants gangliocytoma and desmoplastic infantile ganglioglioma), the complex, simple and nonspecific forms of dysembryoplastic neuroepithelial tumor, and the rare pleomorphic xanthoastrocytoma. The efficacy of MR imaging is not as good for the diagnosis of focal cortical dysplasia (FCD), as it does not necessarily correlate with histopathological FCD subtypes and does not show the real extent of the dysplasia which may even be missed in a high percentage of cases. Further developments with better, multichannel coils, higher magnetic fields, specific sequences, and different approaches (such as diffusion tensor imaging) for depicting the structural abnormalities may hopefully improve this efficacy. A general review of the MR features of the diverse pathologies concerned with epilepsy surgery in the pediatric context is provided with illustrative images.

Brain Diseases↗

[Molecular pathology of colorectal cancer].

The identification of several types of familial colorectal cancer has led to the discovery of some of the genes involved in these diseases. It was subsequently shown that somatic mutations of these genes (APC, mismatch repair genes, TP53) also occur in sporadic colorectal cancer. Gradually, this molecular information is being incorporated into the standard histopathological analysis of colorectal cancer and can be used for the characterization of primary tumors. Although attempts have been made to use molecular parameters to better define dysplasia grades, differentiate between adenoma and carcinoma, and subtype carcinomas, histological parameters remain the standard for the classification of primary tumors. Nonetheless, molecular parameters may help define subgroups of colorectal carcinoma differing in prognosis and requiring individualized treatment regimens. Interesting possibilities are predicting the response of chemotherapy or radiotherapy at a molecular level and the search for metastasis by looking for molecular markers in lymph nodes or circulating blood. Other pathological tests being developed include the detection of K-ras, TP53 or APC mutations in stool and plasma. Such approaches will have a significant impact on the clinical management of colorectal cancer.

Biomarkers, Tumor↗

Phage types and genotypes of shiga toxin-producing Escherichia coli O157:H7 isolates from humans and animals in spain: identification and characterization of two predominating phage types (PT2 and PT8).

Phage typing and DNA macrorestriction fragment analysis by pulsed-field electrophoresis (PFGE) were used for the epidemiological subtyping of a collection of Shiga toxin-producing Escherichia coli (STEC) O157:H7 strains isolated in Spain between 1980 and 1999. Phage typing distinguished a total of 18 phage types among 171 strains isolated from different sources (67 humans, 82 bovines, 12 ovines, and 10 beef products). However, five phage types, phage type 2 (PT2; 42 strains), PT8 (33 strains), PT14 (14 strains), PT21/28 (11 strains), and PT54 (16 strains), accounted for 68% of the study isolates. PT2 and PT8 were the most frequently found among strains from both humans (51%) and bovines (46%). Interestingly, we detected a significant association between PT2 and PT14 and the presence of acute pathologies. A group of 108 of the 171 strains were analyzed by PFGE, and 53 distinct XbaI macrorestriction patterns were identified, with 38 strains exhibiting unique PFGE patterns. In contrast, phage typing identified 15 different phage types. A total of 66 phage type-PFGE subtype combinations were identified among the 108 strains. PFGE subtyping differentiated between unrelated strains that exhibited the same phage type. The most common phage type-PFGE pattern combinations were PT2-PFGE type 1 (1 human and 11 bovine strains), PT8-PFGE type 8 (2 human, 6 bovine, and 1 beef product strains), PT2-PFGE subtype 4A (1 human, 3 bovine, and 1 beef product strains). Nine (29%) of 31 human strains showed phage type-PFGE pattern combinations that were detected among the bovine strains included in this study, and 26 (38%) of 68 bovine strains produced phage type-PFGE pattern combinations observed among human strains included in this study, confirming that cattle are a major reservoir of strains pathogenic for humans. PT2 and PT8 strains formed two groups which differed from each other in their motilities, stx genotypes, PFGE patterns, and the severity of the illnesses that they caused.

Animals↗

Does the histology of nodal metastasis predict systemic relapse after retroperitoneal lymph node dissection in pathological stage B1 germ cell tumors?

