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PubMed1999

[The most common complications associated with nephrectomy].

Access to the kidney and technical performance of nephrectomy should be related to the stage of the disease and degree of pathological process development (I. Viktorov 1983, S. Lambrev and T. Andreev 1961, T. Patrashkov 1982, F. S. Judy et al 1995). Advanced pathoanatomical changes in the kidney and pararenal space greatly interfere with the operation, especially in the event of adhesions to peritoneum and contiguous tissues (N. A. Lopatkina et al 1986, N. Minkov 1987, T. Patrashkov and H. Kumanov 1988). In the authors' reports presented are analyzed 388 patients nephrectomized in the University Hospital "Alexandrovska", covering the period 1990 through 1995. All updated methods are used in diagnosing. The commonest intraoperative complications recorded in a series of 188 nephrectomies (48.45%) include: 1. Pus collections in the kidney--88 cases (46.80%). 2. Opening of peritoneum--64 (34.04%). 3. Decompressive puncture of the kidney--15 (7.97%). 4. Neoplastic masses escaping from the renal parenchyma into the operative field--7 (3.72%). 5. Opening of pleura--5 (2.66%). 6. Purposeful opening of the tumor itself for decompression--3 (1.95%). 7. Kidney removal gives rise to diffuse bleeding necessitating inserting a tampon for hemorrhage control--2 (1.06%). 8. Splenectomy--1 (0.53%). 9. Because of advanced neoplastic process only biopsy is taken--1 (0.53%). 10. Hemicolectomy--1 (0.53%). 11. Injury to v cava inferior--1 (0.53%). As shown by the experience gained, nephrectomy is a technically difficult operation, particularly in case of altered topoanatomical interrelations during secondary interventions on the kidney and ureter, or in case of concomitant pyelonephritis. Intraoperative complications are not life endangering provided treatment is undertaken in opportune time.

Adult↗
PubMed2006

Activation of the NF-kappaB pathway by the leukemogenic TEL-Jak2 and TEL-Abl fusion proteins leads to the accumulation of antiapoptotic IAP proteins and involves IKKalpha.

Abnormal activation of tyrosine kinases and of signaling pathways they control plays a critical role in the neoplastic process of human hematopoietic malignancy. The nuclear factor-kappaB (NF-kappaB) pathway is one of the signalings activated by the TEL-Jak2 and TEL-Abl oncoproteins and required for their antiapoptotic activity. To define the signal relay responsible for this activation, we used mouse embryonic fibroblast (MEF) cells and observed that TEL-Jak2- and TEL-Abl-mediated NF-kappaB induction was abolished in cells lacking the IkappaB kinase (IKK)alpha but not in IKKbeta(-/-) cells. Similar observations were performed with oncogenic forms of the FMS-like tyrosine kinase 3 (Flt-3) involved in the pathogenesis of one-third of acute myeloid leukemias. Rescue of TEL-Jak2-mediated NF-kappaB activation was obtained with a kinase-proficient form of IKKalpha in IKKalpha(-/-) MEF. Hematopoietic cells transformed by TEL-Jak2 and TEL-Abl showed sustained IKKalpha activity without promotion of NF-kappaB2/p100 processing, generally associated to IKKalpha functions. Furthermore, IAP1, IAP2 and XIAP, which are central regulators of the NF-kappaB-mediated survival pathway, were highly expressed in cells transformed by these oncoproteins. Our results indicate that these oncogenic tyrosine kinases preferentially use an IKKalpha-dependent mechanism to induce a persistent NF-kappaB activity and allow the production of antiapoptotic effectors that participate to their leukemogenic properties.

Animals↗
PubMed2002

Angiogenic markers, neovascularization and malignant deformation of Barrett's esophagus.

