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PubMed2003

Hodgkin's disease in the setting of human immunodeficiency virus infection.

The incidence of Hodgkin's disease appears to progressively increase in human immunodeficiency virus (HIV)-infected patients, with the relative risk of developing this malignancy rising from the early phase to the advanced stage of HIV disease. Clinical and pathological features of Hodgkin's lymphoma in HIV-positive subjects differ from those of the general population, showing a higher frequency of unfavourable histological subtypes, advanced stage with frequent extranodal involvement at initial diagnosis, and a poor therapeutic outcome. The optimal therapeutic strategy is still controversial, and median overall survival is short, ranging from 12 to 18 months. In this report cases of Hodgkin's disease are described among over 1,000 HIV-infected patients referring to a tertiary care centre during a 6 y study period.

Adult↗
PubMed2004

P2X7 receptor expression after ischemia in the cerebral cortex of rats.

Large amounts of adenosine 5'-triphosphate (ATP) released from cellular sources under pathological conditions such as ischemia may activate purinoceptors of the P2X and P2Y types. In the present study, the expression of the P2X7 receptor-subtype in the brain cortex of spontaneously hypertensive rats was investigated using a permanent focal cerebral ischemia model. Immunocytochemistry with antibodies raised against the intracellular C-terminus of the P2X7 receptor showed a time-dependent upregulation of labeled cells in the peri-infarct region after right middle cerebral artery occlusion (MCAO) in comparison to controls. Double immunofluorescence visualized with confooal laser scanning microscopy indicated the localization of the P2X7 receptor after ischemia on microglial cells (after 1 and 4 days), on tubulin betaIII-labeled neurons (after 4 and 7 days), and on glial fibrillary acidic protein (GFAP)-positive astrocytes (after 4 days). In the following experiments, changes occurring 4 days after MCAO were investigated in detail. Western blot analysis of the cortical tissue around the area of necrosis indicated an increase in the P2X7 receptor protein. Immunoelectron microscopy revealed the receptor localization on synapses (presynaptically), on dendrites, as well as on the nuclear membrane of neurons (postsynaptically) and glial cells. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling in combination with P2X7 receptor immunocytochemistry indicated a co-expression on the apoptotic cells. Active caspase 3 was especially observed on GFAP-positive astrocytes. In conclusion, the present data demonstrate a postischemic, time-dependent upregulation of the P2X7 receptor-subtype on neurons and glial cells and suggest a role for this receptor in the pathophysiology of cerebral ischemia in vivo.

Adenosine Triphosphate↗
PubMed1990

S-antigen and rod-opsin immunoreactions in midline brain neoplasms of transgenic mice: similarities to pineal cell tumors and certain medulloblastomas in man.

Transgenic mice expressing the large T-antigen of the simian virus 40 (SV 40) under the control of 1) the enhancer of Moloney murine sarcoma virus (MSV) and 2) the SV 40 promoter develop undifferentiated neuroectodermal tumors located in the midline of the dorsal brain surface, abnormalities in lens fiber differentiation and retinal dysplasia. In this study the brain neoplasms of six adult animals and the brain of one 11-day old mouse were examined by conventional histology and immunocytochemical demonstration of S-antigen, rod-opsin, neuron-specific enolase, neurofilaments (160 and 200 kDa) and glial fibrillary acidic protein. According to histologic criteria the neoplasms were characterized as "primitive" neuroectodermal tumors composed mainly of small cells with scanty and ill-defined cytoplasm. Neoplastic cells displaying immunoreactive S-antigen were found in five brain tumors; three of these tumors also contained a limited number of rod-opsin immunoreactive neoplastic cells. Some tumor cells had neurite-like processes containing immunoreactive neurofilament (200 kDa). No pathologic lesions were found in the brain of the 11-day old animal. Tumors in transgenic mice may resemble pineal cell tumors and a special subtype of medulloblastoma in man. These neoplasms contain S-antigen immunoreactive and also rod-opsin immunoreactive tumors cells in certain cases. The findings suggest that transgenic mice expressing the large T-antigen of SV 40 may become a valuable animal model for analysing the origin, histogenesis and development of primitive neuroectodermal tumors with photoreceptor-like features (pineal cell tumors and certain medulloblastomas).

