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PubMed2000

Insular and anaplastic carcinoma of the thyroid: a 45-year comparative study at a single institution and a review of the significance of p53 and p21.

OBJECTIVE: To analyze the clinicopathologic features of a large cohort of patients with insular or anaplastic carcinomas treated at a single institution. SUMMARY BACKGROUND DATA: Insular and anaplastic carcinomas of the thyroid, although uncommon, have more aggressive clinical behavior than well-differentiated carcinomas of the thyroid. In the literature, the incidence and features of these carcinomas have not been fully characterized. METHODS: The authors reclassified 740 primary thyroid carcinomas diagnosed and treated between January 1, 1954, and December 30, 1998, to select those with features that met the histologic criteria of insular or anaplastic carcinoma. The clinicopathologic features of these carcinomas were studied and compared. The expression of p53 and p21 in these tumors was analyzed by immunohistochemistry. RESULTS: Twenty-two patients (5 men, 17 women) with insular carcinoma and 38 patients (7 men, 31 women) with anaplastic carcinoma were found. Patients with insular carcinomas were younger (mean age 45 vs. 70 years) and had smaller tumors than those with anaplastic carcinomas (mean diameter 5 vs. 8 cm). Insular carcinomas were commonly mislabeled as other histologic subtypes, whereas anaplastic carcinomas might be overdiagnosed on pathologic examination. A history of longstanding goiter (>10 years) was noted in 27% of patients with insular carcinoma and 24% of patients with anaplastic carcinomas. Concomitant well-differentiated carcinomas of the thyroid were noted in 59% of patients with insular carcinoma and 39% of patients with anaplastic carcinoma. In anaplastic carcinomas, 13% of patients had concomitant insular carcinoma. Calcification or bone was noted in the stroma of 23% of patients with insular carcinomas and 47% of those with anaplastic carcinomas. The 10-year survival rates for patients with insular carcinoma and anaplastic carcinoma were 42% and 3%, respectively. Distant metastases were seen in 32% of patients with insular carcinoma and in 47% of patients with anaplastic carcinomas. In both types of carcinomas, metastatic tumors were often seen in bone and lung. Distant metastases were noted in a variety of organs in anaplastic carcinomas. In insular carcinoma, neither p53 nor p21 expression was present. In anaplastic carcinoma, p53 and p21 expression was identified in 69% and 3%, respectively. Concomitant expression of p53 and p21 was noted in one tumor. CONCLUSIONS: Insular carcinoma and anaplastic carcinoma had distinctive clinicopathologic features, and recognition of these histologic variants is important for better management of these tumors in the future. p53 overexpression might have a role in dedifferentiation from insular carcinoma to anaplastic carcinoma.

Adolescent↗
PubMed1999

Soft tissue sarcoma in adults.

Soft tissue sarcomas are a heterogeneous group of tumors, consisting of numerous histiotypes that all share a putative common mesenchymal origin. Although prognosis of these tumors is determined by clinical parameters (size, location, and resection margin status) and pathologic features (mitotic activity and necrosis), the histologic subtype has never been shown to be a consistent independent prognostic factor. Some relevant differences among these histiotypes are emerging, in specific biological parameters such as proliferation indices, in integrin expression profiles, and with regard to drug sensitivity. Several biological factors are considered to be prognostically important. Most attention is directed to regulators of cell-cycle progression. The significance of p53 dysregulation is confirmed by the inhibition of cellular proliferation, both in in-vitro and in in-vivo sarcoma models, after reintroduction of wild type p53. A multidisciplinary approach is essential for the optimal treatment of soft tissue sarcomas. Multimodality treatment has led to a patient-tailored approach with limb-sparing resections integrated with external and/or interstitial irradiation. The value of chemotherapy both in the neoadjuvant and the adjuvant setting, although of critical value in other sarcomas such as Ewing's sarcoma and osteosarcoma, remains to be established for soft tissue sarcomas.

Adult↗
PubMed2000

Hodgkin's disease in primary care.

