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Effects of 5-azacytidine on expression of endogenous retrovirus-related sequences in C3H 10T1/2 cells.

In a previous study (22) we found that transient exposure of C3H 10T1/2 mouse embryo fibroblasts to 5-azacytidine (5-azaC) induced several changes in growth properties. The treated cells showed progressive changes in morphology, saturation density, growth rate, and serum dependence. By passage 5, the cells had acquired the ability to grow in 0.3% agarose, and by passage 30, they had given rise to fully transformed foci that grew in agarose, agar, and liquid suspension. This progression was rapidly accelerated if the cultures derived from 5-azaC-treated cells were exposed for 48 h to the carcinogen benzo[a]pyrene. The present studies demonstrate that both type C and type A, but not type B, retrovirus-related sequences were expressed in the 5-azaC-treated cells. There was negligible expression of these sequences in the control 10T1/2 cells. The level of expression of the related RNAs tended to correlate with loss of anchorage dependence and other markers of an increase in the transformed phenotype. These changes were associated with hypomethylation of the corresponding cellular DNA sequences, as revealed by differential digestion with the restriction enzymes HpaII and MspI. These studies provide evidence that aberrations in DNA methylation and induction of expression of certain endogenous retroviruses may be one of a series of critical events during the course of multistage carcinogenesis, thus enhancing the evolution of malignant tumor cells.

Animals↗

[Primary thymic lymphomas].

INTRODUCTION: Primary thymic lymphomas (PTLs) are uncommon, and their prognosis is linked with early treatment. A review is carried out of this disease in our hospital in order to determine the best diagnostic-therapeutic management for these patients. MATERIAL AND METHODS: Ten LPTs--four Hodgkin's and six non-Hodgkin's (4 primary mediastinal B lymphomas [PMBLs] and 2 lymphoblastic T lymphomas [LTLs]--were reviewed. Most of the patients were females, with a mean age of 23 +/- 10 years. RESULTS: The initial diagnostic suspicion in the Hodgkin's lymphomas was thymoma in two cases and lymphoma in the other 2. All of them underwent surgery, including an intra-operative biopsy, which was completed with a thymectomy in the two in which thymoma was reported. They were treated with radio and chemotherapy. The response was partial in two cases, and treatment was completed with a bone marrow transplant (BMT) (one died and the other had active disease). The non-Hodgkin's lymphomas had large tumors and short evolution. All of them received surgery, with an intra-operative biopsy in four and a thymectomy in two. They were treated with chemotherapy, with associated radiotherapy in two. The response was total in three, with two recurring, who are in complete remission after a BMT. In the other three the response was partial. CONCLUSIONS: In a patient with thymic tumour with a preoperative or intraoperative study suspected of having a lymphoma, it is necessary to do a biopsy and not resective surgery, to avoid unnecessary resections and morbidity. PTLs are uncommon but aggressive, principally the non-Hodgkin's lymphomas. The main treatment is radio and chemotherapy, with associated bone marrow transplantation in selected cases.

Adolescent↗

Preradiation chemotherapy with VM-26 and CCNU in patients with glioblastoma multiforme.

AIMS AND BACKGROUND: The objective of the study was to evaluate the efficacy of combined chemoradiation in patients with newly diagnosed glioblastoma multiforme. The main end points were time to progression and overall survival. METHODS: Thirty-one patients with glioblastoma multiforme underwent surgery whenever possible and then received intravenous VM26 (120 mg/m2) and oral CCNU (120 mg/m2) for three cycles followed by radiotherapy (60 Gy). RESULTS: Surgery consisted of a complete resection in 39% of patients, partial resection in 35% and a biopsy in 26%. Sixteen patients had clinical or radiological evidence of progression during or after chemotherapy. Hematologic toxicity was mild. Forty-five percent of patients received the scheduled dose of radiation. The outcome was disappointing, with a median time to progression of 18 weeks and median survival of 37.17 weeks. CONCLUSIONS: The survival of patients with glioblastoma multiforme remains disappointing. Multimodal therapy does not seem to modify the evolution of the tumor. Stratification according to prognostic factors might detect a potential benefit of other therapeutic approaches.

Administration, Oral↗

Histologic-prognostic correlations in adenoid cystic carcinoma of major and minor salivary glands of the oral cavity.