The molecular events underlying progression of Barrett's esophagus to adenocarcinoma remain an area of active investigation. Neovascularization and angiogenesis have been studied in esophageal adenocarcinomas by counting of microvessels after staining with vascular markers, and by immunohistochemistry for vascular endothelial growth factor. Angiogenesis appears to be increased early in the neoplastic process, but has poor prognostic value. We have demonstrated that expression levels of two important genes that regulate cell growth, namely inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, are frequently upregulated in Barrett's esophagus and associated adenocarcinomas. COX-2 expression may be related to reflux of bile salts, which induce COX-2 expression in Barrett's tissues and esophageal adenocarcinoma cells in vitro. COX-2 inhibition induces apoptosis and blocks proliferation in COX-2-expressing esophageal adenocarcinoma cells in vitro, and blocks angiogenesis in both in vivo and in vitro models. Although controversial, recent evidence suggest that iNOS-derived NO can inhibit angiogenesis in some model systems. In conclusion, both iNOS and COX-2 appear to be involved in Barrett's-associated neoplastic progression, but COX-2 inhibition is more promising as a chemopreventive strategy. COX-2 inhibition may exert beneficial effects by decreasing angiogenesis and epithelial proliferation, and by facilitating apoptosis of epithelial cells that have undergone DNA damage.

Adenocarcinoma↗
PubMed2003

High rate of neoplasia and other co-morbid conditions in type-2 diabetic patients with longer duration of disease and poor metabolic control.

AIM: The aim of the study was to assess the rate of neuroendocrine malignancies in the gastrointestinal tract, other malignancies and mitotic processes, in type-2 diabetic patients. In particular, we tested the hypothesis that a poor metabolic control is associated with a higher rate of neoplasms and other co-morbid conditions, such as hypertension and peripheral neuropathy. METHODS: Forty-one consecutive asymptomatic type-2 diabetic outpatients were followed for 8 years and clustered in 2 groups, according to disease duration, insulin need, and dose of oral antidiabetic agents. Physical examination, blood pressure measurements, and neurophysiologic studies were serially performed during the follow-up. In each subject, a general biochemistry was performed, aspecific and specific antigens (alpha-fetoprotein, carcinoembrionic-antigen and prostate specific antigen PSA and F-PSA) levels were measured, and invasive and non-invasive procedures were carried out, when necessary, to detect a neoplastic process. RESULTS: The rate of malignancies and mitotic processes was significantly higher in patients with longer duration of disease and poor diabetes control (72% vs 13%, p=0.02). Hypertension (83% vs 54%) and peripheral neuropathy (67% vs 21%) were also more common in this group. CONCLUSION: These data, although obtained in a relatively small population, highlight the importance of closely monitoring type-2 diabetic patients with poor diabetes control as this might be associated with the presence of malignancy or other co-morbid conditions. This may be particularly true when the poor glycemic control is characterised by a sudden onset or significant worsening despite streghtening of antidiabetic therapy.

Adult↗
PubMed2001

Phosphorylation of the EWS IQ domain regulates transcriptional activity of the EWS/ATF1 and EWS/FLI1 fusion proteins.

Specific chromosomal translocations are commonly present in mesenchymal tumors and frequently involve genes encoding transcription factors. The combination of different domains from unrelated genes results in chimeric proteins believed to play a key role in the neoplastic process. The EWS/ATF1 and EWS/FLI1 fusion proteins associated with Clear Cell Sarcoma and Ewing's Sarcoma, respectively, were utilized to study the comparative effect of the EWS component on two different DNA binding partners. A potential regulatory site within the EWS IQ domain at serine266 was identified, and studies were performed to demonstrate that EWS is phosphorylated in cells and phosphorylation of serine266 regulates transcriptional activity. Mutational analysis showed that elimination of phosphorylation significantly reduced DNA binding activity by EMSA and reporter activation in luciferase assays, whereas phosphorylation mimicry resulted in a partial restoration to wild-type levels. Phosphorylation was also observed to mediate cellular compartmentalization. These studies confirm that IQ domain phosphorylation regulates the transcriptional activity of exogenous EWS/ATF1 and EWS/FLI1 and suggests that post-translational modifications may potentiate the neoplastic behavior of fusion proteins in general. Since the IQ domain is incorporated into only a subset of fusion transcripts, these findings may provide insight into the molecular mechanism underlying clinical heterogeneity observed in Ewing's sarcoma.

3T3 Cells↗
PubMed1999

Tumor progression, early diagnosis and prognosis of melanoma.

