Histologic transformation in marginal zone lymphomas†.

BACKGROUND: Histologic transformation (HT) is a poorly understood event in patients with marginal zone lymphoma (MZL). The aim of this study was to analyze incidence and risk factors for HT in a large series of MZL patients. PATIENTS AND METHODS: The studied cohort included 340 MZL patients diagnosed and treated between 1995 and 2012: 157 extranodal MZLs [mucosa-associated lymphoid tissue (MALT) lymphoma, 46%], 85 splenic MZLs (SMZLs, 25%) and 37 nodal MZLs (NMZLs, 11%). Sixty-one patients (18%) had bone marrow infiltration at presentation, with or without detectable involvement of peripheral blood, but without other involved sites; they were considered clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ). RESULTS: With a median follow-up of 4.8 years, the median overall survival and progression-free survival of the whole population were 14.5 and 5 years, respectively. HT was observed in 13 cases [3.8%, 95% confidence interval (95% CI) 2%-6.5%]. Elevated lactate dehydrogenase (LDH) at diagnosis was associated with the risk of HT (P = 0.019). HT occurred in 5% of SMZLs, 4% of MALT lymphomas, 3% of NMZLs and 3% of CBL-MZ (P = 0.974). The risk of HT was 5% (95% CI 3-9%) at 5 and 10 years after diagnosis and 10% (95% CI 5%-20%) at 12 years. At the time of HT, most patients had high LDH and B symptoms. At a median follow-up of 12 months after HT, 4 of 13 patients died, all for lymphoma-related causes, with a 2-year post-transformation survival rate of 57% (95% CI 13%-86%). CONCLUSIONS: In this large retrospective series, the risk of HT across all MZL types appeared lower than the one reported for follicular lymphoma.

Laser capture microdissection is a valuable tool in the preoperative molecular screening of follicular lesions of the thyroid: an institutional experience.

OBJECTIVES: The application of molecular tests to thyroid fine needle aspiration (FNA) has been shown to be a valuable tool to better refine the pre-operative malignant risk of patients with indeterminate cytology results. In this study, we investigated the feasibility of using the laser capture microdissection (LCM) technique to obtain DNA and RNA for molecular tests in routine thyroid FNA smears. METHODS: Nine coupled FNA and histological retrospective cases and 31 prospective FNA cases with a follicular neoplasm/suspicious for a follicular neoplasm (FN/SFN) diagnosis were included in this study. Both cytological and histological specimens were investigated by direct sequencing and reverse transcription-polymerase chain reaction (RT-PCR) for BRAF and RAS mutations and for PAX8/PPARG and RET/PTC rearrangements, respectively. RESULTS: LCM yielded good DNA and RNA quality in all cases (100%) in both series, irrespective of the staining used (Giemsa, Papanicolaou, immunostain for thyroglobulin) and the cytology technique (conventional or liquid-based preparations). Total mutations found in the FNA and in the corresponding histological specimen in both series were: one PAX8/PPARG rearrangement in a follicular carcinoma (FC), four NRAS mutations [in two FCs, one papillary carcinoma and one follicular adenoma (FA)] and one HRAS mutation in one FA. The sensitivity was 67% and the specificity was 91%. CONCLUSIONS: LCM is a valuable tool to obtain good quality DNA and RNA for molecular tests in cytological material from thyroid FNA, and can be a useful option in the management of patients with an FN/SFN FNA diagnosis.

HER2 gene copy number status may influence clinical efficacy to anti-EGFR monoclonal antibodies in metastatic colorectal cancer patients.

