Search PubMed⌕ Search

Biomedical subjects

M Werner

Publications and source records attributed to M Werner.

At least 109 records · Page 6Linked to original sources
PubMed2000

Chromosomal imbalances in Barrett's adenocarcinoma and the metaplasia-dysplasia-carcinoma sequence.

To characterize cytogenetic alterations found in Barrett's adenocarcinoma (BA) and, more importantly, its premalignant stages, we studied chromosomal imbalances in various lesions in the histologically proposed metaplasia-dysplasia-carcinoma sequence using comparative genomic hybridization (CGH). Using 30 esophageal adenocarcinoma resection specimens, we were able to study 30 areas of Barrett's adenocarcinoma and 8 lymph node metastases (LN). In addition, we investigated 25 premalignant lesions adjacent to BA derived from a subset of 14 resection specimens including 11 areas of high grade dysplasia (HGD), 8 areas of low grade dysplasia (LGD), and 6 areas of intestinal metaplasia (IM), which were laser-microdissected and studied with CGH. To validate the CGH findings, fluorescence in situ hybridization analysis on 13 BA with probes specific for HER-2/neu and 20q13.2 were performed. The chromosomal alterations most often identified in BA were: gains on 8q (80%), 20q (60%), 2p, 7p and 10q (47% each), 6p (37%), 15q (33%) and 17q (30%). Losses were observed predominantly on the Y-chromosome (76%), 4q (50%), 5q and 9p (43% each), 18q (40%), 7q (33%) and 14q (30%). High-level amplifications were observed on 8q23-qter, 8p12-pter, 7p11-p14, 7q21-31, 17q11-q23. Recurrent chromosomal changes were also identified in metaplastic (gains on 8q, 6p, 10q, losses on 13q, Y, 9p) and dysplastic epithelium (gains on 8q, 20q, 2p, 10q, 15q, losses on Y, 5q, 9p, 13q, 18q). Novel amplified chromosomal regions on chromosomes 2p and 10q were detected in both Barrett's adenocarcinoma and premalignant lesions. An increase of the average number of detected chromosomal imbalances from IM (7.0 +/- 1.7), to LGD (10.8 +/- 2.2), HGD (13.4 +/- 1.1), BA (13.3 +/- 1.4), and LN (22 +/- 1.2) was seen. Although the detection of common chromosomal alterations in premalignant lesions and adjacent carcinomas suggest a process of clonal expansion, the occurrence of several chromosomal changes in an apparently random order relative to one another is striking evidence that clonal evolution is more complex than would be predicted by linear models. This is probably a reflection of the existence of many divergent neoplastic subpopulations and highlights one of the main problems associated with surveillance of Barrett's patients, namely sampling error.

Adenocarcinoma↗
PubMed2000

Molecular genetic changes in metastatic primary Barrett's adenocarcinoma and related lymph node metastases: comparison with nonmetastatic Barrett's adenocarcinoma.

Lymph node metastasis is one of the strongest negative prognostic factors for patients with Barrett's adenocarcinoma (BCA). However, despite the importance of the metastatic process in BCA, the molecular basis of it remains poorly understood. To search for cytogenetic events associated with metastasis in regional or distant lymph nodes in BCA, we investigated 8 primary BCA and their lymph node metastases and compared them with 18 nonmetastatic BCA. In metastatic primary BCA, we observed significantly more DNA gains on 3q (P = .013), 17q (P = .019), and 22q (P = .021) compared with nonmetastatic primary BCA. No statistically significant correlation could be observed between DNA copy number changes and the histopathologic stage, grade, or survival (P > .05). The most frequent alteration observed only in lymph node metastases but not in the related primary tumor was loss of 2q (5 of 8). Coamplification of 7p and chromosome 17 was found in 6 of 8 lymph node metastases. A comparison of DNA copy number changes between primary tumors and their corresponding metastases indicated a high degree of genetic heterogeneity. Fluorescence in situ hybridization analysis demonstrated the involvement of the Her-2/neu gene in primary BCA and its related lymph node metastases. Each of the investigated primary tumors and related lymph node metastases also showed striking heterogeneity with respect to Her-2/neu, with several areas displaying different levels of amplification. In summary, our data indicate that DNA copy number changes on 2q, 3q, 7p, 17q, and 22q may be involved in the metastatic process in BCA. Furthermore, the striking genetic heterogeneity that we found between primary BCA and its lymph node metastases may underlie BCA's poor responsiveness to therapy and could help explain why prognostic biomarkers measured exclusively in primary tumors give an incomplete view of the biologic potential of BCA.