PURPOSE: We evaluated the prognostic significance of the histology of metastatic lymph nodes to predict postoperative relapse in pathological stage B1 nonseminomatous germ cell tumor (NSGCT). MATERIALS AND METHODS: A retrospective review of the testicular cancer database was performed to identify all patients with clinical stage A NSGCT who underwent primary retroperitoneal lymph node dissection and were found to have pathological stage B1 disease. No patient received adjuvant chemotherapy and minimal followup was 24 months. RESULTS: A total of 118 patients were identified with a 5-year disease-free survival (DFS) of 68% and a median followup of 43 months. Embryonal cell carcinoma was identified in 92 of 118 (77%) surgical specimens, which was significantly greater than the presence of teratoma (22%), seminoma (16%) and yolk sac (14.4%, p < or = 0.001) with no difference in 5-year DFS comparing the presence or absence of each histology. Solitary histology was noted in 88 of 118 patients (74.5%). Embryonal cell carcinoma was the most common single histology identified at surgery at 64 of 88 (73%), with the incidence of seminoma, teratoma and yolk sac being 12.5%, 9.0% and 5.5%, respectively (p < or = 0.001). There was no statistical difference in DFS for each of the solitary histological subtypes (p=0.67). Recurrence rates were similar for pure embryonal cell carcinoma (69%), mixed embryonal cell carcinoma (63%) and no embryonal cell carcinoma (73%) in the retroperitoneum (p=0.63). CONCLUSIONS: Retroperitoneal histology does not appear to predict outcome in patients with pathological stage B1 NSGCT.

Carcinoma, Embryonal↗

Staging laparotomy in Hodgkin's disease: Mayo Clinic experience.

Between 1967 and 1979, 316 patients with Hodgkin's disease underwent staging laparotomy. Histologic examination demonstrated lymphocyte predominance in 40 (12.7%) patients, nodular sclerosis in 178 (56.3%), mixed cellularity in 80 (25.3%), and lymphocyte depletion in seven (2.2%); results in 11 (3.5%) patients were considered unclassifiable. There were no deaths. Major complications occurred in 7.9% and required reoperation in 1.9%. Pathologic stage differed from clinical stage in 111 (35.1%) patients. In 90 (28.5%) patients, the stage advanced; in 21 (6.6%) patients, the stage was reduced; and in five (1.6%) patients, the histologic subtype was changed. Stage changes occurred in 40% of those with lymphocyte predominance, in 27.5% with nodular sclerosis, in 46.3% with mixed cellularity, and in 85.7% with lymphocyte depletion. The reliability of staging laparotomy for the determination of appropriate treatment favors its continued use.

Adolescent↗

Clinical characteristics of older psychiatric inpatients with borderline personality disorder.

This case study investigation considers typical and potentially unique characteristics of older (> 50 years) Borderline Personality Disorder (BPD) patients and describes their impact on an inpatient psychiatric unit encompassing a therapeutic milieu setting and multidisciplinary treatment teams. The somatization of symptoms, in particular, and the associated therapeutic, medical, and psychopharmacological interventions, result in prolonged and elaborate treatments that undermine clinical and personal boundaries, clash with managed care directives, and engender frustrating and elusive transferential and countertransferential reactions. Moreover, the guilt-inducing nature of somatization and physical frailty in older individuals, combined with the well-documented ability of BPD patients, regardless of age, to incite stormy and 'split' relationships, are linked characteristics that may describe a diagnostic subtype of BPD. Rather than suggesting a diminution of psychopathology as BPD patients age, the results of this investigation indicate that their persistent difficulties may only be altering in content and in pathological adaptation to changing needs.

Adaptation, Psychological↗

HIV-associated neuropathies: role of HIV-1, CMV, and other viruses.

The role of the human immunodeficiency virus (HIV) and other viruses in the development of neuropathies associated with HIV infection is controversial. Distal symmetric polyneuropathy (DSP), the most common subtype of HIV-associated neuropathy, is characterized by an abundance of reactive macrophages within the peripheral nerve, but HIV replication is limited to a small percentage of the macrophages. Thus, the pathological destruction may be mediated by pro-inflammatory signals amplified by activated glial elements within the nerve, similar to the proposed mechanism of damage caused by HIV within the central nervous system. In contrast, in mononeuropathy multiplex (MM) and progressive polyneuropathy (PP), cytomegalovirus (CMV) replication in the peripheral nerve is consistently demonstrable, and this replication likely results in direct damage to the infected cells (neurons and glia). The rarest form of HIV-associated neuropathy, the diffuse infiltrative lymphocytosis syndrome (DILS), is characterized by an intense CD8+ T lymphocyte infiltration into the nerve and abundant HIV infection of macrophages. Finally, while other viruses (varicella zoster, herpes simplex) are associated with myelitis in HIV-infected individuals, there is little support for a role for these viruses in HIV-associated neuropathy.