BACKGROUND: In metastatic colorectal cancer (mCRC), KRAS is the only validated biomarker used to select patients for administration of epidermal growth factor receptor (EGFR)-targeted therapies. To identify additional predictive markers, we investigated the importance of HER2, the primary EGFR dimerisation partner, in this particular disease. METHODS: We evaluated the HER2 gene status by fluorescence in situ hybridisation (FISH) in 170 KRAS wild-type mCRC patients treated with cetuximab or panitumumab. RESULTS: Depending on HER2 gene copy number status, patients showed three distinct cytogenetic profiles: 4% of patients had HER2 gene amplification (R:HER2/CEP17 ≥ 2) in all neoplastic cells (HER2-all-A), 61% of patients had HER2 gain due to polysomy or to gene amplification in minor clones (HER2-FISH+*), and 35% of patients had no or slight HER2 gain (HER2-FISH-). These subgroups were significantly correlated with different clinical behaviours, in terms of response rate (RR; P=0.0006), progression-free survival (PFS; P<0.0001) and overall survival (OS; P<0.0001). Patients with HER2-all-A profile experienced the worst outcome, patients with HER2-FISH- profile showed an intermediate behaviour and patients with HER2-FISH+* profile were related to the highest survival probability (median PFS in months: 2.5 vs 3.9 vs 7.6, respectively; median OS in months: 4.2 vs 9.7 vs 13, respectively). CONCLUSION: HER2 gene copy number status may influence the clinical response to anti-EGFR-targeted therapy in mCRC patients.

Tumefactive demyelinating lesions during etanercept treatment requiring decompressive hemicraniectomy.

Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory and immunoregulatory cytokine involved in the pathogenesis of several autoimmune disorders. Etanercept, a TNF-α antagonist (anti-TNF-α) acting as a soluble TNF-α receptor, has been associated with neurological demyelinating disorders. This paper aims to report an unusual case showing tumefactive central nervous system (CNS) inflammatory demyelination in a patient in the course of TNF -α antagonist therapy, requiring decompressive hemicraniectomy. This report is based on magnetic resonance imaging (MRI) findings and histology. A biopsy confirmed the inflammatory demyelinating nature of the lesions. The clinical presentation is unusual due to the severity of the disease process, requiring decompressive hemicraniotomy with a clinically favorable outcome.

Molecular characterization of EGFR and EGFR-downstream pathways in triple negative breast carcinomas with basal like features.

AIMS: Triple negative breast cancer with basal like features (TN-BCBL) do not benefit from hormonal and anti-HER2 therapies. As a considerable fraction of TN-BCBLs shows EGFR deregulation, EGFR-targeted therapies have been proposed as an option. The characterization of EGFR and EGFR-downstream members may therefore provide important predictive information. METHODS AND RESULTS: Based on morphological and immunophenotypic features, we identified 38 TN-BCBLs that were subsequently investigated for alterations in EGFR signaling pathways. EGFR and PTEN protein levels were studied by immunohistochemistry, EGFR gene status by FISH, EGFR, H-Ras, K-Ras, N-Ras, BRAF and PIK3CA gene mutations by direct sequencing. EGFR overexpression and loss of PTEN expression characterized the majority of TN-BCBLs (76% and 74% of patients, respectively). EGFR gene copy number gain (FISH+) was identified in 51% of analyzable patients. PIK3CA gene mutations were detected in three cases (8%), whereas EGFR, H-Ras, K-Ras, N-Ras and BRAF genes showed no mutations. Overall, out of 17 patients classified as FISH+, 12 cases (70%) showed a concomitant alteration in PI3K/PTEN pathway. CONCLUSIONS: These results provide evidence that the efficacy of anti-EGFR drugs in TN-BCBL patients could be impaired by frequent alterations in the PI3K/PTEN axis, and suggest that TN-BCBLs could benefit from tailored treatments against this axis.

The impact of the introduction of total mesorectal excision on local recurrence rate and survival in rectal cancer: long-term results.