Adenocarcinoma↗
PubMed2000

Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas.

Despite its clinical and histological heterogeneity, anaplastic large cell lymphoma (ALCL) is now a well-recognized clinicopathological entity accounting for 2% of all adult non-Hodgkin's lymphomas (NHL) and about 13% of pediatric NHL. Immunophenotypically, ALCL are of T cell (predominantly) or Null cell type; by definition, cases expressing B cell antigens are officially not included in this entity. The translocation (2;5)(p23;q35) is a recurring abnormality in ALCL; 46% of the ALCL patients bear this signature translocation. This translocation creates a fusion gene composed of nucleophosmin (NPM) and a novel receptor tyrosine kinase gene, named anaplastic lymphoma kinase (ALK). The NPM-ALK chimeric gene encodes a constitutively activated tyrosine kinase that has been shown to be a potent oncogene. The exact pathogenetic mechanisms leading to lymphomagenesis remain elusive; however, the synopsis of evidence obtained to date provides an outline of likely scenarios. Several t(2;5) variants have been described; in some instances, the breakpoints have been cloned and the genes forming a new fusion gene with ALK have been identified: ATIC-ALK, TFG-ALK and TPM3-ALK. Cloning the translocation breakpoint and identifying the ALK and NPM genes provided tools for screening material from patients with ALCL using various approaches at the chromosome, DNA, RNA, or protein level: positive signals in the reverse transcriptase-polymerase chain reaction (RT-PCR) and the immunostaining with anti-ALK monoclonal antibodies (McAb) serve as the most convenient tests for detection of the t(2;5) NPM-ALK since the fusion gene and ALK protein expression do not occur in normal or reactive lymphoid tissue. The wide range of NPM-ALK positivity reported in different series appears to be dependent on the inclusion and selection criteria of the ALCL cases studied. Overall, however, 43% of ALCL cases were NPM-ALK+ (83% of pediatric ALCL vs 31% of adult ALCL). Occasional non-ALCL B cell lymphomas (4%) with diffuse large cell and immunoblastic histology and Hodgkin's disease cases (3%) were NPM-ALK-, but these data are questionable. The aggregate results indicate that, in contrast to primary nodal (systemic) ALCL, the t(2;5) may be present in only 10-20% of primary cutaneous ALCL and rarely, if at all, in lymphomatoid papulosis, a potential precursor lesion; however, these 10-20% positive cases were not confirmed by anti-ALK McAb immunostaining and may represent an overestimate. Positivity for NPM-ALK is associated to various degrees with the following parameters: 44% and 45% of ALCL cases with T cell and Null cell immunophenotype, respectively, are positive, whereas only 8% of cases with a B cell immunoprofile are positive; the mean age of positive patients is significantly younger than that of negative patients; positive cases carry a better overall prognosis (but not in all studies). Recently, the homogenous category of ALK lymphoma ('ALKoma') has emerged as a distinct pathological entity within the heterogenous group of ALCL. The fact that patients with ALK lymphomas experience significantly better overall survival than ALK- ALCL demonstrates further that analysis of ALK expression has important prognostic implications. The term ALK lymphoma signifies a switch in the use of the diagnostic criteria: cases are selected on the basis of a genetic abnormality (the ALK rearrangement), instead of the review of morphological or immunophenotypical features which are clearly more prone to disagreement and controversy. Since its initial description in 1985 ALCL has become one of the best characterized lymphoma entities.

