Premalignant State Research Articles

Transforming Growth Factor-βSignaling in Normal and Malignant Hematopoiesis

Transforming growth factor-β (TGF-β) is an important physiologic regulator of cell growth and differentiation. TGF-β has been shown to inhibit the proliferation of quiescent hematopoietic stem cells and stimulate the differentiation of late progenitors to erythroid and myeloid cells. Insensitivity to TGF-β is implicated in the pathogenesis of many myeloid and lymphoid neoplasms. Loss of extracellular TGF receptors and disruption of intracellular TGF-β signaling by oncogenes is seen in a variety of malignant and premalignant states. TGF-β can also affect tumor growth and survival by influencing the secretion of other growth factors and manipulation of the tumor microenvironment. Recent development of small molecule inhibitors of TGF-β receptors and other signaling intermediaries may allow us to modulate TGF signaling for future therapeutic interventions in cancer.

The high‐risk benign tumor: Evidence from the two‐stage skin cancer model and relevance for human cancer

Benign tumors that form following chemical initiation and promotion in the mouse skin can be grouped into two classes. The majority of papillomas do not progress to squamous cell carcinoma (SCC), and these are designated as low-risk or terminally benign papillomas. In contrast, a much smaller group forms the true precursor to the SCC, and these have a significantly higher frequency and rate of malignant conversion than the bulk of low-risk papillomas. In standard two-stage carcinogenesis studies both tumor types are present, but grossly indistinguishable. Here we describe properties and potential origins of high-risk papillomas and discuss the relevance of this model for certain human cancers with defined premalignant states.

Anomalies génétiques dans le myélome: rôle dans l'oncogenèse et implications pronostiques

Recent development of interphase fluorescence in situ hybridization (FISH) allows analysis on non-proliferant plasma cells. We describe the most frequent genetic abnormalities in multiple myeloma and their prognostic value. Most frequent genetic abnormalities are illegitimate rearrangements involving the IGH gene at 14q32 (60% of patients), hyperdiploidy (50 to 60% of patients), chromosome 13 deletion (40 to -50% of patients), chromosome 1q gain (30 to -40% of patients) chromosome 17 deletion (10% of patients). Some of these genetics abnormalities are observed in monoclonal gammopathy of undetermined significance (MGUS), a pre-malignant state. t(4;14) and t(14;16) translocations and chromosome 17 deletion negatively impact the overall survival. Patients with these genomic aberrations should be treated with specific treatment. Identification of genetic abnormalities is important for evaluation of prognosis and treatment protocol in multiple myeloma.

Diminished Potential for B-Lymphoid Differentiation after Murine Leukemia Virus Infection In Vivo and in EML Hematopoietic Progenitor Cells

Infection with a recombinant murine-feline gammaretrovirus, MoFe2, or with the parent virus, Moloney murine leukemia virus, caused significant reduction in B-lymphoid differentiation of bone marrow at 2 to 8 weeks postinfection. The suppression was selective, in that myeloid potential was significantly increased by infection. Analysis of cell surface markers and immunoglobulin H gene rearrangements in an in vitro model demonstrated normal B-lymphoid differentiation after infection but significantly reduced viability of differentiating cells. This reduction in viability may confer a selective advantage on undifferentiated lymphoid progenitors in the bone marrow of gammaretrovirus-infected animals and thereby contribute to the establishment of a premalignant state.

Vibrational spectroscopy for cervical cancer pathology, from biochemical analysis to diagnostic tool

Cervical cancer is the second most common cancer in women worldwide with 80% of cases arising in the developing world. The mortality associated with cervical cancer can be reduced if this disease is detected at the early stages of development or at the pre-malignant state (cervical intraepithelial neoplasia, CIN). The aim of this study was to investigate the potential of Raman spectroscopy as a diagnostic tool to detect biochemical changes accompanying cervical cancer progression. Raman spectra were acquired from proteins, nucleic acids, lipids and carbohydrates in order to gain an insight into the biochemical composition of cells and tissues. Spectra were also obtained from histological samples of normal, CIN and invasive carcinoma tissue from 40 patients. Multivariate analysis of the spectra was carried out to develop a classification model to discriminate normal from abnormal tissue. The results show that Raman spectroscopy displays a high sensitivity to biochemical changes in tissue during disease progression resulting in an exceptional prediction accuracy when discriminating between normal cervical tissue, invasive carcinoma and cervical intraepithelial neoplasia (CIN). Raman spectroscopy shows enormous clinical potential as a rapid non-invasive diagnostic tool for cervical and other cancers.