Hodgkin's disease is a common hematologic malignancy in young adults. The typical patient is a young adult male presenting with painless cervical adenopathy or a mediastinal mass on chest X-ray. If diagnosed early and aggressively treated, long-term survival rates are excellent. The subtypes of Hodgkin's disease are differentiated by pathologic examination of an affected lymph node. Chemotherapy, with or without adjuvant radiation, is the favored therapeutic regimen for most patients. A comprehensive approach to care, which incorporates psychosocial implications, can improve quality of life for Hodgkin's disease patients.

Adolescent↗
PubMed2002

Myasthenia gravis in a patient with pauciarticular juvenile chronic arthritis.

There have been reported cases of children with histories of pauciarticular juvenile chronic arthritis (JCA) later developing myasthenia gravis (MG) as young adults. This is intriguing because it had been considered rare to diagnose a second autoimmune disease in a patient with pauciarticular JCA, unlike in those with adult-onset rheumatoid arthritis. We report a case of MG in a 20-year-old woman with a history of pauciarticular JCA. She presented with bilateral ptosis, weakness, and a history of dysphagia. The diagnosis was confirmed with positive serum acetylcholine receptor antibodies (2000 nm/L) and electromyography showing a decremental response to repetitive muscle stimulation. The patient's inflammatory arthritis was quiescent at diagnosis. The patient underwent a surgical thymectomy and was treated with pyridostigmine, intravenous immunoglobulin, and corticosteroids with a fluctuating clinical course. Previous cases have been reported of MG associated with this subtype of JCA, suggesting a connection in autoimmune pathology. The earlier recognition and management of MG in a patient with pauciarticular JCA presenting with weakness may improve the prognosis of this disease.

Journal Article↗
PubMed1980

Bilateral germ cell tumours of the testis.

Between 1952 and 1976, 760 men with testicular tumours were seen at The Royal Marsden Hospital. Of this group 21 (2.75%) developed tumours of the contralateral testis, in 2 instances synchronously and in the remaining 19 at intervals from 4 months to 15 years. Of 15 men in whom adequate history has been obtained, 7 (46%) had a history of maldescent and in all 7 patients the pathology of both tumours showed the same histological subtype. Only one example of malignant teratoma undifferentiated (MTU) as first tumour was encountered; 13 of 19 (68%) patients had seminomas and the second tumour was a seminoma in 11 patients (58%). Of the group of 21 patients, 12 (57%) are alive and disease-free. Of 14 Stage I patients (second tumour), 12 (85%) are considered cured of their 2 tumours. However, patients with evidence of extratesticular spread did badly, even if the second tumour was a seminoma, and treatment for these patients should include chemotherapy. Similarly, both Stage I MTU second tumours did badly.

Cryptorchidism↗
PubMed2005

Over-expression of tumor necrosis factor-alpha in bone marrow biopsies from patients with myelodysplastic syndromes: relationship to anemia and prognosis.

OBJECTIVES: An excessive intramedullar progenitor cell apoptosis, to which elevated expression of tumor necrosis factor-alpha (TNF-alpha) might contribute, is considered the main cause of inefficient hematopoiesis in myelodysplastic syndromes (MDS). Enhanced bone marrow (BM) angiogenesis is regarded as an essential cofactor in the progression of MDS to acute myelogenous leukemia (AML) and microvessel formation may be induced by TNF-alpha as well. To investigate TNF-alpha signaling and neoangiogenesis as potential molecular pathways for therapeutic intervention in MDS with respect to the various MDS subtypes, we performed a morphological and clinico-pathological study on a large series of paraffin-embedded trephine BM biopsies. METHODS: TNF-alpha expression and BM vessels were immunohistochemically analyzed on 89 paraffin-embedded BM biopsies from patients with MDS and secondary AML, including 12 control samples. Data were correlated with clinico-pathological and laboratory parameters and analyzed for their prognostic significance considering overall survival. RESULTS: TNF-alpha was over-expressed in MDS patients, especially in those with refractory anemia and its expression correlated with BM cellularity and with magnitude of anemia as well as with microvessel density (MVD). TNF-alpha over-expression was associated with premature deaths. MVD was increased in MDS and secondary AML and correlated with marrow cellularity and expression of TNF-alpha, but was not of prognostic significance. CONCLUSIONS: TNF-alpha expression and MVD are elevated in MDS and secondary AML. TNF-alpha expression in BM progenitor cells appears to negatively impact erythropoiesis and overall survival in MDS, and may serve as a potential therapeutic target in patients with hypercellular MDS with marked anemia.