Age Factors↗
PubMed2000

PCR analysis of IgH-gene rearrangements in small lymphoid infiltrates microdissected from sections of paraffin-embedded bone marrow biopsy specimens.

The differentiation of benign lymphoid infiltrates from nodular infiltrates of B-cell lymphoma is difficult in bone marrow (BM) biopsy specimens taken from patients with non-Hodgkin's lymphoma (NHL). We investigated whether the determination of clonality by polymerase chain reaction (PCR) analysis of the immunoglobulin heavy chain (IgH) genes could be of help for the distinction of benign and malignant lymphoid infiltrates. BM biopsy specimens of 28 patients were studied, comparing PCR of entire bone marrow sections with microdissected nodular lymphoid infiltrates. Patients were divided into 4 groups according to morphologic criteria: group 1 (n = 12), positive for B-NHL infiltration; group 2 (n = 5), suspicious for infiltration by known B-NHL; group 3 (n = 5), morphologically benign infiltrates in patients with B-NHL; group 4 (n = 6), benign lymphoid infiltrates in patients without history of B-NHL. PCR products were analyzed using polyacrylamide gels and a fragment length analysis system (Genescan). PCR of whole sections showed clonal amplification products in all cases of group 1 and 1 case of group 2. PCR analysis from microdissected nodular infiltrates showed the presence of a clonal B-cell population in 5 additional cases of groups 2 and 4. In 3 of these cases, clonal rearrangements of corresponding size were obtained from the primary lymphoma biopsy specimens. None of the cases of group 3 showed evidence of a clonal population with either technique. The results indicate that microdissection of small nodular lymphoid infiltrates from paraffin-BM sections increases the sensitivity of IgH gene rearrangement analysis. To avoid detection of biologically irrelevant clonal populations, comparison of PCR products obtained from the BM and the primary lymphoma biopsy is advisable.

Biopsy↗
PubMed2000

Increasing chromosome 1 copy number parallels histological progression in breast carcinogenesis.

Chromosome 1 copy number in the benign breast lesions hyperplasia and atypical duct hyperplasia (ADH) was investigated using fluorescence in situ hybridization on paraffin sections. Progression of chromosome 1 changes occurring in parallel with histological progression from normal through hyperplasia and ADH to ductal carcinoma in situ (DCIS) and invasive carcinoma was also assessed, both overall and within individual patients. The mean signal number for normal cells was 1.14, while that for hyperplasia was 1.56 and ADH was 1.5, while values for DCIS of 1.95 and invasive duct carcinoma of 1.79, were higher (P < 0.001). Six of the seven cases also showed a significant trend towards an increasing proportion of cells with greater than 2 signals per nucleus occurring with histological progression (P < 0.001). These results support the concept that benign proliferative breast disease is a biological precursor of in-situ and invasive ductal carcinoma, the early histological changes possibly indicating a field effect with further genetic changes required for the development of a malignant phenotype.

Breast Neoplasms↗
PubMed2000

Endohyperthermia--experimental evaluation of a new therapeutic approach for treatment of biliary carcinoma.