Radiation-Induced Leukemia at Doses Relevant to Radiation Therapy: Modeling Mechanisms and Estimating Risks

Because many cancer patients are diagnosed earlier and live longer than in the past, second cancers induced by radiation therapy have become a clinically significant issue. An earlier biologically based model that was designed to estimate risks of high-dose radiation-induced solid cancers included initiation of stem cells to a premalignant state, inactivation of stem cells at high radiation doses, and proliferation of stem cells during cellular repopulation after inactivation. This earlier model predicted the risks of solid tumors induced by radiation therapy but overestimated the corresponding leukemia risks. To extend the model to radiation-induced leukemias, we analyzed--in addition to cellular initiation, inactivation, and proliferation--a repopulation mechanism specific to the hematopoietic system: long-range migration through the blood stream of hematopoietic stem cells (HSCs) from distant locations. Parameters for the model were derived from HSC biologic data in the literature and from leukemia risks among atomic bomb survivors who were subjected to much lower radiation doses. Proliferating HSCs that migrate from sites distant from the high-dose region include few preleukemic HSCs, thus decreasing the high-dose leukemia risk. The extended model for leukemia provides risk estimates that are consistent with epidemiologic data for leukemia risk associated with radiation therapy over a wide dose range. For example, when applied to an earlier case-control study of 110,000 women undergoing radiotherapy for uterine cancer, the model predicted an excess relative risk (ERR) of 1.9 for leukemia among women who received a large inhomogeneous fractionated external beam dose to the bone marrow (mean = 14.9 Gy), consistent with the measured ERR (2.0, 95% confidence interval [CI] = 0.2 to 6.4; from 3.6 cases expected and 11 cases observed). As a corresponding example for brachytherapy, the predicted ERR of 0.80 among women who received an inhomogeneous low-dose-rate dose to the bone marrow (mean = 2.5 Gy) was consistent with the measured ERR (0.62, 95% CI = -0.2 to 1.9). An extended, biologically based model for leukemia that includes HSC initiation, inactivation, proliferation, and, uniquely for leukemia, long-range HSC migration predicts, with reasonable accuracy, risks for radiation-induced leukemia associated with exposure to therapeutic doses of radiation.

C-Reactive Protein in Nipple Aspirate Fluid

Proteins expressed in nipple aspirate fluid (NAF) have been associated with breast cancer risk and may serve to detect inflammatory or premalignant states. Obesity, hyperlipidemia, and metabolic syndrome are associated with increased rates of breast cancer and are systemic markers of chronic inflammation. The aim of this study was to determine if one NAF protein, C-reactive protein (CRP), associated elsewhere in the human with cancer, relates to reproductive, nutrition, and body composition and activity factors. Women (n = 59) aged 30 to 64 years from the midwestern United States and Kenya were evaluated regarding the relation between reproductive (age, pregnancy, and breast-feeding indices), nutrition (serum lipids, serum, or NAF carotenoid), body composition and activity (activity, waist-hip ratio, fat percentage (% fat), and body mass index [BMI]) factors and CRP in NAF. Age at first pregnancy (p < .05), gravidity (p < .05), wean time from breast-feeding last baby (p < .05), serum triglycerides (p = .01), % fat (p < .05), and BMI (p < .05) were related significantly to CRP levels in NAF. A model derived from selective women's reproductive, nutritional, and body composition and activity factors significantly (p < .05) accounted for the variance in breast microenvironment inflammation as measured by CRP in NAFs. Detecting CRP in NAF may indicate local mammary inflammation, which has been associated with carcinogenesis. Specific NAF risk modeling that addresses reproductive, nutritional, and body composition and activity factors may be used for further advances in the prevention of breast cancer and the early detection and treatment of the disease.