Animals↗
PubMed2002

Prospects for rational development of pharmacological gap junction channel blockers.

Connexin-null mice and human genetic gap junction diseases illustrate the important roles that gap junction channels play under normal conditions, and the neuro- and cardioprotective effects of gap junction blocking agents demonstrate that closure of these channels may be beneficial in certain pathological situations. This overview summarizes studies in which gap junction modifying reagents have been characterized, highlighting examples of agents for which selectivity for gap junction subtypes has been demonstrated. In addition, strategies for targeting connexin domains through peptide inhibitors are outlined, which may ultimately provide agents that are not only connexin-selective in their actions, but also affect only a subset of a gap junction channel's gating responses.

Animals↗
PubMed2003

[New trends in the diagnosis and treatment of malignant lymphoma].

The present status of the following aspects of diagnosis and treatment of malignant lymphoma are reviewed, and future directions are discussed. 1. Epidemiology 2. Pathological classification 3. Molecular analysis of oncogenesis and disease progression 4. Staging classification and response evaluation 5. State-of-the art therapy of major subtypes 1) Hodgkin's lymphoma 2) Aggressive non-Hodgkin's lymphoma 3) Indolent B-cell non-Hodgkin's lymphoma 4) Salvage therapy for relapsed cases 6. New agent development focusing on antibody therapy 1) Principles and history of antibody therapy 2) Clinical development of rituximab in the USA and Japan 3) Radioimmunotherapy Recently, the importance of evidence-based medicine has been widely recognized not only by physicians but also by patients themselves. To further improve the therapeutic results, it is extremely important to conduct well-designed clinical trial consecutively.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

[Clinicopathological features and prognosis of thymic carcinoma].

OBJECTIVE: To investigate the clinicopathologic features of thymic carcinoma and assess its prognostic factors. METHODS: A retrospective analysis was performed in 54 patients with thymic carcinoma who underwent surgical resection. Eighteen patients were treated by total resection of the tumor, 17 partial resection and 10 exploratory thoracotomy. The clinical stage was determined according to Masaoka's classification. The survival time and prognostic factors were evaluated by the log-rank and Cox multivariate analysis model. RESULTS: The overall 5-year survival rate was 44.4%. Being located in anterior mediastinum and noncalcification in the tumor pathognomonically played an important role in the differential diagnosis. According to the multivariate analysis, tumor maximum diameter (OR = 1.84), histological subtype (OR = 1.70), completeness of resection (OR = 1.37), tumor invasion of peritumoral organs (OR = 1.32) and postoperative recurrence (OR = 1.26) were significant prognostic factors. Compared with other subtypes, carcinoid tumor had the characteristics of earlier lesion, better resection rate and better prognosis. CONCLUSION: The most important prognostic variables for thymic carcinoma are tumor maximum diameter, histological subtype, completeness of resection, tumoral invasion and postoperative recurrence. Complete resection followed by chemoradiotherapy should be considered as favorable on the basis of a definitive pathologic diagnosis.

Adult↗
PubMed2006

The impact of cell heterogeneity and immunophenotypic changes on monitoring minimal residual disease in acute myeloid leukemia.

Monitoring of minimal residual disease (MRD) becomes increasingly important for the more accurate stratification of the therapy in acute leukemia. The purpose of this study was to characterize in detail the phenotypes of heterogeneous population in various AML subtypes and to identify the leukemia associated aberrant phenotype (LAP) in individual patients with AML for precise investigation of MRD. The impact of heterogeneity of pathological populations, the effectiveness of location AML blasts on CD45/SSC dot plots in AML patients during follow-up and phenotype changes on MRD monitoring were evaluated in the second step. Bone marrow samples from 63 patients with AML were analyzed at diagnosis, 33 were selected for monitoring of MRD during follow-up and 13 analyzed at relapse using a wide antibody panel in quadruple combinations by multiparameter flow cytometry. In 88% of AML patients at least one LAP was defined at diagnosis, two or more aberrancies coexisted in 60% of them. The total number of LAPs identified by application of various combinations of antibodies was 112 (mean = 2.04 LAP/patient) and the median percentage of blasts carrying the LAP was 53.57%. In half of the patients, we were able to detect the presence of at least two subpopulations, which not always shared the same aberrancy. Although AML cells often have light scattering properties similar to those of normal (myeloid and B-lymphoid precursors, basophiles etc.) in a fraction of cases we found also very useful the location on CD45/SSC dot plots for MRD discrimination. In 13 patients relapse occurred and although we found in 69% changes of phenotype when comparing diagnosis and the first relapse, at least one LAP was constant in 92%. According to our observations, in majority of patients with AML monitoring of MRD by multiparameter flow cytometry is feasible although in some cases could present some specific difficulties owing to their immunophenotypic heterogeneity, similarity with other cell subpopulations or shifts at relapse. In conclusion, investigation of MRD should be based on the phenotypic characteristics of each subpopulation even if it is present in low frequencies.