BACKGROUND AND STUDY AIMS: To improve the prognosis of patients with unresectable, locally advanced bile duct carcinoma, new treatment strategies need to be evaluated. Hyperthermia has been successfully applied as part of multimodal therapy in esophageal and rectal carcinoma. We performed in-vitro and in-vivo experiments with a new intraluminal hyperthermia system in the biliary tract. METHODS: A radiofrequency system (13.56 MHz, Endoradiotherm XERT-200A; Olympus Optical Co., Tokyo, Japan) was used with a special intraluminal microelectrode (diameter 4.5 mm, length 40 mm) covered by a silicone balloon with cooling water and a large counter electrode for focusing the electromagnetic field around the electrode. The heating capacity of the endohyperthermia unit was examined in vitro in a muscle-equivalent phantom (agar 4 %), in isolated livers of pigs and cows, as well as in vivo in anesthetized sheep. Continuous thermometry was done with thermosensors at the applicator surface, and with multichannel thermocouple probes in the environment of the applicator. RESULTS: Endohyperthermia induced a homogeneous heating of the phantom and the isolated liver bile duct preparation to a temperature > or = 40 degrees C in an area at least 10 mm in depth. After placement of the applicator into the common bile duct of anesthetized sheep, endohyperthermia led to a consistent and repeatable heating of the surrounding tissue to 40.5 +/- 0.5 degrees C at 1 cm distance, and 39.9 +/- 0.7 degrees C at 2 cm distance. Blood pressure, heart rate, and systemic temperature did not change in vivo. Histological examination of the bile duct showed superficial mucosal necrosis (depth 100-200 microm), microvascular damage with petechiae, congestion and edema of the bile duct wall and adventitia after hyperthermia treatment in vivo. CONCLUSIONS: The intraluminal endohyperthermia system produces consistent and repeatable heating of the surrounding tissue. Since effective thermal power can reach a depth of up to 2 cm, tumors may also be heated adequately.

Animals↗
PubMed2000

Effect of formalin tissue fixation and processing on immunohistochemistry.

Although immunohistochemistry is routinely performed by many pathology laboratories, its standardization still lags behind. A major cause of variation in the reproducibility of immunohistochemical staining is induced by tissue fixation and, to a lesser degree, tissue processing. This report, stemming from the first meeting of the International Consensus Group on Standardization and Quality Control (ICGSQC) in Nice, France, summarizes the problem and suggests solutions to begin to achieve standardization of fixation and processing. Most laboratories use neutral-buffered formalin (10%) for tissue fixation which introduces cross-links, whereas coagulative fixatives are less popular. Problems with formalin fixation comprise delay of fixation and variations in the duration of the fixation mainly. Solutions to these problems could be to start fixation soon (<30 min) after surgical removal of the tissue and to avoid overfixation (>24-48 hrs). For tissue processing, the most important problem is inadequate tissue dehydration prior to paraffin embedding. This can be prevented by preparing all solutions freshly every week, depending on the volume of tissue processed. If consistently applied, these procedures could eliminate some of the sources of variation in immunohistochemical stains.

Artifacts↗
PubMed2000

A clinical pathway to accelerate recovery after colonic resection.

OBJECTIVE: To investigate the feasibility of a 48-hour postoperative stay program after colonic resection. SUMMARY BACKGROUND DATA: Postoperative hospital stay after colonic resection is usually 6 to 12 days, with a complication rate of 10% to 20%. Limiting factors for early recovery include stress-induced organ dysfunction, paralytic ileus, pain, and fatigue. It has been hypothesized that an accelerated multimodal rehabilitation program with optimal pain relief, stress reduction with regional anesthesia, early enteral nutrition, and early mobilization may enhance recovery and reduce the complication rate. METHODS: Sixty consecutive patients undergoing elective colonic resection were prospectively studied using a well-defined postoperative care program including continuous thoracic epidural analgesia and enforced early mobilization and enteral nutrition, and a planned 48-hour postoperative hospital stay. Postoperative follow-up was scheduled at 8 and 30 days. RESULTS: Median age was 74 years, with 20 patients in ASA group III-IV. Normal gastrointestinal function (defecation) occurred within 48 hours in 57 patients, and the median hospital stay was 2 days, with 32 patients staying 2 days after surgery. There were no cardiopulmonary complications. The readmission rate was 15%, including two patients with anastomotic dehiscence (one treated conservatively, one with colostomy); other readmissions required only short-term observation. CONCLUSION: A multimodal rehabilitation program may significantly reduce the postoperative hospital stay in high-risk patients undergoing colonic resection. Such a program may also reduce postoperative ileus and cardiopulmonary complications. These results may have important implications for the care of patients after colonic surgery and in the future assessment of open versus laparoscopic colonic resection.