Curcumin Combats Against Cigarette Smoke and Ethanol-Induced Lipid Alterationsin Rat Lung and Liver

Human population, in spite of the medical and scientific achievements, still fall as a prey to the evils of habitual smoking and alcohol, thus necessitating safer counteracting measures. To evaluate the effect of cotreatment of curcumin (Curcuma longa) in rats subjected to acute exposure to cigarette smoke (CS) and ethanol (EtOH). Of the four groups of experimental rats, a set of rats was subjected to whole body exposure to cigarette smoke along with ethanol administration serving as a model of CS+EtOH injury. Curcumin treatment was given to two sets of rats: (i) one set receiving simultaneous CS+EtOH and (ii) one set of normal rats without any administration. The other group of rats served as control. Blood, liver and lung of rats were selected for assessment of CS+EtOH injury as well as curcumin treatment. Altered lipid, lipoprotein profile and bile acid excretion were observed in CS+EtOH rats along with premalignant pathological state in tissues. In treated rats, the levels were maintained at near-normal levels along with near-normal histology. This biochemical picture on cotreatment with curcumin suggests that curcumin could counteract the injurious effects of combined CS and EtOH and thus might help to reduce the risk of hyperlipidemic disorders which develop due to smoking and drinking.

TEL-AML1 Transgenic Zebrafish Model of Acute Lymphoblastic Leukemia (ALL).

TEL-AML1 (ETV6-RUNX1) fusion is the product of the t(12;21) chromosomal translocation, the most common chromosomal rearrangement in childhood cancer. The translocation fuses two highly conserved transcription factors, TEL and AML1 that have essential roles in hematopoiesis. Genetic studies of identical twins with concordant leukemia, the detection of leukemia-specific fusion genes in neonatal blood spots, and the existence of multiple leukemic subclones at ALL diagnosis point to prenatal origin of the fusion and long latency before leukemia development. Additionally, a study in growth factor-dependent cell lines and transgenic mice, and several mouse transplant models suggest that TEL-AML1 is insufficient by itself for leukemic transformation. To determine whether TEL-AML1 has selective transforming impact on a particular stem cell lineage, we established stable zebrafish transgenic lines expressing the TEL-AML1 fusion protein both constitutively, and within the lymphoid progenitors. In these lines, either the zebrafish β-actin (ZBA) promoter or the xenopus elongation factor-1 (XEF1) promoter drives TEL-AML1 expression constitutively, while the zebrafish RAG-2 promoter (RAG2) selectively drives TEL-AML1 expression in committed lymphocyte precursors, but not in earlier multilineage hematopoietic precursors. TEL-AML1 expression, alone or fused to EGFP, was detected at 24-hour post fertilization (hpf) with fluorescent microscopy or RT-PCR and confirmed with western blot analysis. In-Situ Hybridization and confocal microscopy revealed that transgenic zebrafish maintained TEL-AML1 expression throughout adulthood. The expression of TEL-AML1 was associated with accumulation of immature hematopoietic progenitor cells, mostly in the kidney and spleen of several transgenic zebrafish lines, within a few weeks of development, indicating an expansion of the progenitor cell population. To date, a small number (5 out of 391 transgenic fish; 1.3%) of founders and progeny of zebrafish transgenic for ZBA- or XEF1-TEL-AML1 fusion developed an infiltrating lymphoid neoplasm, most likely acute lymphoblastic leukemia with a latency of 8–12 month. The lymphoblasts were negative for myeloperoxidase and PAS staining, with abundant expression of both EGFP in lymphoblasts from EGFP-TEL-AML1 line, and pre-B-cell leukemia transcription factor-1 (PBX1; also called cALLa) indicating that Leukemias originated in a TEL-AML1 expressing cell(s), and mimic the human CD10-positive precursor-B cell ALL. None of 350 wild-type, 125 control EGFP fish or 353 RAG2-TEL-AML1 transgenic zebrafish had any leukemia or hematopoietic changes. Therefore, the expression of TEL-AML1 fusion in our ZBA- and XEF1-TEL-AML1 transgenic lines generates a premalignant state, which appears to require additional genetic events for acquisition of the leukemic phenotype. The fact that none of the RAG2 zebrafish expressing TEL-AML1 in committed lymphoid progenitors developed leukemia or progenitor expansion indicates that the leukemic stem cell associated with TEL-AML1 leukemia is an immature progenitor earlier than the committed lymphoid progenitors where RAG2 expression is detected. The TEL-AML1 transgenic zebrafish lines provide a basis for large scale and targeted mutagenesis screens aimed at identifying mutations and cooperating events that are required for TEL-AML1 induced leukemias.