PURPOSE: To investigate the influence of the introduction of total mesorectal excision (TME) on local recurrence rate and survival in patients with rectal cancer. METHODS: A total of 171 consecutive patients underwent anterior or abdominoperineal resection for primary rectal cancer. When the TME technique was introduced, the clinical setting, including the surgeons, remained the same. Group 1 (1993-95, n =53) underwent conventional surgery and group 2 (1995-2001, n = 118) underwent TME. All patients were followed for 7 years or until death. RESULTS: Between the two groups, no statistically significant differences were present with regards to patient-, treatment-, or tumor-related characteristics apart from the time point of radiotherapy. The total local recurrence rates were 11 of 53 (20.8%) in group 1 and 7 of 118 (5.9%) in group 2, and the rates of isolated local recurrences were 6 of 53 (11.3%) in group 1 and 2 of 118 (1.7%) in group 2. Both differences were highly statistically significant. The disease-free survival in groups 1 and 2 was 60.4 and 65.3% at 5 years, and 58.5 and 65.3% at 7 years, respectively. Excluding patients with synchronous or metachronous distant metastasis from the analysis, both the disease-free survival and the cancer-specific survival were statistically significantly better in group 2 than in group 1. No statistically significant difference between the two groups was detected regarding the overall survival. CONCLUSIONS: The introduction of TME led to an impressive reduction of the local recurrence rate. Survival is mainly determined by the occurrence of distant metastasis, but TME seems to improve survival in patients without systemic disease.

Prognostic and predictive value of TOPK stratified by KRAS and BRAF gene alterations in sporadic, hereditary and metastatic colorectal cancer patients.

BACKGROUND: Our aim was to investigate the prognostic and predictive value of the oncogenic MAPKK-like protein T-cell-originated protein kinase (TOPK) stratified by KRAS and BRAF mutations in patients with sporadic, hereditary and metastatic colorectal cancer (CRC) treated with anti-EGFR therapy. METHODS: Immunohistochemistry (IHC) for TOPK was performed on four study groups. Group 1 included two subgroups of 543 and 501 sporadic CRC patients used to test the reliability of TOPK expression by IHC. In Group 2, representing an additional 222 sporadic CRCs, the prognostic effect of TOPK stratified by KRAS and BRAF was assessed. The prognostic effect of TOPK was further analysed in Group 3, representing 71 hereditary Lynch syndrome-associated CRC patients. In Group 4, the predictive and prognostic value of TOPK was analysed on 45 metastatic patients treated with cetuximab or panitumumab stratified by KRAS and BRAF gene status. RESULTS: In both sporadic CRC subgroups (Group 1), associations of diffuse TOPK expression with clinicopathological features were reproducible. Molecular analysis of sporadic CRCs in Group 2 showed that diffuse TOPK expression was associated with KRAS and BRAF mutations (p<0.001) and with poor outcome in patients with either mutation in univariate and multivariate analysis (P=0.017). In hereditary patients (Group 3), diffuse TOPK was linked to advanced pT stage. In metastatic patients treated with anti-EGFR therapy (Group 4), diffuse TOPK expression was linked to dismal outcome despite objective response to treatment (P=0.01). CONCLUSIONS: TOPK expression is an unfavourable prognostic indicator in sporadic patients with KRAS or BRAF mutations and also in patients with metastatic disease experiencing a response to anti-EGFR therapies. The inhibition of TOPK, which could benefit 30-40% of CRC patients, may represent a new avenue of investigation for targeted therapy.

Assessment of breast cancer opportunistic screening by clinical-pathological indicators: a population-based study.