Acute Disease↗
PubMed1990

Gross classification of 175 cases of rat pleural mesothelioma induced by chrysotile.

This paper reports an analysis of the gross pathologic classification of 175 cases of rat pleural mesothelioma induced by chrysotile. The mesotheliomas were divided into diffuse and localized types, and further into four subtypes according to the form of the tumors (massive, nodule, plaque, and mixed). Diffuse pleural mesothelioma accounted for 58.9% of the tumors and occurred mainly as the nodular type. Among the localized type (41.1%) the massive subtype was most prevalent.

Animals↗
PubMed1986

[Nuclear DNA content in nasopharyngeal carcinoma (NPC) cells].

Cancer cell nuclear DNA content of 40 biopsy imprints of NPC was measured by Leitz MPV3 microspectrophotometer using scanning method. The pathological diagnosis and histological classification were done on the same specimens. By morphology, the poorly differentiated squamous carcinoma (34 cases) could be divided into four subtypes: ordinary nucleus type (14), spindle nucleus type (5), large and pleomorphic nucleus types (12 and 3). The first two types revealed a bimodal peak DNA histogram (2C and 4C) and slightly scattering toward the right to the 8C region in some nuclear DNA. The large nucleus type showed the bimodal peaks with a broad 4C and many nuclear DNA located in the 4C-8C range. The pleomorphic nucleus type appeared as multiple low peaks diffusing between 2C-12C. The vesicular nucleus cell carcinoma (3 cases) had a double peak DNA histogram similar to the ordinary nucleus type. The undifferentiated cell carcinoma (1 case) showed a broad unimodal peak DNA, ranging from 2C to 6C. The well differentiated squamous carcinoma (2 cases) had a double peak DNA, which was close to the normal diploid pattern but each peak was relative wide and a few DNA value located beyond the 4C region. The results indicate that DNA values showing a predominance of double peak histogram and diploid pattern imply the low grade malignancies in its biological behavior. In contrast, those showing the aneuploid and multiploid patterns in the majority of cancer cells point to the high grade malignancies. Hence, the supplementary DNA measurement of NPC cells can judge exactly the malignant degree of the tumor and provide evidence for prognosis.

Carcinoma, Squamous Cell↗
PubMed1992

Lack of prognostic value of histopathologic parameters in Hodgkin's disease, nodular sclerosis type. A study of 123 patients with limited stage disease who had undergone laparotomy and were treated with radiation therapy.

The value of histopathologic parameters in predicting the long-term overall survival probabilities was studied in a series of 123 patients with pathologic stage IA, IB, IIA, IIB, or IIIA Hodgkin's disease, nodular sclerosis type who were treated with curative radiation therapy. The parameters that were studied included the relative proportion of atypical vs reactive cells, amount of eosinophils, presence of necrosis, degree of mitotic activity, intensity of different types of mesenchymal reactions, classification in three subtypes (ie, lymphocyte predominance, mixed cellularity, and lymphocyte depletion) or in two grades (ie, grades 1 and 2), and identification of the syncytial variant. For each parameter, the association with clinical risk factors was also analyzed. The results of this study show that there are no pathologic features that carry a significant predictive value of the overall survival.

Adolescent↗
PubMedDate not supplied

Hodgkin's disease: a retrospective analysis of 15 years experience at a large referral centre.

