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Ectopic adrenocorticotropic hormone-syndrome in medullary carcinoma of the thyroid: a retrospective analysis and review of the literature.

Cushing's syndrome (CS) in medullary thyroid carcinoma (MTC) is rare. Only 50 cases have been reported. We report 10 cases of MTC with ectopic adrenocorticotropic hormone (ACTH)-dependent syndrome (EAS), analyzed retrospectively. Among 1640 patients with MTC, 13 developed EAS (0.7%). In 10 patients CS could unequivoqually be related to MTC (0.6%). CS was always clinically obvious. It revealed MTC in 3 cases and followed diagnosis by an average of 34.5 months in the others. Metastases were often present at diagnosis. Immunohistochemistry with ACTH antibodies was positive in one case. Diagnosis of ectopic CS was established according to clinical and biologic features, and absence of corticotropic adenoma as well as parallel evolution between tumor and CS. Therapy was medical and surgical: anticortisolic drugs alone or in association with somatostatin analogue, somatostatin analogue alone, and bilateral adrenalectomy. Eight patients died within 2 to 30 months, 4 of hypercortisolism complications (3 peritonitis and 1 hypokalaemia), 4 of MTC progression. EAS is a rare complication of MTC. The prognosis is poor because of frequency of metastasis at diagnosis. Persistent hypercortisolism can, by itself, lead to death, and has to be treated specifically.

Adrenocorticotropic Hormone↗

Necrotic areas in VX2 carcinoma of rabbits. Correlation of magnetic resonance imaging and pathologic appearance.

RATIONALE AND OBJECTIVES: To assess the potential of magnetic resonance imaging (MRI) for evaluating the evolution of tumor necrosis, the authors evaluated 28 VX2 carcinomas inoculated in the thigh muscles of rabbits. METHODS: MRI of VX2 carcinomas at 2.0 T was done with spin-echo technique 1 week (14 tumors) and 3 weeks (14 tumors) after the inoculation of tumor cells. T1- and T2-weighted images were obtained with 500/30 and 2,500/80 sequences; the authors also performed enhanced T1-weighted images with contrast medium. MRI and histopathologic findings were compared. RESULTS: Enhanced T1-weighted images with gadolinium-DTPA (Gd-DTPA) (dimeglumine gadopentetate) could depict necrosis in almost all tumors (27/28) and were the most sensitive technique followed by T2- and T1-weighted images. T2-weighted images best permitted the evaluation of the characteristics of necrotic areas in VX2 carcinomas, followed by T1-weighted images with contrast enhancement, and unenhanced T1-weighted images. On T2-weighted images, low-intensity areas of necrotic areas correspond to areas of early necrosis, isointense areas corresponded to areas of intermediate necrosis, and high-intensity areas corresponded to the late phase of necrosis. CONCLUSIONS: MRI is useful in depicting necrosis and characterizing different phases of necrosis in VX2 carcinomas.

Animals↗

Fuzzy differential inclusions in atmospheric and medical cybernetics.

Uncertainty management in dynamical systems is receiving attention in artificial intelligence, particularly in the fields of qualitative and model based reasoning. Fuzzy dynamical systems occupy a very important position in the class of uncertain systems. It is well established that the fuzzy dynamical systems represented by a set of fuzzy differential inclusions (FDI) are very convenient tools for modeling and simulation of various uncertain systems. In this paper, we discuss about the mathematical modeling of two very complex natural phenomena by means of FDIs. One of them belongs to the atmospheric cybernetics (the term has been used in a broad sense) of the genesis of a cyclonic storm (cyclogenesis), and the other belongs to the bio-medical cybernetics of the evolution of tumor in a human body. Since a discussion of the former already appears in a previous paper by the first author, here, we present very briefly a theoretical formalism of cyclone formation. On the other hand, we treat the latter system more elaborately. We solve the FDIs with the help of an algorithm developed in this paper to numerically simulate the mathematical models. From the simulation results thus obtained, we have drawn a number of interesting conclusions, which have been verified, and this vindicates the validity of our models.

Algorithms↗

Kaposi's sarcoma associated with lung cancer and immunosuppression.