Primary melanomas evolve from melanocytes or from precursor lesions through two stages: the radial and vertical growth phases. The radial growth phase may be in situ or microinvasive, but is a non-tumorigenic neoplastic process, while the vertical growth phase is tumorigenic. The prognosis in radial growth phase is excellent irrespective of thickness or other variables. Curable radial growth phase melanomas can be recognized by surveillance of patients identified by screening for risk markers which include dysplastic nevi, common nevi, freckles, and other indicators of chronic or acute sun exposure or sun sensitivity. The prognosis in vertical growth phase depends on attributes of the tumor and of the host. The tumor mitotic rate, the presence of host tumor-infiltrating lymphocytes (TIL) within the vertical growth phase, and tumor thickness are the most powerful predictors of survival. New prognostic attributes are needed not only to provide for more accurate prognosis and diagnosis, but also to test the relevance of in vitro or animal studies in a human neoplastic system. Such attributes will be developed in the future based on markers that are associated with tumor progression. Candidate markers include growth factors and cytokines and their receptors, adhesion molecules and their ligands, chemotactic and motility factors, immune response-related molecules, and tumor-associated proteases. Some of these markers that are represented in the transition from radial to vertical growth phase will be reviewed. The tumor progression model presented here has been of value in the development of more accurate prognostic models, and in the elucidation of mechanisms of the malignant phenotype in melanoma.

Biomarkers, Tumor↗
PubMed1979

Clinical comparison of computed tomography and lymphangiography for detection of retroperitoneal lymphadenopathy.

The advantages of CT scan over lymphangiography are numerous and significant. The accuracy of CT scan was virtually identical to lymphogram for the detection of para-aortic lymph node involvement; however, CT provides a better means of assessing the true extent of disease. In such cases it is possible to determine whether the neoplastic process involves retroperitoneal structures such as the kidneys, ureters, pancreatic region, hilum of the liver, or the major vessels. Moreover, this excellent definition permits accurate follow-up assessment of therapy. Finally, CT is a noninvasive examination and does not require significant technical expertise, and the examination is easily reproducible following any time period from the initial examination. Finally, although we have not specifically discussed biopsy procedures, the CT scan is an excellent means for guiding biopsy procedures even for retroperitoneal abnormalities, perhaps precluding the necessity for laparotomy in order to provide histologic diagnosis of disease (Fig. 11). The disadvantages of CT are several. Of course, the acquisition of CT equipment is expensive and the cost effectiveness has not yet been proven. The most significant disadvantage is its inability to resolve or detect neoplastic disease within normal-sized lymph nodes. This was not a significant problem in our series, because our series contained only a few cases of suspected metastatic disease as opposed to lymph node neoplasms. The advantages of lymphography have been discussed by other authors. Because of the better spatial resolution of lymphograms, it is possible by proper interpretation to distinguish between neoplastic disease and lipogranulomatous changes. In a few cases in our series, this did not prove to be true; however, this may have been due to deficiencies in our interpretations (two cases of lymphoma were called positive for neoplasm, but proved to be lipogranulomatous changes by biopsy). Secondly, surveillance films may be easily and cheaply obtained to detect recurrences of disease. In addition, lymphography also provides the opportunity for biopsy of lymphoma masses, but to date this has only been accomplished by skinny-needle biopsy aspirations and not by large core biopsy techniques. After reviewing the literature and evaluating our data, we believe that several recommendations are appropriate with respect to the roles of computed tomography and lymphography. We agree with the previously stated concept that CT should be used for screening for lymphoma; however, we disagree that lymphograms have a greater advantage over CT in the biopsy-proven cases of lymphoma. Rather we believe that CT is better suited than lymphography for those cases with biopsy proven lymphoma. CT is better able to accurately localize the lymph node masses for surgeons if the surgical approach is desired and better able to define the extent of the disease throughout the abdomen. As a result of this it is capable of providing a better follow-up for therapy...

Biopsy, Needle↗
PubMed2004

Exploratory analysis of quantitative histopathology of cervical intraepithelial neoplasia: objectivity, reproducibility, malignancy-associated changes, and human papillomavirus.