BACKGROUND: Although some clinical-pathological features of breast cancers, such as the incidence of ductal cancer in situ (DCIS) and the diameter of invasive tumours, are sensitive indicators of early detection, comprehensive population-based studies of opportunistic screening are needed. METHODS: Cases of DCIS or invasive breast cancer diagnosed in 1996-2007 were identified from the Ticino Cancer Registry (south of Switzerland). Time trends of age-adjusted incidence and mortality, as well as main clinical-pathological features, such as tumour diameter, AJCC stage and histological grade, were analysed. RESULTS: A total of 3047 incident cases of female breast cancer were identified. The proportion of DCIS with respect to invasive cases increased from 5.8% in the period 1996-2001 to 6.4% in the period 2002-2007. The median tumour size of invasive cancers decreased from 20 mm in 1996-2001 to 18 mm in 2002-2007 (P<0.0001). An increase in well/moderately differentiated invasive tumours, from 67% in the period 1996-2001 to 73% in 2002-2007 (P<0.001), was detected and resulted in an Annual Percentage Change of incidence of 2.8 (95% confidence interval: 1.3; 4.3). CONCLUSION: An opportunistic screening strategy can lead to an improvement of prognostic features at diagnosis, but these features are still less favourable than those achieved by organised screening programmes.

Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic sites may be clinically relevant.

Cetuximab and panitumumab efficacy in metastatic colorectal cancer (mCRC) may be influenced by EGFR gene status and/or deregulation of its downstream signalling proteins detected in primary tumour. However, metastasis might have different molecular patterns with respect to primary tumour, possibly affecting the prediction of EGFR-targeted therapy efficacy. We analysed primary tumour and metastasis in 38 mCRC patients. Twelve cases were cetuximab/panitumumab treated. EGFR gene status and protein expression were investigated through fluorescent in situ hybridisation and immunohistochemistry (IHC), K-Ras/BRAF mutations by sequencing and PTEN expression by IHC. We observed EGFR gene deregulation in 25 out of 36 primary tumours and 29 out of 36 metastases, K-Ras mutations in 16 out of 37 cancers and in 15 out of 37 metastases, BRAF mutations in 2 out of 36 cancers and 2 out of 36 metastases and PTEN loss in 8 out of 38 cancers and 12 out of 38 metastases. For the first time in literature, we show that primary colorectal cancer and paired metastasis may exhibit difference with respect to EGFR pathway deregulation mechanisms possibly implying a different response to cetuximab or panitumumab treatment. The investigation of treated patients confirms this hypothesis. We therefore suggest that the analysis of metastatic lesion should be considered in patient management as well as in designing future clinical trials aimed to investigate the effect of anti-EGFR monoclonal antibodies in the treatment of mCRC.

Long-term outcome following Helicobacter pylori eradication in a retrospective study of 105 patients with localized gastric marginal zone B-cell lymphoma of MALT type.

BACKGROUND: Treatment aimed at eradicating Helicobacter pylori infection results in lymphoma remission in most localized gastric mucosa-associated lymphoid tissue (MALT) lymphomas. The aim of this survey is to investigate the long-term effect of this therapeutic approach in a large series of patients. METHODS: One hundred and five patients with localized gastric MALT lymphoma were initially treated only with H. pylori eradication regimens. Lymphoma responses were graded using the Wotherspoon score. RESULTS: Helicobacter pylori, detected by histology in 81% of cases, was eradicated in all positive patients. Histological regression of the lymphoma was achieved in 78 of 102 assessable patients [76%, 95% confidence interval (CI): 67% to 84%] with complete remission (score 0-2) in 66 and partial remission (score 3) in 12. At a median follow-up time of 6.3 years, histological remission was consistently confirmed in 33 of 74 assessable patients, while 25 had score fluctuations (from 0 to 4) and 13 presented a lymphoma relapse (score 5). Only one patient had a distant progression. Transformation to a large-cell lymphoma was seen in two cases. The 5- and 10-year overall survival is 92% (95% CI: 84% to 96%) and 83% (95% CI: 70% to 91%), respectively. Only one patient died of lymphoma after transformation to a high-grade lymphoma. CONCLUSIONS: Helicobacter pylori eradication resulted in complete lymphoma remission in the majority of cases. Long-term clinical disease control was achieved in most patients. A watch and wait policy appears to be safe in patients with minimal residual disease or histological-only local relapse.

An overview of the epidermal growth factor receptor fluorescence in situ hybridisation challenge in tumour pathology.