Thirty-four cases of adenoid cystic carcinoma (ACC) of the major and minor salivary glands of the oral cavity, treated by wide surgical excision, were studied. The relationship between prognosis of the neoplasm and various morphologic factors were evaluated. Among the morphologic parameters previously studied, which according to various authors may be linked to the evolution of this tumor, we confirmed correlations for both histologic patterns and perineural invasion. In addition, the authors propose neoplastic growth type as a new parameter prognostically significant in ACC. In fact, none of the patients with the pushing type growth pattern died during the study period (p = 0.007). These same patients presented disease-free periods (mean 56 months, median 58 months) significantly longer than those with the infiltrating type growth pattern (mean 28 months, median 24 months).

Carcinoma, Adenoid Cystic↗

Radiotherapy in the maxillary hemangioma.

We present the case of a large maxillary hemangioma treated by radiotherapy. Only 4 cases managed by radiotherapy have been reported in the literature, and most authors negate the radiosensitivity of the tumor. In our patient, the outcome was excellent; by 6 months tumor reduction was more than 50%. This is the first case referred to in the literature whose radiotherapy response was evaluated by magnetic resonance imaging. We describe the clinical and imaging findings of this very rare tumor and its evolution. We also comment on the literature reviewed.

Adult↗

Neuroendocrine carcinomas of the esophagus.

Of a total of 928 primary esophageal cancers, 16 cases of "undifferentiated" esophageal carcinoma were isolated. The topographic and age distributions as well as the clinical presentation and evolution of these tumors were basically similar to those of the usual esophageal squamous carcinoma. By light microscopy, the tumors were comprised exclusively or predominantly of small, round-to-fusiform cells. The cytoplasm appeared scanty and the nuclei were comparatively large and hyperchromatic. Mitotic activity was prominent. Four of the sixteen neoplasms showed occasional foci of squamous differentiation. Argyrophilic cells were seen in all cases, although their number and distribution were variable. Occasional mucosubstance droplets were present in 2 cases. Argentaffin and amyloid stains were negative in all tumors. Ultrastructural studies revealed variable numbers of granules consisting of a dense core, a pale halo, and a single, delimiting membrane; these measured between 80 and 220 nm in diameter. Four of the sixteen cases displayed conspicuous tonofilament bundles and rare keratohyalin granules. The predominant ultrastructural common denominator of these tumors was the presence of characteristic neurosecretory-type granules; thus, their classification as neuroendocrine carcinomas would appear justified. Nevertheless, the abundant tonofilaments and the rare keratohyalin granules and mucosubstance droplets seen in several cases indicate that some of these epithelial cancers possess and express variable capabilities toward multidirectional differentiation.

Adult↗

Neuroendocrine skin carcinoma coexpressing cytokeratin and neurofilament proteins.

Neuroendocrine (Merkel cell) carcinomas of the skin have been recognized as such for several years. Given the reported wide variability in the morphology and clinical evolution of these tumors, the notion that may they comprise several variants rather than a single type has been advocated. Electron microscopy has played a key role in the early recognition of these tumors while immunohistochemical studies for various neuroendocrine markers have facilitated their subsequent diagnosis and improved our understanding as to their complexity by the demonstration of immunoreactivity for NSE (neuron specific enolase) and a number of neuropeptides. There has also been considerable interest in the study of the cytoskeletal intermediate filament complement of neuroendocrine neoplasms in general and of those of the skin in particular. Early reports indicated that neuroendocrine skin carcinomas had neurofilaments while subsequent investigations determined that they had cytokeratin. However, more recent studies have indicated that at least some neuroendocrine skin carcinomas could in fact coexpress both aforementioned classes of intermediate filament proteins. This brief report is presented to confirm the latter investigations.

Carcinoma↗

Retinoblastoma. Analysis of 75 cases and proposal for a new model of oncogenesis and tumor growth kinetics.

A series of 75 retinoblastoma patients were analyzed at the Institute of Ophthalmology, Siena, and a mathematical model for the 'nodule to cancer' transformation applied to it. The authors obtained data in disagreement with Knudson's 'two hit' hypothesis but fitting an alternative model of oncogenesis. This model is based on probabilistic arguments and a possible pattern of tumor growth and evolution is given in detail.

Adolescent↗

[Paratesticular rabdomyosarcoma: report of one case in an adult patient].