BACKGROUND: As part of a project to evaluate emerging optical technologies for cervical neoplasia, our group is performing quantitative histopathological analyses of biopsy specimens from 1,190 patients. Objectives in the interim analysis are (a) quantitatively assessing progression of the neoplastic process of cervical intraepithelial neoplasia (CIN)/squamous intraepithelial lesions (SIL), (b) detecting malignancy-associated changes (MACs), and (c) phenotypically measuring human papillomavirus (HPV) detected by DNA testing. METHODS: The diagnostic region of interest (ROI) from immediately adjacent sections were imaged, and the basal lamina and surface of the superficial layer were delimited. Nonoverlapping quantitatively stained nuclei were selected from 1,190 samples with histopathological characteristics of normal (929), koilocytosis (130), CIN 1 (40), CIN 2 (23), and CIN 3/carcinoma in situ (CIS) (68). A fully automatic procedure located and recorded the center of every nucleus in the region of interest (ROI). We used linear discriminant analysis to assess the changes between normal and CIN 3/CIS. RESULTS: Scores computed from the cell-by cell features and the clinical grade of CIN/SIL were highly correlated, as were those of the architectural features and the clinical grade of CIN/SIL. We found even higher correlations between a combination of cell-by-cell and architectural scores, and clinical grade. Using these scores, we found MACs in the normal biopsy specimens from patients with high-grade CIN/SIL. Furthermore, the same scores correlated with the molecular detection of HPV. CONCLUSIONS: Quantitative histopathology can be used in large clinical trials as an objective and reproducible measure of CIN/SIL. Detectable phenotypic changes correlate well with CIN/SIL neoplastic progression. It can also be used to infer the presence of CIN/SIL (MACs) and molecular changes associated with increased risk of cancer development (high-risk HPV).

DNA, Viral↗
PubMed2006

Biological tolerance of different materials in bulk and nanoparticulate form in a rat model: sarcoma development by nanoparticles.

In order to study the pathobiological impact of the nanometre-scale of materials, we evaluated the effects of five different materials as nanoparticulate biomaterials in comparison with bulk samples in contact with living tissues. Five groups out of 10 rats were implanted bilaterally for up to 12 months with materials of the same type, namely TiO2, SiO2, Ni, Co and polyvinyl chloride (PVC), subcutaneously with bulk material on one side of the vertebral column and intramuscularly with nanoparticulate material on the contralateral side. At the end of each implantation time, the site was macroscopically examined, followed by histological processing according to standard techniques. Malignant mesenchymal tumours (pleomorphic sarcomas) were obtained in five out of six cases of implanted Co nanoparticle sites, while a preneoplastic lesion was observed in an animal implanted with Co in bulk form. In the Ni group, all animals rapidly developed visible nodules at the implanted sites between 4 and 6 months, which were diagnosed as rhabdomyosarcomas. Since the ratio of surface area to volume did not show significant differences between the Ni/Co group and the TiO2/SiO2/PVC group, we suggested that the induction of neoplasia was not mediated by physical effects, but was mediated by the well-known carcinogenic impact of Ni and Co. The data from the Co group show that the physical properties (particulate versus bulk form) could have a significant influence on the acceleration of the neoplastic process.

Animals↗
PubMed1992

Progressive atypia in spontaneous and N-nitrosodiethylamine-induced hepatocellular adenomas of C3H/HeNCr mice.

The progression of hepatocellular adenomas to carcinomas has been less well documented in mice than in rats. We studied progression of spontaneous and chemically induced hepatocellular adenomas in male C3H/HeNCr mice by image analysis. Spontaneous lesions in 15, 18 and 21 month old untreated male C3H/HeNCr mice and experimentally induced lesions were examined. Experimental group 1 received a single i.p. injection of N-nitrosodiethylamine (DEN) (5 mg/kg body wt) at 15 days of age. Groups 2 and 3 were injected a second time with DEN at 15 or 20 weeks of age (75 mg/kg body wt), with interim sacrifices at 11, 16 and 34 weeks after the second DEN injection. Atypia in adenomas were classified into four grades according to cell size, tinctorial changes, cellular pleomorphism and trabecular pattern. At earlier stages of the neoplastic process (11 or 16 weeks after the second DEN dose), most adenomas were well-differentiated lesions with no atypia or focal grade 1 or 2 atypia. At later stages (34 weeks after the second DEN dose), a large proportion of hepatocellular tumors were classified as adenoma with grade 3 atypia or carcinoma. The proportion of carcinomas in mice treated with a second dose of DEN at 20 weeks of age was significantly higher than in mice treated with a single dose of DEN or in mice given a second dose of DEN at 15 weeks. A positive correlation was found between increase in the size of lesions and increased atypia in both spontaneous and DEN-induced lesions and with age for spontaneous tumors. These results support the hypothesis that mouse hepatocellular adenomas are truly neoplastic lesions in different stages of progression toward malignancy.