Involvement of oxidative stress in the pre-malignant and malignant states of cervical cancer in women

Objectives: To evaluate the potential role of oxidative stress in the evolution of cervical cancer, including its pre-malignant states. Design and methods: Erythrocytes thiobarbituric acid reactive substances (TBARS) levels, plasma vitamin C and thiol content and total blood δ-ALA-D levels were estimated in 46 untreated cervical cancer and pre-malignant patients and in 46 age–sex-matched controls. Results: Erythrocytes from patients, regardless of disease state, pre-malignant (low squamous intraepithelial lesion—LSIL and high squamous intraepithelial lesion—HSIL) or cancer, showed a significant 2–3 times increase in TBARS levels ( P < 0.01). Plasma vitamin C was lower in the carcinoma group ( P < 0.01). The reactivation index of δ-aminolevulinate dehydratase (δ-ALA-D) was higher in the patient group, when compared to control ( P < 0.01). Conclusion: LSIL, HSIL or cervical cancer can be associated with changes in 3 indicators of oxidative stress: increase in erythrocyte TBARS, ALA-D reactivation index and a decrease in vitamin C content, that may play an important role in carcinogenesis.

Proteomic Strategies and their Application in Cancer Research

The understanding of carcinogenesis and tumor progression on a molecular basis needs a detailed study of proteins as effector molecules and as critical components of the multiple interconnected signaling pathways that drive the neoplastic phenotype. Thus, the proteomic approach represents a powerful tool for the challenge of the post-genomic era. The term "cancer proteome" refers to the collection of proteins expressed by a given cancer cell and should be considered as a highly dynamic entity within the cell, which affects a variety of cellular activities. The emerging proteomic analysis platforms including 2D-PAGE, mass spectrometry technologies, and protein microarrays represent powerful tools to study and understand cancer. These systems aim to not only identify, catalogue, and characterize cancer proteins, but also to unveil how they interact to affect overall tumor progression. Moreover, recent studies on various cancers have reported promising results concerning the detection of novel molecular biomarkers useful in the early diagnosis of cancer and in drug discovery. Thus, a new subdiscipline named clinical proteomics, concomitant with new molecular technologies that are developed, demonstrates promise to discover new cancer biomarkers. The early diagnosis of cancer, even in a premalignant state, is crucial for the successful treatment of this disease. For these reasons, it is clear that the identification of biomarkers for the early diagnosis of cancer should represent one of the main goals of this emerging field of study.

Biomarkers of Myeloma-Associated Lytic Bone Disease Using SELDI-TOF MS.

MGUS is a pre-malignant state, with a 1% annual risk of progression to overt myeloma (Kyle, NEJM 346:564, 2004). Progression of MGUS to myeloma is preceded and can be predicted by increased rates of bone turnover (Betaille, JCI 88:62, 1991). Progress to overt myeloma is associated with lytic bone disease in about 80% of patients. A simple, reliable test that identifies MGUS patients at risk of progression to symptomatic myeloma would elucidate biological mechanisms that govern the process and identify targets for early intervention. The intimate association of progression with changes in bone biology suggested that early recognition of changes in bone turnover would serve such a purpose. Therefore, we sought to identify protein biomarkers of bone disease in the sera of patients with myeloma that can be used as early predictors of progression. Given the limited reliability of individual markers of bone turnover to identify changes in bone metabolism, we elected to adopt a global proteomics approach. Sera from 62 untreated myeloma patients were collected and stored at −80°C for future analysis. 35 serum samples were from myeloma patients with 1–26 lytic bone lesions as identified on X-ray skeletal surveys and 27 serum samples were from patients without lytic lesions. The sera were analyzed by surface-enhanced laser desorption and ionization-time of flight mass spectroscopy (SELDI-TOF MS) using Ciphergen's ProteinChip Biology System II (PBS II), to identify protein patterns associated with lytic bone disease. Each sample was applied in 4 replicates to randomly assigned spots on 12 IMAC30 ProteinChips placed in a bioprocessor and activated with Cu++ ions using a Biomek2000 robot. The chips were read on a PBS II reader. The mass spectra of proteins, generated using an average of 66 laser shots, were calibrated using peptide and protein standards and normalized to total ion current using CiphergenExpress 2.0 software. To develop a classification model that separates non-treated patients with focal lesions from those without focal lesions, we identified among the low molecular weight (1500–25000 kDa) proteins a set of 17 protein peaks that were differentially expressed between the two groups at a significance level of p<0.005. We then randomly selected 80% of patients for developing a model based on these peaks using a stepwise logistic regression method; 198 calibrated and normalized spectra from 50 randomly selected patients,28 with lytic bone lesions and 22 without lytic lesions (2 samples had only 3 replicates) were used for model development. The model used 10 protein peaks to classify the patients, with a receiver operating characteristic (ROC) area of 0.897. Finally the model was challenged by the set-aside test set of 50 spectra from 12 randomly selected patients (one patient had 6 replicates). The model exhibits high sensitivity and specificity, and its overall prediction accuracy is around 90%. Studies are underway to identify the biomarkers and to validate the utility of this model to predicting progression of MGUS to overt myeloma.