We report a 65-year-old Japanese woman with Kaposi's sarcoma (KS). The eruption first occurred on the legs while she was admitted for treatment of poorly differentiated lung cancer. Approximately eight months after the evolution, cutaneous tumors rapidly spread to the forearms, trunk, and pharynx. At that time, the patient had received systemic corticosteroid (10-40 mg/day of prednisolone) for about three months to reduce pulmonary inflammation. The laboratory data showed anemia, lymphopenia, hypogammaglobulinemia, and a decreased T cell count, although the serological test for HIV infection was negative. The patient was treated with radiation (X-ray for KS of pharynx and electron beam for KS of lower legs) and local intralesional injection of vinblastine. Although both therapies were very effective and well tolerated, she died of bacterial pneumonia and sepsis. Autopsy revealed KS tumors, unknown before death, in both lungs, the esophagus, and the stomach. The left lung cancer had disseminated and metastasized to the right lung, pleura, mediastinum, and abdominal cavity. It is suspected that chronic respiratory distress and systemic use of corticosteroids might have induced the rapid extension of KS.

Fatal Outcome↗

The use of flow cytometry in the diagnosis and biological characterization of the non-Hodgkin's lymphomas.

The detection of aneuploidy and the estimation of the fraction of cells in S in DNA histograms from patients with human non-Hodgkin's lymphoma are reviewed. Karyotype studies and DNA histograms each have advantages and disadvantages in the detection and monitoring of aneuploidy. The choice of fluorescent stain, staining artifacts, and the criteria for the detection of aneuploidy by FCM must be considered carefully. In general, the B-cell lymphomas are more frequently aneuploid by FCM than the T-cell lymphomas. When determining S fractions in the lymphomas, care must be taken not to exclude the aneuploid cases on methodological grounds; these cases generally have the highest S fractions and their exclusion would bias the data. Multiparameter studies have shown that the most aneuploid component of a mixed clinical sample generally has the highest S fraction in the sample, favoring the concept of clonal selection and clonal evolution of tumors.

Aneuploidy↗

Effects of 5-azacytidine on the progressive nature of cell transformation.

C3H 10T1/2 mouse embryo fibroblasts were exposed to 3 microM 5-azacytidine for 24 h and then serially passaged in the absence of 5-azacytidine and examined for subsequent changes in growth properties. The treated cells showed changes in morphology, saturation density, growth rate, and serum dependence. By the 5th passage they acquired the ability to grow in 0.3% agarose, and by the 30th passage they gave rise to fully transformed foci that grew in agarose, in agar, and in liquid suspension. This progression was rapidly accelerated if the cultures derived from 5-azacytidine-treated cells were exposed for 48 h to the carcinogen benzo[a]pyrene. Results of these studies provide evidence that aberrations in DNA methylation may be one of a series of critical events during the course of multistage carcinogenesis and thus enhance the evolution of tumor cells.

Animals↗

Antibodies to bladder-tumor-associated antigens as prognosis probes in the flow-cytometric analysis.

Monoclonal antibodies directed against bladder tumor cells (10D1, 7C12, 6D1, 3C6, G4 and E7) and human leukocyte antigen (HLe1) were tested by flow cytometry on 68 bladder tumors involving 10 grade I, 29 grade II and 29 grade III tumors (WHO classification). According to their evolution stage, these tumors can be subdivided into 17 stage Pa, 34 stage P1, 7 stage P2 and 10 stage P3. Fifteen normal bladder samples were used as a control. Analysis of DNA content revealed a first group of 31 tumors with a unimodal DNA profile. In the second groups of 37 tumors, the DNA profile was bimodal. Cells from grade I tumors were labelled with 10D1 and 6D1 antibodies; all these cells showed a unimodal DNA profile. Grade III tumor cells were labelled with antibodies G4 and E7; most of these cells showed a bimodal DNA profile. The percentage of HLe1-positive cells decreased with the pathological grade and stage of tumor. The composition of infiltrating leukocytes was different in unimodal and bimodal tumors. In conclusion, cells of low-grade tumors can be identified with 10D1 and 6D1 antibodies, and antigens recognized by G4 and E7 antibodies are mostly expressed by aneuploid cells. HLe1 antibody demonstrates the importance of the inflammatory reaction in bladder tumors. Moreover, in flow cytometry, leukocytes within a tumor could be used as internal reference for precise measurement of the DNA content of tumor cells.

Antibodies, Monoclonal↗

Dual parameter flow cytometry studies in human lymphomas.