Adult↗
PubMed2000

Adenocarcinoma of the esophagogastric junction: results of surgical therapy based on anatomical/topographic classification in 1,002 consecutive patients.

OBJECTIVE: To assess the outcome of surgical therapy based on a topographic/anatomical classification of adenocarcinoma of the esophagogastric junction. SUMMARY BACKGROUND DATA: Because of its borderline location between the stomach and esophagus, the choice of surgical strategy for patients with adenocarcinoma of the esophagogastric junction is controversial. METHODS: In a large single-center series of 1,002 consecutive patients with adenocarcinoma of the esophagogastric junction, the choice of surgical approach was based on the location of the tumor center or tumor mass. Treatment of choice was esophagectomy for type I tumors (adenocarcinoma of the distal esophagus) and extended gastrectomy for type II tumors (true carcinoma of the cardia) and type III tumors (subcardial gastric cancer infiltrating the distal esophagus). Demographic data, morphologic and histopathologic tumor characteristics, and long-term survival rates were compared among the three tumor types, focusing on the pattern of lymphatic spread, the outcome of surgery, and prognostic factors in patients with type II tumors. RESULTS: There were marked differences in sex distribution, associated intestinal metaplasia in the esophagus, tumor grading, tumor growth pattern, and stage distribution between the three tumor types. The postoperative death rate was higher after esophagectomy than extended total gastrectomy. On multivariate analysis, a complete tumor resection (R0 resection) and the lymph node status (pN0) were the dominating independent prognostic factors for the entire patient population and in the three tumor types, irrespective of the surgical approach. In patients with type II tumors, the pattern of lymphatic spread was primarily directed toward the paracardial, lesser curvature, and left gastric artery nodes; esophagectomy offered no survival benefit over extended gastrectomy in these patients. CONCLUSION: The classification of adenocarcinomas of the esophagogastric junction into type I, II, and III tumors shows marked differences between the tumor types and provides a useful tool for selecting the surgical approach. For patients with type II tumors, esophagectomy offers no advantage over extended gastrectomy if a complete tumor resection can be achieved.

Adenocarcinoma↗
PubMed2000

Limited resection for early adenocarcinoma in Barrett's esophagus.

OBJECTIVE: To assess the extent of disease in patients with pT1 esophageal adenocarcinoma and to evaluate the feasibility and outcomes of a limited surgical approach. SUMMARY BACKGROUND DATA: Radical esophagectomy with systematic lymphadenectomy is widely advocated as the treatment of choice in patients with early adenocarcinoma of the distal esophagus. This approach, however, is associated with substantial complications and long-term side effects. The extent of resection necessary to achieve cure in such patients is not clear. METHODS: Seventy-one patients with pT1 adenocarcinoma of the distal esophagus underwent transmediastinal or transthoracic esophagectomy with two-field lymphadenectomy. Twenty-four patients with uT1N0 tumors underwent a limited resection of the distal esophagus and esophagogastric junction, regional lymphadenectomy, and reconstruction by interposition of an isoperistaltic pedicled jejunal segment. The two groups were compared for extent and multicentricity of the primary tumor and associated high-grade dysplasia, pattern of lymph node metastases, complications, deaths, and outcome of surgical treatment. RESULTS: Multicentric tumor growth or associated high-grade dysplasia was observed in 60.6% of the resection specimens. Complete resection of the tumor and the entire segment with intestinal metaplasia was achieved in all patients, irrespective of the surgical approach. Patients undergoing limited resection had fewer complications. Lymph node metastases or micrometastases were present in none of the 38 patients with tumors limited to the mucosa (pT1a) versus 10 of the 56 (17.9%) patients with tumors invading the submucosa (pT1b). Distant lymph node metastases occurred only in patients with more than three positive regional lymph nodes. Lymph node metastases were prognostic, but the pT1a/pT1b category and the surgical approach were not. The mean Gastrointestinal Quality of Life Index after limited resection did not differ from that of healthy controls: 20 of the 24 patients were completely asymptomatic. CONCLUSIONS: In patients with early adenocarcinoma in the distal esophagus, resection of the distal esophagus and esophagogastric junction, with regional lymphadenectomy and jejunal interposition, is an attractive limited surgical alternative to radical esophagectomy.