Infection with human herpesvirus 8 and transplant-associated gammopathy.

The role of human herpesvirus (HHV)-8 in the pathogenesis of multiple myeloma and its pre-malignant state of monoclonal gammopathy is unclear. HHV-8 is transmitted by organ transplantation, representing a unique model with which to investigate primary HHV-8 infection. The authors studied the incidence of clonal gammopathy in renal transplant recipients and correlated it with previous and recent HHV-8 infection. Clonal gammopathy was observed in 31 of 162 (19%) HHV-8-seronegative patients, in 5 of 17 (29%) HHV-8-seropositive patients, and in 9 of 24 (38%) HHV-8 seroconverters within 5 years after transplantation. Gammopathy was often transient, and no progression to myeloma was observed. Two patients with persistent gammopathy developed B-cell lymphoma. In a logistic regression model, HHV-8 serostatus of the graft recipient was significantly associated with subsequent development of gammopathy, with a relative risk (RR) of 1.9 and a 95% confidence interval (CI) of 0.5 to 6.4 for an HHV-8-seropositive recipient and an RR of 2.9 and a 95% CI of 1.01 to 8.0 for seroconverters as compared with baseline (HHV-8 seronegative). Other significant variables were cytomegalovirus (CMV) serostatus and the intensity of immunosuppression (RR of 10.4 and 95% CI of 2.6-41.7 for a CMV-negative recipient with a CMV-positive donor vs. a CMV-negative recipient with a CMV-negative donor and RR of 17.6 and 95% CI of 2.0-150.8 if OKT3 was used vs. no use of antilymphocytic substances). Transplant recipients with HHV-8 infection are more likely to develop clonal gammopathy. However, this risk is much lower than the risk conferred by CMV infection and antilymphocytic therapy, arguing against a major role of HHV-8 infection in the pathogenesis of clonal plasma cell proliferation.

Brain tumours: classification and genes

This paper aims to provide an outline of the surgical pathology of the most common tumours of the nervous system in children and adults, and briefly summarise their common genetic...

The NOD2 3020insC Mutation and The Risk of Familial Pancreatic Cancer?