Aging↗
PubMed1995

Follicular large cell lymphoma of the testis in a child.

BACKGROUND: A unique case of primary testicular lymphoma in a child is reported. METHODS: Tumor tissue was studied using immunohistochemical techniques and southern blot hybridization to detect immunoglobulin and bcl-2 gene rearrangement and in situ hybridization for the Epstein-Barr virus (EBV) genome. RESULTS: Light microscopy revealed a lymphocytic infiltrate with a follicular pattern. Immunohistochemical staining revealed lambda light chain restriction and gene rearrangement studies revealed a clonal rearrangement of the immunoglobulin heavy chain, confirming a clonal neoplastic process. Immunostaining failed to detect bcl-2 protein expression, and no evidence of bcl-2 gene rearrangement was noted on southern blot analysis. In situ hybridization for EBV nucleic acid in tumor tissue was negative. CONCLUSIONS: To the authors' knowledge, this is the first report of a case of a primary testicular lymphoma with follicular histology in a child. Despite the follicular histology, no evidence of bcl-2 expression or gene rearrangement was detected.

Child↗
PubMed1996

Molecular genetic basis of colorectal cancer susceptibility.

The past decade has seen considerable advances in understanding of the molecular processes involved in the development of colorectal cancer. With an increased awareness of genetic aspects of the disease there have already been significant changes in clinical management. This is exemplified by familial adenomatous polyposis, where identification of mutations in the adenomatous polyposis coli (APC) gene in affected individuals can be used directly to reduce the requirement for clinical screening in at-risk relatives. In other more common but less well defined heritable forms of colorectal cancer, testing to identify individuals for early diagnosis and treatment will soon become routine practice. This review does not set out to discuss all aspects of the molecular genetics of colorectal cancer but concentrates on the roles of the APC gene and the recently discovered DNA mismatch repair genes in colorectal cancer. The identification of these genes and their functional significance in the neoplastic process is discussed, and the relevance of such discoveries to future research and clinical management explored.

Colorectal Neoplasms↗
PubMed2000

[Profiles of expression of genes coding kininogen and kinin receptors as a marker of tissue pathology in cervical cancer coexisting with HPV infection].

Kinins are peptides involved in inflammatory processes, vascular permeability, proliferation and mitogenesis of tumor cells. The majority of kinins actions are mediated through an interaction with cell surface bradykinin receptors BR1 and BR2. Kinins precursor is kininogen (kng). The changes in proteins are initiated by changes in the expression of genes coding these proteins, thus can be a valuable diagnostic markers of malignant processes including cervical carcinoma. The paper presents an analysis of kininogen-kinins receptor genes expression in women treated surgically because of a carcinoma of uterine cervix. Among the studied women in 5 cases previously brachyHDR therapy was applied. In all studied cases HPV 18 infection and in 2 cases a co-infection HPV 16/18 by use of Consensus Primers MY09, MY 11 and type specific primers for HPV 16, 18 was ascertained. In RNA extracts the number of the mRNA copies for kiningen, BR1 and BR2 was assessed using QRT-PCR Taq Man. The higher expression of BR1 than BR2 was marked in the tissue with cancer cells. In the patients after brachytherapy higher expression of BR2 than BR1 mRNA was found. The higher BR1 expression was also shown in iliac lymph nodes in patients with active neoplastic process, opposite to the patients after brachytherapy in whom higher BR2 expression was ascertained. The lack of expression of kng mRNA was found only in 3 specimens. The high expression of kinin receptors especially BR1 in infiltrating carcinoma margin can be a marker of pathology intensity: proliferative potential of neoplasms cells or chronic inflammatory state in the presence of invasive carcinoma.