Cytomegalovirus↗

Crypt dysplasia with surface maturation: a clinical, pathologic, and molecular study of a Barrett's esophagus cohort.

Little is known regarding the significance of esophageal biopsies that show dysplasia-like atypia limited to the bases of the crypts, without involvement of the surface epithelium in Barrett's esophagus (BE). The aim of this study was to evaluate the clinical, pathologic, immunohistochemical, and molecular characteristics of basal crypt dysplasia-like atypia (BCDA) with surface maturation in surveillance endoscopic mucosal biopsies to gain insight into its biologic significance. The Seattle Barrett's Esophagus Project is a prospective cohort study in which patients and their biopsies have been evaluated prospectively for clinical, pathologic, and molecular markers. As part of continued surveillance of the cohort, 206 consecutive BE patients were evaluated prospectively for BCDA between July 1, 2001 and August 13, 2003; 15 patients had BCDA (prevalence rate = 7.3%). These 15 patients were evaluated for clinical, pathologic, and immunohistochemical (p53 and MIB-1) features during the study period (2001-2003) as well as associations with clinical, pathologic, and molecular markers [17p(TP53) loss of heterozygosity (LOH), 9p(p16) LOH, tetraploidy, and aneuploidy] that were detected previously in the same patients in the cohort study (1983-2001). All BE patients with BCDA (male-to female ratio, 12:3; mean age, 72 years; mean length of BE, 7.0 cm; mean duration of BE, 95.1 months), except 2 (87%), had dysplasia or adenocarcinoma detected in biopsies either prior to or concurrent to the one that contained BCDA. In contrast, only 112 of 191 (59%) controls had neoplasia during the same time period (59%, P = 0.05). The difference between BCDA and controls was particularly significant with regard to the association with high-grade dysplasia (P = 0.004). Compared with adjacent nonatypical and nondysplastic (metaplastic) BE, areas of BCDA showed a significantly elevated prevalence rate of p53 positivity (60% vs. 13%, P<0.02) and a significantly elevated total crypt and basal crypt MIB-1 proliferation rate (P<0.001). Indeed, the MIB-1 proliferation rate in the basal portion of the crypts in BCDA was similar to that detected in conventional low- or high-grade dysplasia. Patients with BCDA showed a significantly increased rate of 17p(TP53) LOH (P = 0.016), aneuploidy (P = 0.004), and a trend in increased 9p(p16) LOH (P = 0.08), compared with control patients without BCDA. The clinical, pathologic, immunohistochemical, and molecular abnormalities were similar in BCDA cases that were considered low-grade versus those considered high-grade by histologic evaluation, except that high-grade cases tended to be older (79 years vs. 68 years, P = 0.06). BCDA with surface maturation, in mucosal biopsies from patients with BE, is an uncommon but significant pathologic change that shows a variety of proliferative and molecular abnormalities and has a high association with conventional dysplasia and/or adenocarcinoma. Based on these findings, BCDA warrants further investigation as a possible subtype of true dysplasia despite the morphologic appearance of surface maturation.

Adenocarcinoma↗

Sodium channel expression in hypothalamic osmosensitive neurons in experimental diabetes.

Vasopressin is synthesized by neurons in the supraoptic nucleus of the hypothalamus and its release is controlled by action potentials produced by specific subtypes of voltage-gated sodium channels expressed in these neurons. The hyperosmotic state associated with uncontrolled diabetes mellitus causes elevated levels of plasma vasopressin, which are thought to contribute to the pathologic changes of diabetic nephropathy. We demonstrate here that in the rodent streptozotocin model of diabetes there are increases in expression of mRNA and protein for two sodium channel alpha-subunits and two beta-subunits in the neurons of the supraoptic nucleus. Transient and persistent sodium currents show parallel increases in these diabetic neurons. In the setting of chronic uncontrolled diabetes, these changes in sodium channel expression in the supraoptic nucleus may be maladaptive, contributing to the development of secondary renal complications.