BACKGROUND: The prognosis of patients with Hodgkin's disease has improved significantly over the past two decades, primarily as a result of the development of curative combination chemotherapy. However, data on the presentation and results of treatment in Indian patients are scarce. We reviewed the clinical and pathological data and the treatment outcome of patients with Hodgkin's disease seen at our centre over the last 15 years. METHODS: The case records of 289 patients diagnosed to have Hodgkin's disease at our centre between 1977 and 1992 were reviewed. Their clinical characteristics, treatment outcome and prognostic factors for survival were analysed. RESULTS: The median age of the patients was 26 years with 30% being in the third decade. The male:female ratio was 4:1. The mixed cellularity histological subtype was the most common (68.5%), followed by nodular sclerosis (8.9%). 'B' symptoms were present in 73% of patients and 9.4% had bone marrow involvement. At the time of presentation, 70% of patients had advanced disease (stage III: 36%, stage IV: 34%). Complete response to treatment was obtained in 65.7% of patients while 17.3% had partial response. The predictors of decreased overall survival were age > 40 years, presence of 'B' symptoms, lymphocyte depletion histological subtype and stage IV disease. Disease-free survival was influenced by the presence of 'B' symptoms, bone marrow involvement and stage IV disease. CONCLUSION: Hodgkin's disease in Indian patients has a distinct clinico-pathological profile. Combination chemotherapy has high response rates even in patients with advanced disease at presentation.

Adolescent↗
PubMed1999

The impact of margin of resection on outcome in pediatric nonrhabdomyosarcoma soft tissue sarcoma.

BACKGROUND/PURPOSE: Because the management of pediatric nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) is determined by extrapolation from adult studies, the effect of margin of tumor resection and postoperative radiation therapy (RT) on local tumor recurrence in children has not been assessed. METHODS: Records of NRSTS patients from a single institution were reviewed with regard to demographic data, TNM staging, grade, histological type and site of primary tumor, RT, and local tumor recurrence. The margin of resection was determined by pathological review and did not necessarily reflect operative margins. RESULTS: Eighty-eight clinical group I patients were treated over a 30-year period. The most common histological tumor subtypes were synovial cell sarcoma (n = 26), malignant fibrous histiocytoma (n = 17), and fibrosarcoma (n = 7). The mean age was 9.4 years (range, 0 to 29 years). Thirty-four patients had high-grade tumors. Two of ten patients with low-grade tumors and margins less than 1 cm, including one of five who had received RT, had a local recurrence. Patients with low-grade tumors and margins greater than 1 cm (n = 44) had a lower recurrence rate (2 of 44, 4.5%). None of these patients had received RT. Fourteen patients with high-grade tumors had margins less than 1 cm. Seven of these had RT and had no recurrence. Three of the seven patients who received no RT had a recurrence (42.9%). None of the 20 patients with high-grade tumors and margins greater than 1 cm received RT; four of these patients had recurrences (20%). Seven of the 12 irradiated patients (58.3%) had serious radiation-associated complications (wound dehiscence, fracture, growth retardation, and joint dysfunction). CONCLUSIONS: Grade alone does not determine the rate of local recurrence. In both low- and high-grade tumors, a pathological margin of resection greater than 1 cm reduced local recurrence. Radiotherapy provided no advantage in low grade tumors but did decrease local recurrence rates in high-grade tumors with less than 1 cm pathological margins.

Adolescent↗
PubMed2005

The excitatory amino acid transporters: pharmacological insights on substrate and inhibitor specificity of the EAAT subtypes.