OBJECTIVES: To report one case of right paratesticular rabdomyosarcoma in a 21-year-old young adult. METHODS: After treatment with right radical orchiectomy through an inguinal incision it was classified as clinical group I A following the IRS-III (localized disease completely excised) and received adjuvant treatment with Vincristine and actinomicin D. RESULTS/CONCLUSIONS: The patient is disease free 18 months after surgery. We emphasize the importance of adjuvant treatment in the posterior evolution of the tumoral disease.

Adult↗

[Apical pleural fibrosis related to inhalation of asbestos fibers].

The involvement of the apical pleura is infrequent in diffuse pleural thickening secondary to asbestos exposure. Most often diffuse pleural thickening is accompanied by an obliteration of the costophrenic angle and the posterior and paraspinous pleural surfaces of the pleura are involved to the greatest extent. Unlike this typical form, we observed in five patients exposed to asbestos an apical pleural fibrosis, uni or bilateral, accompanied with lung retraction, hilar ascension and tracheal attraction. Apical pleural thickening with upper lobe changes in asbestos-exposed persons should be regarded as due to the asbestos exposure, after exclusion of other causes like tuberculosis and the apex tumors. Usually the evolution of the lesions is slowly progressive over several years or even decade, and results in mild restrictive defect.

Aged↗

[Experimental production of bone sarcomas in the rabbit by a single local injection of beryllium].

The local intra-osseous injection of double zinc beryllium silicate into the tibial or femoral epiphysis of a rabbit causes an osteogenic sarcoma in 70 p. 100 of cases. These experimental conditions make it possible to reveal early non specific radiological alterations, later on secondary alterations corresponding to the development of the sarcoma and finally to follow the spontaneous evolution of the tumor. Moreover, this experimental process of induction of an osteogenic sarcoma by means of a local intra-osseous injection is vastly better than an intra-venous injection which causes straight-away multiple visceral lesions.

Animals↗

[Bilateral renal angiomyolipoma associated with tuberous sclerosis: report of a case].

The authors report a case of bilateral renal angiomyolipoma, associated with tuberous sclerosis revealed by abdominal pains, in a 30-year-old man. The diagnosis, suspected by the clinic and ultrasonography, is affirmed by CT scan. In light of this case, the authors review the features of this disease, the ambiguous character of angiomyolipoma, the prognosis and choice of management. Several elements incited us to adopt therapeutic abstention with regular monitoring of the patient for this begin tumor with slow evolution.

Abdominal Pain↗

Bronchoscopic, radiologic and pulmonary function evaluation of endobronchial tuberculosis.

OBJECTIVE: Endobronchial tuberculosis (EBTB) causes problems in both making a diagnosis and following up the endobronchial lesion, because the lesion is not evident in simple chest radiograph. Frequently, the diagnosis and follow up of EBTB lesion during treatment mainly depend on bronchoscopy. Chest computed tomography (CT) and pulmonary function test (PFT) have also been used in evaluating EBTB and differentiating it from the other diseases. Primary purpose of the present study was to observe the change of EBTB lesion during treatment and determine the optimal time and the indication of follow-up bronchoscopy. We also evaluate the usefulness of chest CT and PFT in EBTB. METHODOLOGY: Eighty-one biopsy-proven EBTB patients were enrolled from 1992 to 1997. Endobronchial tuberculosis was classified into seven subtypes: actively caseating, fibrostenotic, oedematous-hyperaemic, tumorous, ulcerative, granular, and non-specific bronchitic type according to bronchoscopic features by Chung's Classification. The change of bronchoscopic findings during treatment in each subtype of EBTB was evaluated prospectively. Follow-up bronchoscopy was done each month until there was no subsequent change in endobronchiat lesion, and every 3 months thereafter, and at the end of treatment. Chest CT and PFT were performed in 26 and 68 patients respectively, at initial bronchoscopy. RESULTS: Twenty-two of the 34 cases of actively caseating EBTB changed into the fibrostenotic type, and the other 12 healed without sequelae. Seven of the 11 cases of oedematous-hyperaemic EBTB changed into the fibrostenotic type, and the other four healed. Nine of the 11 cases of granular EBTB, six cases of non-specific bronchitic EBTB, and two cases of ulcerative EBTB resolved completely. However, the other two cases of granular EBTB changed into the fibrostenotic type. Seven cases of fibrostenotic EBTB did not improve despite antituberculosis chemotherapy. These various changes in bronchoscopic findings occurred within 3 months of treatment. In 10 cases of tumorous EBTB, seven progressed to the fibrostenotic type. In addition, new lesions appeared in two cases, and the size of the initial lesions increased in another two cases, even at 6 months after treatment. On chest CT findings of 26 EBTB patients, the length of bronchial involvement was measured from 10 to 55 mm. Bronchial stricture was noticed in 25 cases and the range of narrowing was from total occlusion to near normal, and there was wide variation in bronchial stricture even within same subtype of EBTB. The dominant feature of PFT in EBTB at the diagnosis was restrictive pattern. CONCLUSION: The therapeutic outcome of each subtype of EBTB can be predicted by follow-up bronchoscopy during the initial 3 months, with the exception of the tumorous type. In tumorous EBTB, the evolution of the lesions during treatment is very complicated, and bronchial stenosis may develop at a later time. Chest CT was useful in measuring the length of involved bronchus and degree of stricture in EBTB. PFT may be useful in differential diagnosis and follow up of EBTB.