Animals↗

Subungual glomus tumors: evaluation with MR imaging.

PURPOSE: To determine the magnetic resonance (MR) imaging features of subungual glomus tumors. MATERIALS AND METHODS: Thirty-one patients with a clinical suspicion of glomus tumor and 10 control subjects underwent MR imaging at 1.5 T. MR images of normal glomus bodies of a cadaver finger were correlated with histologic slices. With a local surface gradient coil, the pixel size reached 117 microns in one direction. Relaxation times were measured. Gadoterate meglumine was injected in 19 patients. RESULTS: Normal glomus bodies were visualized in the reticular dermis of the nail bed. Twenty-seven of 28 pathologically confirmed glomus tumors were detected with MR imaging. A peripheral capsule was present in most tumors. The nail matrix was compressed in 13 cases. The authors were able to differentiate three subtypes of glomus tumors (vascular, solid, and myxoid) on the basis of relaxation times and enhancement characteristics. Four patients had mucoid cysts or angioma in the nail bed. CONCLUSION: MR imaging can help accurately define the location and limits of glomus tumors before excision.

Adult↗

Inflammatory mediator receptors and asthma.

Many inflammatory mediators (histamine, prostanoids, leukotrienes, platelet-activating factor, adenosine, bradykinin, and sensory neuropeptides) have been implicated in the pathogenesis of asthma and produce their effects by activating specific cell surface receptors. Activation of these receptors may result in contraction of airway smooth muscle, mucus and fluid secretion, microvascular leakiness, chemotaxis of inflammatory cells, and neuronal activation, indicating that the receptors are localized to a variety of cells. Recent studies have indicated that mediator receptor activation may lead to a response either by modulating adenylate cyclase or by stimulating breakdown of membrane phosphoinositides, which release intracellular calcium ions. The latter mechanism appears to predominate, at least in the case of airway smooth muscle receptors. Several receptors for inflammatory mediators have been characterized functionally and by direct receptor binding techniques, and receptor subtypes have been recognized. Several specific mediator receptor antagonists have been developed but are unlikely to have a major clinical effect because so many different mediators are likely to contribute to the pathology of asthma. Platelet-activating factor, possibly by acting on specific platelet receptors, is able to increase nonspecific bronchial responsiveness in human subjects, so it is possible that specific receptor antagonists of this phospholipid mediator might reduce the enhanced responsiveness to other inflammatory mediators which occurs in asthma.

Animals↗

alpha-Adrenergic receptors in human adipocyte membranes: direct determination by [3H]yohimbine binding.

The presence of alpha 2-adrenergic receptors in membranes derived from human sc adipose tissue was directly demonstrated with a new alpha 2-selective ligand, [3H]yohimbine. Binding of this radiolabeled antagonist to adipocyte membranes was of high affinity (Kd = 3.9 +/- 2.4 nM) and saturable. Computer modelling of [3H]yohimbine saturation curves demonstrated that it binds to a homogeneous class of sites with a density of 145.0 +/- 33.8 fmol/mg protein. Adrenergic agonists competed with [3H]yohimbine in the order expected of alpha-receptors, and their binding was strongly influenced by guanine nucleotides. Competition of alpha-antagonists with this radioligand demonstrated yohimbine to be more potent than prazosin, indicative of alpha 2-receptors. Antagonist binding was unaffected by guanine nucleotides. Paired saturation curves in these adipocyte membranes with the alpha 2-selective [3H]yohimbine and the nonsubtype selective alpha-antagonist [3H]dihydroergocryptine demonstrated similar receptor concentrations. [3H]Dihydroergocryptine has been previously shown to label both alpha 3- and alpha 2-receptors with equal affinity. Therefore, these data indicate that the vast majority of alpha-receptors in human sc fat are of the alpha 2-subtype. [3H]Yohimbine with its alpha 2-selectivity and high specific binding will provide an excellent tool for the clinical investigation of human adipocyte alpha-receptor mechanisms in both normal and pathological states.