Epidermal growth factor receptor (EGFR) is deregulated in a variety of solid malignant tumours. Due to the availability of specific targeted therapies, the request to evaluate EGFR in neoplastic tissues in pathology is dramatically increasing. In analogy to HER2, EGFR evaluation by FISH seems to be superior than immunohistochemistry to select patients for targeted therapies. However, the lack of consensus on how to assess the presence and extent of EGFR gene status deregulation in tissue sections has generated a confusion of inadequately defined criteria, which impairs the quality of communication in both routine patient care and research studies. The objectives of this review are: (1) to analyse methodological aspects, signals evaluation and interpretation criteria related to the detection of EGFR alterations by FISH in cancer samples, highlighting technical limits and controversies; (2) to review the literature concerning EGFR FISH on formalin-fixed paraffin-embedded tissue sections from different types of solid tumours, with a particular focus on the clinical significance of numerical EGFR gene alterations with respect to targeted therapies. Further advances in improving the quality of care of patients with cancers characterised by EGFR gene deregulation will depend on answering some of the questions underlined throughout this overview.

Breast cancer classification according to immunohistochemical markers: clinicopathologic features and short-term survival analysis in a population-based study from the South of Switzerland.

BACKGROUND: Breast cancer may be classified into distinct molecular subtypes based on gene expression profiling and/or immunophenotypic characteristics. Aim of the study was to investigate prevalence, clinicopathologic features and overall survival (OS) of molecular subtypes, in a large European population-based study. PATIENTS AND METHODS: All invasive breast cancers from 2003 to 2007 were selected from the files of Ticino Cancer Registry. Molecular subtypes were defined by immunohistochemical markers. Clinicopathological characteristics and short-term OS were analyzed. RESULTS: Of 1214 invasive breast cancers, 73.2% were luminal A subtype, 13.8% luminal B, 7.4% basal like and 5.6% Her2/neu. Basal like presented largely in premenopausal women and displayed aggressive features, such as large tumor size, poorly differentiated cancers, high Ki-67 proliferation index and the worst 24-month OS. Luminal A included the highest percentage of patients >70, the highest proportion of stage I tumors and well/moderately differentiated lesions. Her2/neu was more frequent in postmenopausal women and showed the highest percentage of positive lymph nodes and stage IV cases. CONCLUSION: This is a comprehensive European population-based study on breast cancer molecular subtypes. We provide strong evidence that the molecular classification is useful for clinical management and superior to World Health Organization classification in terms of short-term prognostic value.

BM-derived cells randomly contribute to neoplastic and non-neoplastic epithelial tissues at low rates.

Epithelial cancers can arise from BM-derived cells (BMCs) in animal models. We studied whether the same phenomenon can occur in humans. Biopsy specimens from carcinomas and healthy adjacent tissues were obtained from three women who had undergone allogeneic BMT from an HLA-matched brother. Complete donor hematopoietic chimerism was verified by cytogenetic analysis, RFLP analysis or by reverse transcription-PCR analysis. Biopsies were studied for the presence of the Y chromosome derived from BM-derived cells by combined FISH and immunohistochemical staining. In our studies, we showed that human epithelial neoplastic and adjacent non-neoplastic tissues incorporate the Y chromosome at low and comparable rates. The lack of enrichment in malignancies argues against the possibility that BM-derived cells represent a direct source of carcinomas, and we suggest that these cells randomly contribute to neoplastic and non-neoplastic epithelial cells. On the basis of the absence of a fusion karyotype, we favor a model in which the differentiation of BM-derived cells is largely determined by the microenvironment encountered.

Human T cell development and HIV infection in human hemato-lymphoid system mice.

Advances in generation of mice that on human hematopoietic stem and progenitor cell transplantation develop and maintain human hemato-lymphoid cells have fueled an already thriving field of research. We focus here on human T cell development and HIV infection in Rag2 -/- gamma(c) -/- mice transplanted as newborns with human CD34+ cord blood hematopoietic stem and progenitor cells.

PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients.

To evaluate whether the epidermal growth factor receptor (EGFR), K-Ras and PTEN, all members of the EGFR signalling pathway, may affect the clinical response in cetuximab-treated metastatic colorectal cancer (mCRC) patients. Twenty-seven cetuximab-treated mCRC patients were evaluated for drug response and investigated for EGFR protein expression and gene status, K-Ras mutational status and PTEN protein expression. Ten patients achieved a partial response (PR) to cetuximab-based therapy. All 27 patients showed EGFR protein overexpression. Epidermal growth factor receptor gene amplification was observed in eight out of 27 (30%) and chromosome 7 marked polysomy in 16 (59%) patients. Partial response was observed in six out of eight patients with EGFR gene amplification, four out of 16 with marked polysomy and none out of three with eusomy (P<0.05). The K-Ras wild-type sequence was observed in 17 patients, and nine of them experienced a PR. Conversely, K-Ras was mutated in 10 cases, of which one patient experienced a PR (P<0.05). The PTEN protein was normally expressed in 16 patients, and 10 of them achieved a PR. In contrast, no benefit was documented in 11 patients with loss of PTEN activity (P<0.001). Patients with EGFR gene amplification or chromosome 7 marked polysomy respond to cetuximab. In addition to K-Ras mutations, we demonstrate for the first time that the loss of PTEN protein expression is associated with nonresponsiveness to cetuximab.

Neuroendoscopic management of a solitary pineal region tumor. Case report of an adenocarcinoma metastasis.

The present case describes a two-step endoscopic management of hydrocephalus and diagnosis of a single pineal region metastasis arising from a gastric adenocarcinoma. A 62-year-old man presenting with signs of subacute obstructive hydrocephalus from a pineal region mass had at first been treated with an endoscopic third ventriculostomy. As cerebrospinal fluid tumor markers (alpha-fetoprotein, beta-human chorionic gonadotropin) were negative, an endoscopic biopsy of the pineal region tumor was performed through a more anterior frontal burr hole. Pathology showed an adenocarcinoma and primary tumor work-up revealed an unsuspected gastric tumor, the pathology of which matched with the intracranial metastasis. The present report emphasizes the role of neuroendoscopy in pineal region tumors and reports a rare case of a solitary gastric adenocarcinoma metastasis in this location.

Activation of the receptor protein tyrosine kinase EphB4 in endometrial hyperplasia and endometrial carcinoma.

BACKGROUND: Members of the Eph family of tyrosine kinases have been implicated in embryonic pattern formation and vascular development; however, little is known about their role in the adult organism. We have observed estrogen-dependent EphB4 expression in the normal breast suggesting its implication in the hormone-controlled homeostasis of this organ. Since the endometrium is a similarly hormone dependent organ and endometrial carcinoma is thought to result from estrogenic stimulation, we have investigated EphB4 expression in normal human endometrium and during its carcinogenesis. PATIENTS AND METHODS: EphB4 expression was analyzed immunohistochemically in 26 normal endometrium specimens, 15 hyperplasias and 102 endometrioid adenocarcinomas and correlated with clinical and prognostic tumor characteristics. RESULTS: In normal endometrial tissue no EphB4 protein was detected. Strikingly, we observed a drastic increase (P <0.0001) in the number of EphB4 protein-expressing glandular epithelial cells in the majority of hyperplasias and carcinomas. Moreover, we found a statistically highly significant positive correlation between EphB4 expression and post-menopausal stage of the patient (P = 0.007). CONCLUSIONS: These findings indicate that in the endometrium, EphB4 is an early indicator of malignant development and, thus, EphB4 may represent a potent tool for diagnosis and therapeutic intervention.

A retrospective analysis of 153 patients treated with or without intravesical bacillus Calmette-Guerin for primary stage T1 grade 3 bladder cancer: recurrence, progression and survival.