Dear Sirs, Pancreatic cancer is an aggressive disease with a poor prognosis but despite much investigation little is known about genetic susceptibilities to this cancer [1-4]. There are several studies showing pancreatic abnormalities in patients with Crohn's disease, a chronic inflammatory condition of the digestive tract. It has been suggested that pancreatitis could be an extrahepatic manifestation of inflammatory bowel disease, since its incidence in this disease is greater than that in the general population and in many cases no aetiological factor has been found [5]. It has been recently identified in Japan that over 6% of Crohn's disease patients had morphological abnormalities of the pancreas [6]. There is also a notion that Crohn's-associated pancreatitis could be a premalignant state for cystadenocarcinoma of the pancreas [7]. Recently in patients with Crohn's disease mutations in CARD15/NOD2 have been found. NOD2 encodes a protein involved in bacterial recognition by monocytes. The NOD2 gene is localized to chromosome 16 and is comprised of 12 exons that encode a protein of 1040 amino acids [8]. Several mutations have been identified in the NOD2 gene, which appear with a significantly higher frequency in patients with Crohn's disease. One such mutation (3020insC) is believed to be clearly causative because it is the only common variant which results in a prematurely truncated protein predicted to reduce its functional efficiency. It has been recognized recently that the presence of this particular NOD2 mutation increases the risk of developing colorectal cancer characterized by a later average age of disease diagnosis [9]. Since the risk of cancers at various sites has been characteristic among patients with Crohn's disease, it was considered justified to study the relationship between the 3020insC mutation and other cancer risks. Here, we report the analyses of the 3020insC mutation in the NOD2 gene in patients with pancreatic cancer. Initially, we have examined the frequency of the 3020insC mutation in a series of 158 patients divided into 3 groups: 1. 127 consecutive pancreatic cancers; 2. 4 familial cases - pancreatic cancer patients from families with at least two pancreatic cancers on the one side of the family; 3. 27 healthy children of pancreatic cancer patients from families with at least two pancreatic cancer cases where DNA samples from affected individuals were not available. Individuals from the last group were younger than 46 years. In the consecutive group peripheral blood samples were available from 58 cases. DNA from the remaining patients was isolated from paraffin embedded tissues. In all familial cases and the group of healthy children DNA samples were obtained from the peripheral blood lymphocytes. The control group consisted of 300 consecutive newborns from the clinical hospitals of Szczecin. DNA samples were obtained from umbilical cord blood. The method described by Ogura et al [8] was used to identify the 3020insC mutation. The sequence of the PCR products was confirmed by DNA sequencing. The frequency of the 3020insC mutation in the control group was 7%. In the group of consecutive cases six C-insertion mutations were identified (4.7%). In the four independent familial pancreatic cancer patients no mutation was found, but four changes (14.8%; 4/27) were detected in the group of healthy children of pancreatic cancer patients derived from families with aggregations of these tumours (Fig. ​(Fig.11). Figure 1 Pedigree of the family with 3020insC mutation. Since our results indicated that there was an increased frequency of the 3020insC mutation in familial pancreatic cancer cases we decided to enlarge this group. 30 additional histologically confirmed familial pancreatic cancer patients of independent families from the German National Case Collection for Familial Pancreatic Cancer of the Deutsche Krebshilfe (FaPaCa) were included in this study [10]. The frequency of the mutant allele in this group did not confirm our initial result since only two changes were found (6.7%; 2/30). However, even if Polish and German familial cases are combined it is still an open question whether 3020insC is related to a predisposition to familial pancreatic cancer. Further investigations on a larger number of cases are needed. In summary we cannot conclude that NOD2 is not involved in familial pancreatic cancer but it appears not to be associated with sporadic cases of disease.

Chemoprevention for Barrett’s Esophagus Trial. Design and outcome measures

Barrett's esophagus is a premalignant condition in which normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. It is a known risk factor for the development of esophageal adenocarcinoma. With the incidence of esophageal adenocarcinoma rising, it is reasonable to study Barrett's esophagus as a potential target for therapy that may prevent, delay and/or reverse ongoing tumorigenic processes. Epidemiologic and animal studies support the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the chemoprevention of several cancers, including esophageal cancer. Cyclo-oxygenase-2 (COX-2) inhibitors are a new class of NSAIDs that inhibit prostaglandin synthesis by selectively blocking the COX-2 enzyme. The COX-2 enzyme has been reported to be over-expressed in premalignant and malignant states, including in Barrett's esophagus and esophageal adenocarcinoma. The Chemoprevention for Barrett's Esophagus Trial (CBET) is a phase IIb, multicenter, randomized, double-masked, placebo-controlled study of the selective COX-2 inhibitor, celecoxib, in patients with Barrett's dysplasia. The sample size is 200 patients with high or low grade Barrett's dysplasia. Celecoxib is administered orally, 200 mg twice per day; the dosing schedule for placebo is the same. Randomization is stratified by dysplasia grade and by clinic. Endoscopy with biopsies is performed at specified time intervals according to the highest grade of dysplasia determined at randomization. The primary outcome measure is the change from baseline to 1 year in the proportion of biopsies exhibiting dysplasia. Secondary outcomes include change from baseline in the maximal grade, extent and surface area of dysplasia. Tertiary outcomes will include measurements of various relevant biomarkers.

Splenic lymphoma arising in a patient with Gaucher disease. A case report and review of the literature.

Patients with Gaucher disease have an increased risk of malignancies, especially the lymphoreticular type. To our knowledge, this is the first reported case of Gaucher disease diagnosed during the workup and diagnosis of a splenic marginal-zone lymphoma with progression to diffuse large B-cell lymphoma. There are several theories as to how Gaucher disease leads to malignancies. The accumulated glucocerebroside in the reticuloendothelial organs, histologically visible as Gaucher cells, is thought to provide chronic antigenic stimulus to the immune system. Polyclonal hypergammaglobulinemia develops, and monoclonal populations of lymphocytes and plasma cells may arise from this premalignant proliferative state. How Gaucher disease is related to nonlymphoid malignancies remains unclear.