Dual parameter flow cytometry studies using Coulter volume and cell DNA content were carried out in monodisperse cell suspensions of 64 samples of human lymphoma, chronic lymphocytic leukemia, hairy cell leukemia, and benign lymphoid proliferations. Differences in mean Coulter volume among the lymphomas were due both to the intrinsic differences in mean G1 cell Coulter volume and to the presence of increased fractions of larger S and G2 cells, especially among the large B cell lymphomas. However, the relative contribution of large non-G1 cells to the overall population Coulter volume distribution was a relatively minor one; the presence of cells in S did not increase mean Coulter volume by more than 10%, even in samples with high S fractions. There was a good correlation between mean G1 cell Coulter volume and the log of the fraction of cells in S among the B cell lymphomas (r = 0.55). Evidence is presented that within individual samples, large cells proliferate more rapidly than small cells. This was seen in every case, both in the normal samples and in the lymphomas, and in the T cell lymphomas as well as in the B cell lymphomas. Aneuploidy was detected by flow cytometry in 11 cases; in 7 cases the aneuploid cell component could be analyzed separately from the diploid cell component on the basis of cell Coulter volume differences. The aneuploid components of diploid-aneuploid mixtures had higher S fractions than the diploid components in six of seven cases (0.16 +/- 0.04 [SE] vs. 0.08 +/- 0.02). These findings are considered in relation to the histopathological classification of the lymphomas, and in relation to the concept of clonal selection and clonal evolution of tumors.

Aneuploidy↗

Nonmutagenic mechanisms in carcinogenesis: role of protein kinase C in signal transduction and growth control.

There is accumulating evidence that the multistage carcinogenic process is associated with the progressive acquisition of mutations in cellular proto-oncogenes and in growth-suppressor genes. At the same time, several types of evidence indicate that nongenotoxic agents and epigenetic events also play an important role in the evolution of tumors. One of the most intensively studied nongenotoxic agents is the phorbol ester tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and related compounds. Since TPA appears to exert its biologic effects through protein kinase C (PKC), a key enzyme in signal transduction, we have studied this enzyme in considerable detail. Our strategy has been to perturb signal transduction by developing cell lines that overexpress the beta 1 isoform of PKC. Such derivatives of rat fibroblasts display alterations in morphology and growth factors, altered expression of c-myc, ornithine decarboxylase, and phorbin, and increased susceptibility to transformation by certain oncogenes, H-ras, myc, and fos. These findings provide direct genetic evidence that PKC plays a critical role in growth control and the action of certain growth factors, tumor promoters, and oncogenes. In related studies, we have characterized the beta 1 isoform that is overproduced in the above cell systems in terms of its biochemical, kinetic, and immunologic properties. The enzyme has several properties characteristic of native PKCs. A surprising finding is that c-H-ras-transformed derivatives of the cells that overexpress PKC beta 1 display a several-fold increase in the expression of the endogenous alpha 1 isoform of PKC and a decrease in the expression of the endogenous epsilon isoform.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Systems biology successes and areas for opportunity in prostate cancer.

Systems biology approaches have been applied to prostate cancer to model how individual cellular and molecular components interact to influence cancer development, progression, and treatment responses. The integration of multi-omic experimental data with computational models has provided insights into the molecular characteristics of prostate cancer and emerging treatment strategies that have the potential to improve patient outcomes. Here, we highlight recent advancements that have emerged from systems modeling in prostate cancer. These include descriptions of the molecular landscape of prostate cancer and how genomic alterations inform computational models of disease progression, how evolutionary processes give rise to mechanisms of therapeutic resistance, and the development of innovative treatment strategies such as adaptive therapy. We also highlight current challenges in prostate cancer that can be addressed through systems biology approaches. These include tumor heterogeneity, poor immunotherapy response, a paucity of experimental model systems, and the ongoing translation of computational models for clinical decision making. Leveraging systems biology approaches has the potential to lead to a better understanding of the disease and better patient outcomes in the treatment of prostate cancer.

Humans↗

[Vertebral aneurysmatic bone cyst: study of three cases].

Aneurysmatic bone cyst is a hypervascularized, benign lesion locally destructive by its progressive growth with greater incidence in the second decade of life. It lodges preferably in the long bones and vertebrae. The clinical picture varies from pain to local edema and even neurological symptoms when in vertebral location. Three cases of vertebral aneurysmatic bone cyst occurring in childhood and all with neurologic deficit symptoms are described. Computerized tomography and/or magnetic resonance imaging confirmed the diagnosis. Patients underwent surgery to remove the tumor. In one of the cases, pre-operative selective arterial embolization of the lesion was performed. The three patients progressed satisfactorily with neurological improvement, which demonstrated the efficiency of the microsurgical technique for the resection of the spinal tumor. The evolution of the cases and the current treatment are discussed.