Adipose Tissue↗

Amino-alkyl-cyclohexanes as a novel class of uncompetitive NMDA receptor antagonists.

Because of its widespread involvement in the physiology and pathology of the CNS, the glutamatergic system has gained considerable attention as a potential target for development of new agents for a number of therapeutic indications. In this respect, the glutamate receptor subtype of the NMDA type has been most intensively studied. The present review describes the rational for developing amino-alkyl-cyclohexanes, as new uncompetitive NMDA receptor antagonists based on our positive experience with memantine which has been used clinically for many years for the treatment of neurodegenerative dementia. Many amino-alkyl-cyclohexane derivatives have been evaluated in vitro and in animal models, and in turn, one structure, namely neramexane HCl (MRZ 2/579) was selected for further development. This agent shows some similarity to memantine e.g. channel blocking kinetics, voltage dependency, and affinity. Preclinical tests indicated particularly good activity in animal models of alcoholism (self-administration, withdrawal-induced audiogenic seizures etc.) and pain (chronic pain, inhibition of tolerance to the analgesic effects of morphine). It turn, this agent has recently entered phase II of clinical trials in alcoholism after a favourable profile seen in phase I studies.

Animals↗

The multidisciplinary approach to treatment of soft tissue sarcomas.

Soft tissue sarcomas are rare tumors including many histological subtypes. They are pre-eminently tumors for which the multidisciplinary approach to treatment is of utmost importance. The two most frequently applied staging systems both require experienced assessment of radiology and pathology, and stage is a prominent prognostic factor for survival that guides the choice of treatment modalities. For primary treatment radical surgery is still the backbone. In many instances postoperative radiotherapy is a valuable and often necessary complementary treatment. The role of preoperative radiotherapy and/or chemotherapy needs to be defined although preliminary results are interesting. Chemotherapy as an adjunct to surgery should still be considered investigational. In metastatic disease "standard" chemotherapy has a definitive though moderate activity, but recent data on dose-intensified chemotherapy suggest that results may be further improved.

Antineoplastic Combined Chemotherapy Protocols↗

Ret/PTC activation does not influence clinical and pathological features of adult papillary thyroid carcinomas.

OBJECTIVE: RET proto-oncogene rearrangements (ret/PTCs) represent the most common genetic alterations found in papillary thyroid carcinomas (PTCs). Correlation of ret/PTC expression with clinical outcome is controversial. The aim of the present study was to analyze the frequency of RET rearrangements in adult PTCs, and to investigate if ret/PTCs influence biological behavior and clinical features of the cancers. DESIGN: Ret/PTC rearrangements were looked for in tIssue samples of 48 PTCs collected at our institution. Data about clinical and pathological features of the tumors were also reviewed. Three separate association analyses were carried out on the cohort evaluating the effects of, respectively, ret/PTC positivity, preferential RET tyrosine kinase domain (RET-TK) expression, and ret/PTC plus RET-TK positivity, on age, sex, tumor size, staging, number of neoplastic foci, and histological subtype. METHODS: The genetic study was conducted with the RT-PCR-Southern blot technique. Standard Student's t-test and Fisher exact test were applied for the association analyses. RESULTS: The molecular genetic study demonstrated the positivity of ret/PTC1 and ret/PTC3 in 13 of 48 tumors (27.1%), and an exclusive or preferential RET-TK expression in 17 cases (35.4%). None of the three genetico-clinical analyses showed any significant association between ret/PTC expression and the clinical and pathological features of the cancers. CONCLUSIONS: These data indicate that RET rearrangements may not play any distinctive role in driving histotype development and cancer progression in these neoplasms. Moreover, they weaken the possibility of using ret/PTC as a prognostic marker for papillary thyroid carcinomas.

Adult↗

Evidence of a cross-protective immune response to influenza A in the cotton rat model.