Adult↗
PubMed1991

Severity and specificity of cognitive impairment in Alzheimer's, Huntington's, and Parkinson's diseases and progressive supranuclear palsy.

To investigate differences in severity and specificity of cognitive impairment among various neurodegenerative diseases, we tested groups of patients presenting with senile dementia of the Alzheimer's type (SDAT) (n = 44), progressive supranuclear palsy (PSP) (n = 45), Huntington's disease (HD) (n = 35), and Parkinson's disease (PD) (n = 164), with an extensive neuropsychologic battery. We found dementia, as defined by a global intellectual performance 2 SD lower than mean control values, in 93% of patients with SDAT, 66% of patients with HD, 58% of patients with PSP, and 18% of patients with PD. Specific features of cognitive impairment distinguished the four groups of patients once they were matched for level of intellectual deterioration. This study shows the frequency of dementia in predominantly subcortical degenerative diseases and indicates that "subcortical dementia," rather than being a homogeneous entity, should be divided into specific subtypes of cognitive impairment related to different underlying pathology.

Alzheimer Disease↗
PubMed2001

Evidence for direct protein kinase-C mediated modulation of N-methyl-D-aspartate receptor current.

Protein kinase-C (PKC) activation differentially affects currents from N-methyl-D-aspartate (NMDA) type glutamate receptors depending upon their subunit composition. Experiments using chimeras initially indicated that the cytoplasmic C-terminal tails of NR2B (responsive to PKC) and NR2C (unresponsive to PKC) subunits contain the amino acid residues responsible for the observed disparity of PKC effects. However, truncation and point mutation experiments have suggested that PKC action on NMDA receptors may be entirely indirect, working via the phosphorylation of associated proteins. Here we suggest that PKC does, in fact, affect NR2B/NR1-011 NMDA currents by direct phosphorylation of the NR2B tail at residues S1303 and S1323. Replacement of either of these residues with Ala severely reduces PKC potentiation. To verify that S1303 and S1323 are sites of direct phosphorylation by PKC, synthetic peptides from the regions surrounding these sites were used as substrates for in vitro assays with purified rat brain PKC. These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels. The direct action of PKC on certain NMDA receptor subtypes may be important in any physiological or pathological process where PKC and NR2B/NR1 receptors interact.

Animals↗
PubMed2001

Acute cerebrovascular disease in women.

In 2,000 consecutive stroke patients collected in a prospective hospital-based stroke registry over a 10-year period, we assessed whether stroke in men and women was different in respect to vascular risk factors, clinical features and natural history. The frequency of the different variable in men and women was analyzed by means of univariate analysis and logistic regression models. Women accounted for 48% of the study population (n = 967) and were older than men (mean age 75 vs. 69 years, p < 0.001). In the age group of 85 years or older, stroke was more frequent in women than in men (69.8 vs. 30.2%, p < 0.001). Women showed a higher frequency of cardioembolic infarction and a lower occurrence of lacunar infarction and stroke of undetermined cause than men. In-hospital mortality (17.4 vs. 13.3%) and length of hospital stay (19.6 vs. 16.7 days) was significantly higher (p < 0.001) in women than in men. In the model based on demographic variables and cardiovascular risk factors, obesity, heart failure, atrial fibrillation and age were significant predictors of stroke in women, while intermittent claudication, ischemic heart disease, chronic obstructive pulmonary disease, cigarette smoking and alcohol abuse were predictors in male sex. Hypertension and limb weakness were predictors for stroke in women, and absence of neurological deficit at hospital discharge, lacunar syndrome and ataxia were predictors in men in the models based on all variables. Women differ from men in the distribution of risk factors and stroke subtype, stroke severity and outcome. Differences in stroke pathology and/or differences in functional anatomy or plasticity of the brain between sexes may account for these findings.