L-glutamate serves as the primary excitatory neurotransmitter in the mammalian CNS, where it can contribute to either neuronal communication or neuropathological damage through the activation of a wide variety of excitatory amino acid (EAA) receptors. By regulating the levels of extracellular L-glutamate that have access to these receptors, glutamate uptake systems hold the potential to effect both normal synaptic signaling and the abnormal over-activation of the receptors that can trigger excitotoxic pathology. Among the various membrane transporters that are capable of translocating this dicarboxylic amino acid, the majority of glutamate transport in the CNS, particularly as related to excitatory transmission, is mediated by the high-affinity, sodium-dependent, excitatory amino acid transporters (EAATs). At least 5 subtypes of EAATs have been identified, each of which exhibits a distinct distribution and pharmacology. Our growing appreciation for the functional significance of the EAATs is closely linked to our understanding of their pharmacology and the consequent development of inhibitors and substrates with which to delineate their activity. As was the case with EAA receptors, conformationally constrained glutamate mimics have been especially valuable in this effort. The success of these compounds is based upon the concept that restricting the spatial positions that can be occupied by required functional groups can serve to enhance both the potency and selectivity of the analogues. In the instance of the transporters, useful pharmacological probes have emerged through the introduction of additional functional groups (e.g., methyl, hydroxyl, benzyloxy) onto the acyclic backbone of glutamate and aspartate, as well as through the exploitation of novel ring systems (e.g., pyrrolidine-, cyclopropyl-, azole-, oxazole-, and oxazoline-based analogues) to conformationally lock the position of the amino and carboxyl groups. The focus of the present review is on the pharmacology of the EAATs and, in particular, the potential to identify those chemical properties that differentiate the processes of binding and translocation (i.e., substrates from non-substrate inhibitors), as well as strategies to develop glutamate analogues that act selectively among the various EAAT subtypes.

Animals↗
PubMedDate not supplied

Intramural carcinomas of the uterine corpus: a clinicopathological study.

Cases in which no sizable amount of tumor was observed in the uterine cavity and the main foci of the carcinoma were exclusively confined to the myometrium, were studied pathologically in a series of carcinomas of the uterine corpus. Ten out of 350 carcinomas of the uterine corpus proper fell into this category, and one case of suspicious metastatic corpus tumor from the ovary was also considered. The growth pattern of these tumors was classified into following 6 groups: (a) growth confined to the myometrium, (b) nodular growth in the myometrium with minimal endometrial involvement, (c) scattered (scirrhous) growth in the myometrium with marked shedding of the endometrium, (d) almost complete replacement of the myometrium by carcinoma with endometrial shedding (e) extreme subtype of usual endophytic growth pattern and (f) diffuse, intra-lymphatic spread of secondary tumor. One, 2, 3, 1, 3, and 1 cases of tumors of group, (a)-(f), were observed respectively in our pathological files. A spectrum of initial symptoms, diagnostic procedures, histology and histogenesis of the tumor was described in this report.

Adenocarcinoma, Clear Cell↗
PubMed1998

Hepatoblastoma: DNA nuclear content, proliferative indices, and pathology.

Hepatoblastoma (HB) is the most frequent malignant liver tumor in infancy, and both its biological features and its prognostic behavior are still under investigation. DNA content and proliferative activity of the tumor have been considered as biological parameters related to the tumor's aggressiveness. The present study attempts to investigate the possible association between histologic subtype, DNA content, and proliferative indices in HB. DNA content and the proportion of cells in the S-phase were assessed by flow cytometry in 34 cases of HB (14 prior to chemotherapy, 20 after chemotherapy), using formalin-fixed, paraffin-embedded archival samples. The proliferative cell nuclear antigen (PCNA) labeling index was also evaluated by immunohistochemistry, and both the flow cytometry (FC) and the immunohistochemical data were correlated with tumor pathology. A significant association was found between histological type, DNA content and the percentage of cells in the S-phase, with aneuploidy and the highest proportions of S-phase cells significantly associated with embryonal tumors. The PCNA labeling index was found to be significantly higher in embryonal than in fetal phenotype. The biological heterogeneity of HB is Confirmed by the different nuclear content of the fetal (diploid) and embryonal (aneuploid) epithelial components of the tumor, also ruling out the likelihood of fetal (diploid) clones deriving from the embryonal (aneuploid) neoplastic cells. Since the highly proliferative neoplastic clones (i.e., embryonal) are thought to be more sensitive to antimitotic drugs, further studies are indicated to determine the relationship between ploidy, proliferative indices and chemoresponsiveness.

Child↗
PubMed1986

Malignant lymphomas in children and adolescents.