Adult↗
PubMed1989

In situ immunophenotyping of lymphocytes in human bone marrow: an immunohistochemical study.

Lymphoid cells in human bone marrow are either assembled focally or occur in a diffuse, loosely scattered infiltrate. While the focal lesions are easily detected, the lymphoid cells of the diffuse infiltrate are hardly recognizable with conventional stains. Quantitative immunohistological analysis of 103 trephine biopsies, including cases with reactive disorders (e.g. myeloid hyperplasia, aplastic anaemia) and neoplastic processes (e.g. myeloproliferative disorders, B-cell non-Hodgkin's lymphomas) and some specimens with normal architecture yielded the following results: (1) Various antibodies recognizing B cells (L26, 4KB5, MB1, Ki-B3), T cells (UCHL1, MT1) and NK cells (Leu-7) are effective in paraffin-embedded bone marrow sections, thus enabling analysis of the in situ distribution of normal lymphocyte subsets and subtyping of lymphomatous infiltrates. (2) The lymphocytes of the diffuse infiltrate constituted about 1-5% of all nucleated cells in normal bone marrow. (3) In the diffuse infiltrate, T lymphocytes were regularly observed in higher numbers than B cells, and Leu-7+ cells were rare or virtually absent, irrespective of the diagnosis. (4) The focally assembled lymphoid cells were mainly B lymphocytes, but many T cells were always intermingled. This was true for both reactive follicles and neoplastic lymphomatous infiltrates, which generally cannot be differentiated on the basis of immunohistological findings alone.

Antibodies, Monoclonal↗
PubMed2000

Heat shock protein expression independently predicts clinical outcome in prostate cancer.

Heat shock proteins (hsps) occupy a central role in the regulation of intracellular homeostasis, and differential expression of individual hsps occurs in a broad range of neoplastic processes. This study was performed to test the hypothesis that the particular patterns by which individual hsps become specifically modulated in human prostate cancers are correlated with behavioral phenotype and hence may be of value in determining the most appropriate clinical management of individual patients. Monoclonal antibodies specific for each hsp protein were used to assess expression of hsp27, hsp60, and hsp70 in formalin-fixed, paraffin wax-embedded, archival tissue specimens of early prostatic adenocarcinomas (pT1-2N0M0) removed at radical prostatectomy (n = 25) and in advanced cancers (n = 95) identified at transurethral resection of prostate (TURP). These findings were compared with similar data from control prostates (n = 10) removed at primary cystectomy for urinary bladder neoplasia not involving the prostate and also at TURP for benign prostatic hyperplasia (n = 50). Western blotting of whole cell lysates derived from established human prostatic epithelial cell lines PNT2, LNCaP, DU145, and PC3 was compared with expression of hsps by the primary human tissues. This study found that early in situ neoplastic transformation of normal prostatic epithelium was consistently associated with loss of hsp27 expression and that the level of hsp27 expression by individual prostate cancers was correlated with their Gleason grade. In advanced cancers, hsp27 expression was invariably associated with poor clinical outcome (P = 0.0001). Data from cell lines supported the primary tissue findings, with elevated hsp27 expression only in aggressive malignant cell lines and androgen-insensitive cell lines. Expression of hsp60 was significantly increased in both early and advanced prostate cancer when compared with nonneoplastic prostatic epithelium (P < 0.0001), as well as in malignant prostate cancer cell lines. Expression of hsp70 was unaltered in early prostate cancers when compared with nonneoplastic prostatic epithelium but showed a diminished expression in morphologically advanced cancers (P = 0.0029). No consistent correlation was found between levels of hsp60 or hsp70 expression and phenotypic behavior of individual primary prostatic cancers. Thus, patterns of hsp expression have been confirmed to be specifically and consistently modulated in both early and advanced human prostate cancers. Whereas absence of hsp27 is a reliable objective marker of early prostatic neoplasia, reexpression of this protein by an individual invasive prostatic carcinoma invariably heralds poor clinical prognosis. Because this protein has been shown to alter the balance between proliferation and apoptosis, understanding the mechanism(s) by which individual hsps regulate intracellular homeostasis may assist in explaining some key processes that occur during evolution of human prostate cancers. We suggest that hsp27 expression provides novel diagnostic and prognostic information on individual patient survival which, if obtained at the time of primary diagnosis, would assist in determining tumor-specific management strategies. Development of techniques to therapeutically modulate hsp27 expression raises the possibility of novel targeted approaches to regulate this homeostatic mechanism, thus allowing better control over tumor cell proliferation and hence patient survival.