Adult↗
PubMed1984

Lymphocyte surface markers in orbital lymphoid neoplasms.

Since the malignant nature of many orbital lymphoid infiltrates is difficult to assess from pathologic examination alone, over the past four years lymphocyte surface marker studies have been added to the evaluation of 23 such cases. Only 10 of the 23 could be confidently classified as malignant lymphoma by histology alone. However, monoclonal surface immunoglobulin was found in 15, supporting the pathologic diagnosis of malignancy in eight and adding seven that could not have been diagnosed otherwise. Clinical evaluation, including a median follow-up of 18 months, revealed manifestations of systemic lymphoma in six of those 15; two had been diagnosed only by surface markers. In contrast, only one of eight cases lacking monoclonal surface immunoglobulin exhibited clinical evidence of malignancy (that case was also indeterminate by histologic criteria). The addition of surface marker analysis permits more accurate diagnosis of orbital lymphoma than is possible from pathologic study alone. This technique can suggest the subtype of lymphoma.

Adult↗
PubMed1987

Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas.

This study addressed two major questions regarding therapeutic use of Adriamycin ([Adr] Adria Laboratories, Columbus, OH) in adult soft tissue sarcomas: the influence of dosing schedule and the value of adding imidazole carboxamide (DTIC) to Adr. Patients with objectively measurable metastatic soft tissue sarcomas were randomized to Adr 70 mg/m2 intravenously (IV) day 1 and every 3 weeks (94 patients); Adr 20 mg/m2 IV day 1, 2, and 3, and 15 mg/m2 IV day 8 and weekly thereafter (89 patients); and Adr 60 mg/m2 IV day 1 and DTIC 250 mg/m2 days 1 to 5, repeated every 3 weeks (92 patients). The regimens using Adr as a single agent resulted in an equivalent response frequency (18% and 16%) and survival (median, 8.0 and 8.4 months). DTIC significantly increased (P less than .02) the overall response frequency of Adr to 30%. However, DTIC did not influence survival (median, 8.0 months) or increase the number of complete responses. The toxicities of the two single-agent regimens differed: Adr weekly resulted in more stomatitis (P = .09) and less hematologic toxicity (P less than .05). DTIC resulted in substantially increased toxicity, primarily gastrointestinal (P less than .002); overall, 98% of patients receiving Adr-DTIC experienced moderate or worse toxicity. To decrease the potential for error in interpretation of treatment results, histopathological confirmation of diagnosis was undertaken by a panel of reference pathologists; pathology slides were submitted on 97% of entered patients. The on-study clinical diagnosis was affirmed in 199 of 316 patients (63%) with a final review. In 23% of patients, the panel agreed with the diagnosis of soft tissue sarcoma, but not with the type. In 14%, the panel concluded that a diagnosis of mesenchymal malignancy could not be affirmed. Final treatment results were based on the 275 pathologically confirmed, eligible patients. The most common histological subtype entered was leiomyosarcoma (99 patients). The response to Adr-DTIC of this subtype was higher (44%) than that of any other subtype. However, this difference alone was not responsible for the overall superiority of the combination. This confirmed that the combination of DTIC plus Adr adds to the response rate of Adr alone in soft tissue sarcomas. Whether the increased response frequency, without an impact on survival, is worth the significantly greater toxicity remains a subjective judgement that must be made within the context of the individual patient.

Adolescent↗
PubMed2004

Serotonin(7) receptors (5-HT(7)Rs) and their ligands.