B lymphocytes in the normal brain: contrasts with HIV-associated lymphoid infiltrates and lymphomas.

In recent years evidence has accumulated which suggests that the brain may not be the immunologically privileged site it was once considered to be. It is now widely accepted that T lymphocytes perform surveillance functions in normal brain parenchyma. However, as yet there are no reports of B lymphocytes entering brain parenchyma in the healthy state. This study aimed to determine first the prevalence of B lymphocytes in normal brain, and subsequently whether advancing HIV infection led to changes in the brain B lymphocyte population, which might contribute to the increased risk of lymphoma seen in AIDS. Our results show that B lymphocytes do enter all parts of the normal human brain in very low numbers and that the B lymphocytes within the brain parenchyma display an activated (CD23 positive) phenotype. In contrast, intravascular B lymphocytes have a much lower expression of activation markers. B lymphocytes were found in increased numbers in both the brain parenchyma and perivascular spaces of pre-AIDS brains. However, brains from the majority of AIDS subjects, including those with primary CNS lymphoma (PCNSL) (outside the area of neoplastic involvement) contained fewer B lymphocytes than normal or pre-symptomatic HIV-infected brains. A subset of AIDS brains, previously shown to have pleomorphic lymphoid infiltrates in the perivascular spaces, had significantly increased numbers of B lymphocytes in both the brain parenchyma and perivascular spaces. Virtually all AIDS-related PCNSL are known to be Epstein-Barr Virus (EBV) positive, in contrast to non-HIV PCNSL and non-CNS AIDS-related lymphomas. We examined the EBV status of brain parenchymal B lymphocytes to investigate whether EBV-positive B lymphocytes are more frequent in HIV-infected brains than normal, thus explaining the propensity for CNS lymphomas in AIDS. In situ hybridization studies showed EBV positivity only in AIDS-related PCNSL cases within the lymphoma deposits. PCR-based studies detected high EBV copy numbers in PCNSL tumour tissue, and low copy numbers in AIDS cases with pleomorphic lymphoid infiltrates. As none of the B lymphocytes in this latter group were EBV positive on in situ hybridization, bearing in mind that this appears to be a prerequisite for PCNSL development, we find no evidence that pleomorphic infiltrates represent a pre-malignant PCNSL state.

Malignancy after liver transplantation in patients with premalignant conditions.

Liver transplant recipients are at increased risk of developing nonhepatic malignant tumors. The aim of the current study was to evaluate the role of premalignant states, not associated with the liver disease prior to transplantation, in the development of posttransplantation malignancy. One hundred seventy-five patients who had undergone liver transplantation were retrospectively evaluated for the development of malignant conditions. Each of the patients who developed malignancy following transplantation was evaluated for the presence of premalignant conditions before transplantation. Post-liver transplantation malignancy was identified in 13 patients (7.4%). Five patients developed non-Hodgkin lymphoma: four had posttransplantation lymphoproliferative diseases, and one had B cell lymphoma of the stomach. Eight patients developed solid tumors. In five of these patients, evidence of a premalignant state was identified: ulcerative colitis was diagnosed in 1 patient with carcinoma of the colon; colonic polyp, 1 patient with carcinoma of the colon; Barrett esophagus, 1 patient with esophageal carcinoma; Caroli disease, 1 patient with anaplastic cholangiocarcinoma; and cervical atypia, 1 patient with carcinoma of the cervix. Premalignant conditions existing before transplantation, which are not associated with the primary liver disease, are major risk factors for posttransplantation malignancy. Screening for premalignant conditions should be included in pretransplantation evaluation. Liver transplant patients with evidence of a premalignant state should be followed after transplantation for detection of malignancy.

Selective COX-2 inhibitors as chemopreventive and therapeutic agents.

Selective cyclooxygenase-2 (COX-2) inhibitors have received increasing attention for their role in the prevention and treatment of cancer. Considerable preclinical data support this use. Furthermore, clinical studies have shown that this enzyme is upregulated in a variety of premalignant and malignant states and that its inhibition can decrease colon polyp formation in patients with familial adenomatous polyposis. A number of studies are now investigating the use of COX-2 inhibitors to prevent or treat a number of different cancers. These ongoing trials will determine whether these agents are useful in the treatment of cancer.