Malignant lymphomas constitute the third most common group of childhood cancers in the United States. Hodgkin's disease (HD) exhibits a bimodal age peak, with the first peak occurring in the 15-34-year age group. Nodular sclerosis is the most common histologic subtype of HD seen in children. The disease tends to be primarily supradiaphragmatic at presentation. Accurate staging is essential for determination of appropriate therapy. Staging laparotomy with splenectomy is indicated for those patients with clinically localized disease whose therapy may be altered by pathologic staging. Radiation therapy is curative in the great majority of patients with localized disease. Multimodality therapy has been employed with increasing success in patients with advanced disease. The late sequelae of therapy must be considered in the design of optimum therapeutic regimens. More than 90% of non-Hodgkin's lymphoma (NHL) in childhood can be grouped into one of three histologic subtypes: lymphoblastic, undifferentiated, and diffuse large cell type. Lymphoblastic lymphomas most commonly present with mediastinal involvement. The majority of nonlymphoblastic lymphomas arise within the abdomen. Because of the tendency of NHL for extralymphatic dissemination, systemic therapy is always required. Treatment is determined by stage and histology. Significant improvements in survival rates have resulted from the development of effective combination chemotherapy programs. Cure rates in excess of 90% can be expected in children with localized disease. The outlook for children with advanced disease of undifferentiated histology remains poor. The presence of central nervous system involvement at diagnosis is a particularly ominous sign.

Adolescent↗
PubMed2000

True recurrence vs. new primary ipsilateral breast tumor relapse: an analysis of clinical and pathologic differences and their implications in natural history, prognoses, and therapeutic management.

PURPOSE: The purpose of this study was to classify all ipsilateral breast tumor relapses (IBTR) in patients treated with conservative surgery and radiation therapy (CS+RT) as either new primary tumors (NP) or true local recurrences (TR) and to assess the prognostic and therapeutic implications of this classification. METHODS AND MATERIALS: Of the 1152 patients who have been treated at Yale-New Haven Hospital before 1990, 136 patients have experienced IBTR as their primary site of failure. These relapses were classified as either NP or TR. Specifically, patients were classified as NP if the recurrence was distinctly different from the primary tumor with respect to the histologic subtype, the recurrence location was in a different location, or if the flow cytometry changed from aneuploid to diploid. This information was determined by a detailed review of each patient's hospital and/or radiotherapy record, mammograms, and pathologic reports. RESULTS: As of 2/99, with a mean follow-up of 14. 2 years, the overall ipsilateral breast relapse-free rate for all 1152 patients was 86% at 10 years. Using the classification scheme outlined above, 60 patient relapses were classified as TR, 70 were classified as NP and 6 were unable to be classified. NP patients had a longer mean time to breast relapse than TR patients (7.3 years vs. 3.7 years, p < 0.0001) and were significantly younger than TR patients (48.9 years vs. 54.5 years, p < 0.01). Patients developed both TR and NP at similar rates until approximately 8 years, when TR rates stabilized but NP rates continued to rise. By 15 years following original diagnosis, the TR rate was 6.8% compared to 13.1% for NP. Of the patients who had been previously tested for BRCA1/2 mutations, 17% (8/52) had deleterious mutations. It is noteworthy that all patients with deleterious mutations had new primary IBTR, while patients without deleterious mutations had both TR and NP (p = 0.06). Ploidy was evenly distributed between TR and NP but NP had a significantly lower S phase fraction (NP 13.1 vs. TR 22.0, p < 0.05). The overall survival following breast relapse was 64% at 10 years and 49% at 15 years. With a mean follow-up of 10.4 years following breast relapse, patients with NP had better 10-year overall survival (TR 55% vs. NP 75%, p < 0.0001), distant disease-free survival (TR 41% vs. NP 85%, p < 0.0001), and cause-specific survival (TR 55% vs. NP 90%, p < 0.0001). CONCLUSION: It appears that a significant portion of patients who experience ipsilateral breast tumor relapse following conservative surgery and radiation therapy have new primary tumors as opposed to true local recurrences. True recurrence and new primary tumor ipsilateral breast tumor relapses have different natural histories, different prognoses, and, in turn, different implications for therapeutic management.

Adult↗