Serotonin (5-HT) is involved in various physiological and pathological processes by interaction with 14 distinct receptor subtypes, grouped in seven classes of receptors (5-HT(1-7)) on the basis of amino acid sequence, pharmacology, and signal transduction pathways. The 5-HT(7)R is a G-protein coupled receptor with seven transmembrane domains. It was found by the application of molecular cloning and has been identified in rat, mouse, human, pig, and guinea pig. Although the biological functions of the 5-HT(7)Rs are poorly understood, preliminary evidence suggests that it may be involved in depression, control of circadian rhythms, and relaxation of vascular smooth muscles. For these reasons, the 5-HT(7)R has become a target for the development of novel drugs. This review will give a brief introduction of the pharmacology of 5-HT(7)R (molecular structure, distribution of 5-HT(7)R mRNA, localization of the 5-HT(7)R protein, functional correlates, and therapeutic potential) and a detailed survey of the 5-HT(7)R ligands, which have appeared in the literature in both papers and patents. Structure-activity relationships (SAR) of these ligands will also be described.

Animals↗
PubMed1981

Stevens-Johnson syndrome associated with intrahepatic cholestasis and respiratory disease: a case report.

In an 8-year-old boy, the Stevens-Johnson syndrome (SJS) was associated with protracted intrahepatic cholestasis and ultimately fatal respiratory disease. No precipitating factors of SJS were identified, but a Mycoplasma pneumoniae infection was suspected. The appearance of jaundice on the seventh day of illness was preceded by the prescription of erythromycin ethyl succinate, but intrahepatic cholestasis has never before been associated with this derivative of erythromycin. It is suggested that there may exist a subtype of SIS with severe hepato-pulmonary pathology.

Child↗
PubMed2000

[An autopsy case of dementia with Lewy bodies who showed the typical parkinsonism in the initial five years].

A 76-year-old man with parkinsonism and dementia was reported. He developed resting tremor at age 69 followed by hypokinesia, rigidity and small step gait. L-dopa ameliorated his symptoms with no hallucinations for the initial 5 years. His mental level did not decrease during that period. He was admitted to our hospital because of dehydration and fever at age 74. Subsequently, his cognitive function deteriorated, with visual hallucination. Serial brain CT studies displayed a progressive cerebral cortical atrophy without focal lesions. He died of respiratory distress syndrome and disseminated coagulopathy resulting from pneumonia, dehydration and syndrome malin. Postmortem examination revealed a marked bilateral loss of melanin-containing neurons with Lewy bodies in the substantia nigra and locus ceruleus. Lewy bodies were also in the basal nucleus of Meynert, with moderate neuronal cell loss. The distribution of Lewy bodies was widespread in the cerebral cortical areas, corresponding to the neocortical subtype according to the consensus guideline for the pathologic diagnosis of dementia with Lewy bodies. According to the criteria of the Consortium to Establish a Registry for Alzheimer's Disease, the age-related plaque score in the present case suggested Alzheimer's disease, although cortical neurofibrillary changes corresponded to stage II by the criteria of Braak and Braak. These pathological findings established the diagnosis of dementia with Lewy bodies from the quantitative and distributional viewpoints. Based on recent neuropathological evidence, a spectral theory, which presents idiopathic Alzheimer's disease and Parkinson's disease as the two extremes of a spectrum of neurodegeneration, has been proposed. Dementia with Lewy bodies is located in the middle of this spectrum. Pathological evaluation based on quantitative consensus guidelines is important to establish the diagnosis in patients with parkinsonism and dementia, since neuropathological changes of Alzheimer's disease, Parkinson's disease and dementia with Lewy bodies are often observed in a mixed manner in these patients.

Aged↗
PubMed1999

Malignant mesothelioma of the pleural space.