Biopsy↗

A gene hypermethylation profile of human cancer.

We are in an era where the potential exists for deriving comprehensive profiles of DNA alterations characterizing each form of human cancer. Such profiles would provide invaluable insight into mechanisms underlying the evolution of each tumor type and will provide molecular markers, which could radically improve cancer detection. To date, no one type of DNA change has been defined which accomplishes this purpose. Herein, by using a candidate gene approach, we show that one category of DNA alteration, aberrant methylation of gene promoter regions, can enormously contribute to the above goals. We have now analyzed a series of promoter hypermethylation changes in 12 genes (p16(INK4a), p15(INK4b), p14(ARF), p73, APC,(5) BRCA1, hMLH1, GSTP1, MGMT, CDH1, TIMP3, and DAPK), each rigorously characterized for association with abnormal gene silencing in cancer, in DNA from over 600 primary tumor samples representing 15 major tumor types. The genes play known important roles in processes encompassing tumor suppression, cell cycle regulation, apoptosis, DNA repair, and metastastic potential. A unique profile of promoter hypermethylation exists for each human cancer in which some gene changes are shared and others are cancer-type specific. The hypermethylation of the genes occurs independently to the extent that a panel of three to four markers defines an abnormality in 70-90% of each cancer type. Our results provide an unusual view of the pervasiveness of DNA alterations, in this case an epigenetic change, in human cancer and a powerful set of markers to outline the disruption of critical pathways in tumorigenesis and for derivation of sensitive molecular detection strategies for virtually every human tumor type.

DNA Methylation↗

[Oncocytic tumors of the kidney apropos of 2 cases. Actualities in the preoperative diagnosis and therapeutic attitude].

The authors report two cases of renal oncocytoma treated by radical nephrectomy. There is still a controversy because the term oncocytoma is used for all tumors containing oncocytes, either true oncocytoma or adenocarcinoma with oncocytoma cells. The main problem is to distinguish, prior to surgery, between renal oncocytoma, a tumor with benign evolution, and renal adenocarcinoma with oncocytes, to offer conservative surgery for renal oncocytoma.

Adenoma↗

[Chordomas. Excision of a lumbar chordoma: 2 1/2 years survival without signs of recurrence and without functional complications].

In connection with surgical removal of a chordoma in the lumbar region by large excision, followed by 31-month survival of the patient without complications, personal experience of 8 chordomas operated on over the last 20 years is reported. The authors believe their observations show the value of active surgical treatment combined with radiotherapy, which has a palliative effect on the pain and slows the evolution of the tumor. The effectiveness of surgical treatment and radiotherapy leads the authors to challenge the negative attitude generally taken towards the treatment of this condition and to adopt a position of moderate optimism.

Abdominal Muscles↗

[A great imitator for the allergologist: intolerance to gluten].