Adenocarcinoma↗
PubMed2005

Functional validation of genes implicated in lymphomagenesis: an in vivo selection assay using a Myc-induced B-cell tumor.

The involvement of the c-Myc transcription factor in neoplastic transformation is well documented. However, which of its numerous target genes are crucial for tumorigenesis remains a frequently contested issue. We have recently established a non-transgenic murine model for B-cell lymphoma based on neoplastic conversion of p53-null bone marrow cells by conditionally active Myc. Using this model, we have identified a number of genes whose expression levels are affected by Myc during B-lymphomagenesis. Here we discuss their possible roles in neoplastic processes and describe an experimental approach allowing in vivo validation of these roles. We demonstrate that lymphoma cells overexpressing one of the Myc targets, the interleukin-10 receptor gene, have a very strong selective advantage over low IL10R expressors. Furthermore, Mcl1, a presumptive IL10R effector, also confers selective advantages when overexpressed in Myc-transformed hematopoietic cells. Thus, both IL10R and Mcl1 might be amenable to therapeutic interventions, and new targets can be identified and validated using the selection approach.

Animals↗
PubMed2002

Appearance and prognosis of dysplasia in Barrett's esophagus.

Dysplasia in a patient who has Barrett's esophagus (BE) is the first step in the neoplastic process. The grade of dysplasia correlates with the likelihood of developing adenocarcinoma of the esophagus during follow-up surveillance endoscopy and biopsy. Surveillance intervals are proposed based on the existing data of the likelihood of developing adenocarcinoma. In the future these intervals will be refined as a result of better definition of the risk factors the development of adenocarcinoma of the esophagus. Risk stratification of the individual patients by age, gender, grade of dysplasia, length of BE, length of hiatal hernia, and presence of genetic mutations will be possible.

Adenocarcinoma↗
PubMed1990

Current concepts in the relationship of human papillomavirus infection to the pathogenesis and classification of precancerous squamous lesions of the uterine cervix.

Pathologic and epidemiologic studies performed over the past three decades have provided evidence that the development of squamous cell carcinoma of the cervix is a multistep process involving a precursor preinvasive stage. The results of recent molecular analyses now suggest that the human papillomavirus (HPV) plays a role in this process and is an important but insufficient factor in the development of invasive carcinoma. Infection by a variety of HPV types may result in active viral intranuclear replication without integration into the cellular genome. This episomal form of infection is manifested morphologically by the development of mild dysplasia, cervical intraepithelial neoplasia (CIN) 1 with koilocytosis and acanthosis. Approximately 20 different HPV types have been associated with CIN 1 lesions, whereas high-grade dysplasia and carcinoma in situ (CIN 2 and 3) are associated with only a few viral types (mainly HPVs 16, 31, 33, and 35). Low-grade lesions are differentiated and have a low risk of progression to cancer, whereas high-grade lesions are characterized by nearly complete or complete loss of squamous maturation and a higher risk of progression to invasive cancer. Based on the biologic dichotomy of an infectious and a neoplastic process and the segregation of HPV types into two groups, a modification of the CIN classification into low-grade and high-grade squamous intraepithelial lesions in accordance with the Bethesda System is proposed. Although HPV plays a significant role in the development of cervical neoplasia, the value of identifying HPV DNA by such molecular techniques as Southern blot analysis, in situ hybridization, and the polymerase chain reaction in the early detection of preinvasive lesions has not been determined and their routine use is not at present recommended.

Adult↗