Malignant pleural mesothelioma is an aggressive tumor associated with exposure to asbestos. Although this disease is rare, with an annual incidence in the United States of 2,000 to 3,000 cases, a steady rise in cases has been reported. Malignant pleural mesothelioma has a variable clinical presentation and may be difficult to diagnose. Pathologically, the disease is subdivided into three microscopic subtypes: epithelial, sarcomatous, and mixed histologies. Although there is no widely accepted staging system for mesothelioma, the Butchart, TNM, and Brigham staging systems have been used most commonly. Diffuse malignant pleural mesothelioma is resistant to standard modes of therapy and, if untreated, results in death 4 to 12 months from the time of diagnosis. For selected patients, an aggressive approach combining radical surgery with chemotherapy and radiotherapy has demonstrated a long-term survival advantage. New and innovative therapeutic modalities are presently being investigated in an attempt to provide viable alternatives for patients with early and advanced disease.

Combined Modality Therapy↗
PubMed1998

Viral hepatitis C.

Identification of a cDNA clone and the genome of hepatitis C virus in 1988-1989 allowed the development of clinical tests that are now used to detect and quantify hepatitis C virus. This has largely eliminated post-transfusion hepatitis C virus infection; however, the overall incidence of chronic hepatitis C and its complications has greatly increased because of its transmission by other means, lack of a protective vaccine, and inadequate virucidal therapy. Drug abuse is the most common cause of hepatitis C; an etiologic mechanism, however, remains unknown in one third of patients referred to the New Jersey Medical School Liver Center. Response to treatment depends on the viral subtype, immune reactivity of the host, and hepatic pathologic alterations. Many patients with hepatitis C improve or are cured by administering an interferon with or without ribavirin; patients refractory to these measures exhibit persistent elevation of serum cytokines and progressive liver disease. New measures, including protease inhibitors and adjunct immunotherapy, should increase effectiveness of therapy, diminishing hepatitis C virus-induced cirrhosis and hepatocellular cancer. Populations, including the underserved, who harbor and transmit hepatitis C virus require special assistance. This is best achieved by community support groups organized through medical schools, physician associations, and churches to help prevent, detect, and treat chronic hepatitis C.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Appearance of meningiomas on diffusion-weighted images: correlating diffusion constants with histopathologic findings.

BACKGROUND AND PURPOSE: Malignant and atypical meningiomas are prone to recurrence and aggressive growth, which affects treatment planning and prognostication. Investigators have used diffusion-weighted imaging and apparent diffusion coefficient (ADC) maps to compare tumor grade and cellularity with the histopathologic findings of intraaxial primary brain neoplasms. The purpose of this study was to determine whether the signal characteristics of meningiomas on diffusion-weighted images correlate with the average diffusion constant (Dav) from ADC maps and histopathologic findings and whether the Dav can reliably distinguish benign from malignant and atypical meningiomas. METHODS: Seventeen patients (13 women and four men; average age, 55 years) with meningiomas were prospectively studied using routine MR imaging and diffusion-weighted imaging with a single-shot gradient-echo echo-planar pulse sequence (6000/100 [TR/TE]) and b values of 0 and 1000. Signal characteristics on routine MR and diffusion-weighted images were compared with the histopathologic findings after resection by using World Health Organization criteria. Dav values were calculated within the tumor mass from ADC maps before resection. RESULTS: Four meningiomas were malignant or atypical (World Health Organization grades II and III). Dav values were lower than normal brain values (average, 0.52 +/- 0.12 x 10(-5) cm2/s; range, 0.45-0.69 x 10(-5) cm2/s) and were hyperintense on diffusion-weighted images and hypointense on ADC maps. Thirteen meningiomas were benign. Dav values were higher than normal brain values (average, 1.03 +/- 0.29 x 10(-5) cm2/s; range, 0.62-1.8 x 10(-5) cm2/s). On diffusion-weighted images and ADC maps, most were isointense. Five benign meningiomas had very high Dav values, bright signal on ADC maps, and distinct histopathologic findings, including microcysts, necrotic infarct, and organizing intratumoral hemorrhage. The difference in Dav values between malignant and benign meningiomas was statistically significant (P < .00029). CONCLUSION: Albeit a small sample size, meningiomas with low Dav tended to be malignant or highly atypical (P < .00029) whereas meningiomas with the highest Dav had increased water content due to either a specific histologic subtype of meningioma or the presence of associated pathologic abnormality.

Adult↗