PURPOSE: We retrospectively evaluated the long-term outcome in patients with newly diagnosed stage T1 grade 3 bladder cancer treated with transurethral resection with or without intravesical bacillus Calmette-Guerin (BCG). MATERIALS AND METHODS: Of 153 patients with a median age of 67 years (range 36 to 88) and a male-to-female ratio of 4:1 we treated 92 with transurethral bladder resection and additional BCG, and 61 with transurethral bladder resection alone. BCG was administered intravesically as 120 mg. BCG Pasteur F dissolved in 50 ml. saline, retained for up to 2 hours weekly for 6 weeks and repeated as necessary. RESULTS: Median followup was 5.3 years (range 0.4 to 18.2). Disease recurred in 70% of the patients treated with BCG and in 75% treated with transurethral resection alone. Median time to recurrence was 38 and 22 months for BCG and resection alone (p = 0.19). Tumor progressed in 33% of patients with BCG and in 36% with resection alone. Deferred cystectomy was performed in 29% of the patients with BCG and in 31% with resection alone. Overall and disease specific survival did not differ significantly. CONCLUSIONS: Our results suggest that intravesical BCG therapy after transurethral bladder resection for stage T1 grade 3 bladder cancer may delay the time to recurrence and cystectomy but it does not substantially alter the final outcome. Our findings reflect the rule of 30% for stage T1 grade 3 cancer, namely approximately 30% of patients never have recurrence, 30% ultimately die of metastatic disease and 30% require deferred cystectomy.

[Barrett's esophagus: screening and prognosis]. / Barrett-Osophagus, Screening und Prognose.

The diagnostic criteria for Barrett's disease have changed very considerably during the last 10 years. Classically, the definition asked for columnar epithelium in the lower esophagus extending for at least 3 cm proximally. Now, the diagnosis rests on the finding of specialised intestinal metaplasia, i.e. columnar epithelium with goblet cells, in the esophagus, regardless of the extension. This is important because it is this type of metaplasia that is associated with an increased risk for the development of esophageal adenocarcinoma and esophageal adenocarcinoma is the tumor with the fastest rising incidence in the western world in recent years. The criteria of the current definition of Barrett's esophagus are described in detail and the implications this change in definition carries for screening and surveillance of patients is discussed.

CC chemokines and the receptors CCR3 and CCR5 are differentially expressed in the nonneoplastic leukocytic infiltrates of Hodgkin disease.

Lymph nodes with Hodgkin disease (HD) harbor few neoplastic cells in a marked leukocytic infiltrate. Since chemokines are likely to be involved in the recruitment of these leukocytes, the expression of potentially relevant chemokines and chemokine receptors were studied in lymph nodes from 24 patients with HD and in 5 control lymph nodes. The expression of regulated on activation, normal T cell expressed and secreted (RANTES), monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta was analyzed by in situ hybridization and that of CCR3 and CCR5 by immunohistochemistry and flow cytometry. It was found that, overall, the expression of all 4 chemokines was markedly enhanced, but the cellular source was different. RANTES was expressed almost exclusively by T cells whereas the expression of MCP-1, MIP-1alpha, and MIP-1beta was confined largely to macrophages. In control lymph nodes, chemokine expression was low, with the exception of MIP-1alpha in macrophages. CCR3 and CCR5 were highly expressed in T cells of HD involved but not of control lymph nodes. CCR3 was equally distributed in CD4+ and CD8+ cells, but CCR5 was associated largely with CD4+ cells. In HD lymph nodes, CCR3 and CCR5 were also expressed in B cells, which normally do not express these receptors. All these chemokines and receptors studied, by contrast, were absent in the neoplastic cells. It was concluded that chemokines are involved in the formation of the HD nonneoplastic leukocytic infiltrate. Expression of CCR3 and CCR5 appears to be characteristic of HD, but the roles of these receptors' up-regulation for the disease process remain unclear.