Intolerance of gluten, resposible for Coeliac disease, is essentially shown by an auto-immune enteropathy, even if the cutaneous manifestation (herpetiform dermatitis) and perhaps certain neurological signs (cerebral syndrome, peripheral neuropathy) may be independent as well as associated with the intestinal illness. This affection is of immunological nature, occuring in a genetic field that predisposes to the illness (familial form: concordance of 70% in homozygote twins; 90% of patients show an HLA molecule of type DQ2, DQ8 in almost all the other cases. The exogenous factor is the gluten content contained in wheat, rye and barley, more precisely by the intermediary "the prolamines" which are the "reactive" element that induces a the same time an inflammatory reaction of type TH11 locally (expressed by the histological aspect of a duodenal biopsy evolving as villous atrophy) and a humoral response with production of anti-gliadine and anti-transglutaminase antibodies (the role of the latter enzyme is intervention in the local transformation of antigens to make them antigenic). It is an illness of adults as well as children and this point must now be emphasized. Recent epidemiological studies insist on a high prevalence (1/300 in Europe). Clinical expression, at the start very polymorphic and so misleading, before the appearance of the more classical signs of malabsorption and development, always feared, towards a lymphoma. These signs are haematological (anemia of various types, hyper platelets by hyposplenism, haemorrhagic signs) cutaneous (herpetiform dermatitis, cutaneous vasculitis) mucosal (aphtose), hepatic (cytolysis), neurophysical (fatigue, troubles of behaviour, cerebral syndrome, neuropathy) and osteo-articulitis (osteopenia, arthralgias, diffuse pains). The association of certain auto-immune illnesses must be emphasized (diabetes, Hashimoto thyroiditis, Gougerot disease, primitive biliary cirrhosis). To think early of the possibility of intolerance to gluten, is to give the means of a very easy diagnosis (measurement of anti-gliadin, anti-endomysium and anti-transglutaminase, and secondarily duodenal biopsy if necessary), and it is early elimination of gluten food which will make the various clinical manifestations disappear and so prevent the risk of evolution to a tumoral pathology.

Adolescent↗

Rhabdomyosarcoma in Karachi 1998-2002.

The epidemiological features of rhabdomyosarcoma (RMS), an uncommon malignancy composed of cells with histopathologic features of striated muscle, were studied in Pakistan. Incident RMS cases recorded at the Karachi Cancer Registry during 1998 to 2004 were reviewed and to ensure maximum completeness of data, only those registered between 1998 and 2002 were considered for the present study. Two hundred and seventeen cases were reported to the Karachi Cancer Registry during this five-year period. One hundred and forty eight of the patients (60.4% males; 39.6% females) were residents of Karachi. The crude and standardized annual incidence rates/100,000 were 0.3 for males and 0.2 for females. The incidence was 0.5 in children below 15 years of age. The primary RMS sites in males were head and neck (28.1%), extremities (25.8%), genitourinary (GU) tract (17.9%), trunk (9.0%), orbit (7.9%), and retroperitoneum (3.4%). RMS occurred at other sites in 7.9% of the patients. Corresponding frequencies in females were head and neck (35.6%), extremities (16.9%), GU tract (16.9%), trunk (8.5%), orbit (8.5%) and other sites in 13.6%. Approximately 60% of the cases were childhood RMS and three fourths were below 21 years. The mean age of RMS cases all sites, males, was 18.5 years (95% CI 15.6; 21.4); for childhood RMS, 7.5 years (95% CI 6.0; 9.2); and for adult RMS 34.2 years (95% CI 28.3;40.2). In females, the corresponding figures were 18.2 (95% CI 13.7; 22.7); 6.6 (95% CI 5.0; 8.1) and 33.9 (95% CI 27.5; 40.5), respectively. One hundred cases were retraceable, and the mean survival time, RMS all sites and ages in both genders, was 1.5 years (95% CI 1.1; 1.9). The 5-year survival was 10%, and 3-year survival was 30% whereas 16.7% of the patients died within a year of diagnosis. The indicators of poor prognosis, a late presentation, rapid evolution, advanced disease, tumor burden (tumor size >5.cms) and regional lymph node involvement, are characteristic of RMS in Karachi. Recent advances in RMS multimodality treatment protocols have improved RMS prognosis in patients with limited disease. Pakistan should focus on early diagnosis and prompt treatment of malignancies. This requires health education for the general population to create awareness and training of health professionals at all levels to promote early diagnosis. An RMS group is required, which would monitor the treatment, recurrence, patient education and provide psychosocial support. Cytogenetic studies are advised for a better understanding of biologic differences in RMS cases in this population.

Adolescent↗