Adolescent↗

Primary bronchopulmonary malignant melanoma. Case report.

A case of pulmonary melanoma is presented. Because of the tumor's evolution and clinical features and, in particular, its pathoanatomic characteristics, we believe that it complied with sufficient criteria for classification as primary bronchopulmonary malignant melanoma. The literature is briefly reviewed.

Bronchial Neoplasms↗

Epigenetic events during the process of cell transformation induced by carcinogens (review).

Recent studies clearly demonstrate that several environmental carcinogens lack the ability to initially induce genetic damage. In that view, multistage chemical carcinogenesis may be processed under the control of a variety of epigenetic events in addition to genotoxic impacts. The understanding of this mechanism as reviewed in this report requires knowledge of early changes induced by carcinogens in target cells, biochemical, biological and molecular reactions closely related to both sides of the growth equation: cell proliferation and programmed death. Among several cell transformation models, the most suitable for carcinogen detection and mechanistic study is the Syrian hamster embryo (SHE) cell transformation assay. This closely mimics the multistage carcinogenesis and we can examine, in a relatively short time (8 days), the mechanisms by which genotoxic and non-genotoxic agents may increase the frequency of cell transformation as a preneoplastic end-point. The mode of action of hundred of compounds, carcinogens and non-carcinogens, has been explored so far using one-stage and two-stage treatment protocols. In general, with the two-stage protocol, all carcinogens, irrespective of their genotoxic or non-genotoxic potential, give unambiguous positive results. Since perturbations of cell proliferation and death are considered essential events in the process of carcinogenesis, studies have been conducted on the dysregulation of two specific parameters, the induction of ornithine decarboxylase (ODC) an enzyme related to cell proliferation, and the apoptosis rate, when SHE cells are exposed to carcinogens. In one-stage treatment (5 h-24 h), only the promoter TPA induces ODC activity, while other carcinogens do not increase this activity. Using the two-stage exposure protocol (1 h xenobiotic/5 h TPA), all carcinogens both genotoxic and non-genotoxic, are able to stimulate ODC activity above the level obtained with TPA alone. Based on the two-stage treatment with carcinogens a close relationship can be obtained between the ODC superinduction and the increase of morphological cell transformation frequency. In cancer development, it is postulated that the inhibition of apoptosis may help altered cells to escape cell death and acquire a tumorigenic phenotype. Two-stage treatment carcinogen/TPA, effectively decreases the apoptotic rate. This is accompanied by an upregulation of the Bcl-2 oncoprotein, a well-known apoptotic inhibitor. However, treatment with a non-carcinogen phthalic anhydride, also inhibits apoptosis while it does not superinduce ODC activity. Although inhibition of apoptosis is not specific to the carcinogenic compound, both superinduction of ODC activity and inhibition of apoptosis via Bcl-2 upregulation may cooperate during the early stages of the carcinogenic process. In a long-term stage transformation assay, the rate of transformed colonies is relatively low (2-8%) bringing about the slow evolution of tumoral disease in humans and tumoral induction in rodents. This could be the consequence of the activation of various cellular repair mechanisms during the exposure time. Experimental data reported so far point out that genotoxic and non-genotoxic carcinogens, thought to be more active in the initiation or in the promotion stage, must share the same stage pathway leading to cancer development.

Animals↗

[Retroperitoneal fibromatosis: report of a case].

We report a 42 years old female that presented with abdominal pain and no palpable mass. Imaging abdominal ultrasound, CAT scan and magnetic resonance showed a solid tumor located in the retroperitoneum. The patient was operated on excising the tumor. Pathological examination of the surgical piece disclosed a retroperitoneal fibromatosis or desmoid tumor. Postoperative evolution of the patient was uneventful and she was discharged 12 days after the surgical procedure.

Adult↗

[XII cranial nerve pseudoneurinoma due to spontaneous fibrous transformation of an aneurysm of the vertebral artery].

The authors report an exceptional case report of tumor like evolution of a completely thrombosed aneurysm of the right vertebral artery suggestive of neurinoma of the XII nerve. We describe CT, MRI, MR-angiography. The diagnosis has been established by pathologic study after surgical extraction. Our case demonstrate the possibility of growth of totally thrombosed aneurysms and we discuss various mechanisms.

Aged↗