Epidemiologic evidence suggests that cross-protective immune responses to influenza A viruses that have different hemagglutinin and neuraminidase subtypes occur in humans. This study characterized this heterosubtypic immunity in cotton rats (Sigmodon hispidus). Animals were infected with influenza A/PR/8/34 (H1N1) or A/Wuhan/359/95 (H3N2), and then challenged with A/Wuhan/359/95(H3N2) virus 4 weeks later. Viral titers, respiratory rates, and pathology of the respiratory tract following primary and secondary infection were compared. Cross-protection from heterosubtypic influenza A challenge in cotton rats was characterized by enhanced viral clearance, protection from tachypnea, a vigorous early cellular recall response, and a reduction in bronchiolar epithelial cell damage. Cross-protection was retained in steroid treated animals, in which the inflammatory recall response was minimal. Identification of the mechanisms that contribute to cross-protection in cotton rats may lead to the development of influenza vaccine strategies that are broadly protective.

Animals↗

The impact of chemotherapy on the survival of patients with high-grade primary extremity liposarcoma.

OBJECTIVE: To determine if chemotherapy offers a survival benefit to patients with large, high-grade, primary extremity liposarcoma. SUMMARY BACKGROUND DATA: The impact of chemotherapy on the survival of patients with primary extremity soft tissue sarcoma is controversial and its effect on individual histologic subtypes is not defined. PATIENT AND METHODS: Two prospectively collected sarcoma databases were used to identify all patients with >5 cm, high-grade, primary extremity liposarcoma that underwent surgical treatment of cure from 1975 to 2003 (n = 245). Clinical, pathologic and treatment variables were analyzed for disease-specific survival (DSS), distant recurrence-free survival (DRFS) and local recurrence-free survival (LRFS). RESULTS: Sixty-three (26%) patients were treated with ifosfamide based chemotherapy (IF), 83 (34%) with doxorubicin based chemotherapy (DOX) and 99 (40%) received no chemotherapy (NoC). To assess the impact of DOX, a contemporary cohort analysis of patients treated from 1975 to 1990 was performed. The 5 year DSS of the DOX treated patients was 64% (53%-74%) compared with 56% (51%-79%) for the NoC patients (log-rank P value = 0.28). To assess the impact of IF, a contemporary cohort analysis of patients treated from 1990 to 2003 was performed. The 5 year DSS of the IF treated patients was 92% (84%-100%) compared with 65% (51%-79%) for the NoC patients (log-rank P value = 0.0003). Independent prognostic factors for improved DSS were smaller size (HR = 0.7, P = 0.01), myxoid/round cell histologic subtype (HR = 0.3, P = 0.03) and treatment with IF (HR = 0.3, P = 0.01). The five-year DRFS of the IF treated patients was 81% (70%-92%) compared with 63% (50%-76%) for the NoC patients (log-rank P value = 0.02). The 5 year LRFS of the IF treated patients was 86% (76%-96%) compared with 87% (77%-97%) for the NoC patients (log-rank P value = 0.99). CONCLUSIONS: In patients with large, high-grade, primary extremity liposarcoma; DOX is not associated with improved DSS and IF is associated with an improved DSS. Treatment with IF should be considered in patients with high-risk primary extremity liposarcoma.

Adult↗

Clinico-pathological data and prognostic factors in completely resected AJCC stage I-III liposarcomas.

BACKGROUND: In general, although biological behavior and prognosis of liposarcomas (LPS) are more favorable compared with most other soft tissue sarcomas (STS), prognosis can vary widely depending on tumor characteristics, especially histological subtype and tumor grade. PATIENTS AND METHODS: All consecutive, completely resected stage I-III LPS (as determined by the American Joint Committee on Cancer staging guidelines), treated at the Groningen University Hospital from 1977-2000, were analyzed. RESULTS: A total of 69 patients, 35 males and 34 females, median age 51 (range 11-80) years, were reviewed. After a median follow-up of 71 (range 5-231) months, the overall local recurrence and metastasis rate at five years after diagnosis were 27% and 16%, respectively. Retroperitoneal localization was a significant negative prognostic factor regarding local recurrence; dedifferentiation, grade II-III, and deep location regarding distant metastasis; and dedifferentiation, grade II-III, stage II-III, size >20 cm and non-radical resection regarding survival. CONCLUSIONS: LPS have a relatively mild biologic behavior, with the exception of very large, deeply located, dedifferentiated and/or grade II-III LPS. Radical resection is important for disease-specific survival. LPS have a relatively mild biologic behavior, with the exception of very large, deeply located, dedifferentiated and/or grade II-III LPS.

Adolescent↗