Adenocarcinoma↗
PubMed2000

Accumulation of chromosomal imbalances from intraductal proliferative lesions to adjacent in situ and invasive ductal breast cancer.

Carcinoma of the breast is thought to evolve through a sequential progression from normal to proliferative epithelium and eventually into carcinoma. Here lumpectomy specimens from five patients were studied, selected for the presence of ductal hyperplasia without atypia, atypical ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. Laser microdissection of tissue allowed precise sampling and direct correlation of phenotypic and genotypic changes. Analyses of the samples revealed an increasing mean number of chromosomal changes occurring with increasing histologic severity, and for the first time chromosomal abnormalities were demonstrated in ductal hyperplasia without atypia. Chromosomal changes found in each of the four histologic entities included gains on 10q, 12q, 16p, and 20q and loss on 13q. In ductal hyperplasia without atypia, gain on 20q as well as loss on 13q was detected with high frequency (four of five samples). Alterations identified in more than 50% of atypical ductal hyperplasia samples included gains on 3p, 8q, 15q, and 22q and loss on 16q. In ductal carcinoma in situ, gain of DNA on 1q and 17q and loss on 4q were additionally found, and in invasive ductal carcinoma, further gains on 6p, 10q, 11q13, and 17p were identified. The chromosomal alterations occurring in the different histopathologic lesions strongly suggest that these regions harbor tumor suppressor genes or oncogenes significant for the development of ductal carcinoma of the breast.

Breast↗
PubMed2000

Massive chemokine transcription in acute renal failure due to polymicrobial sepsis.

Abdominal sepsis and septic shock are still major causes of mortality in intensive care units (ICU). Acute renal failure (ARF) is one of the hallmarks encountered in septic shock. The pathophysiological alterations leading to ARF are poorly understood. A novel murine model of polymicrobial sepsis (colon ascendens stent peritonitis [CASP]) was used to investigate functional renal parameters, renal chemokine transcription levels, and recruitment of inflammatory leukocytes in septic ARF. CASP was induced by inserting a 14-gauge stent into the colon ascendens of C57BL/6 mice, generating a septic focus resulting in polymicrobial sepsis. Mice were monitored for urine output and serum azotemia. Kidneys were harvested for analysis of leukocyte infiltration by immunohistochemistry and chemokine gene expression by RNase protection assay (3, 6, 12, and 18 h). CASP, but not sham-CASP, resulted in anuria immediately after surgery and in elevated serum creatinine and BUN detected 18 h after CASP surgery, confirming acute renal failure. Progressive induction of chemokine gene expression was observed for IP-10, MIP-2, MIP-1alpha, MIP-1beta, MCP-1, and RANTES peaking at 12 h with subsequent decrease. Immunohistochemistry revealed an accumulation of neutrophils and monocytes which had adhered to the renal vascular endothelium. Thus, acute renal failure in sepsis is accompanied by a marked upregulation of chemokines of the CC and CXC group within the kidney.

Acute Kidney Injury↗
PubMed2000

Heterogeneous chromosomal aberrations in intraductal breast lesions adjacent to invasive carcinoma.

There is evidence that breast cancer is a heterogeneous disease phenotypically as well as molecular biologically. So far, heterogeneity on the molecular biological level has not been investigated in potential precursor lesions, such as ductal hyperplasia (DH) and ductal carcinoma in situ (DCIS). In this study we applied comparative genomic hybridization (CGH) to formalin-fixed, paraffin-embedded breast tissue with DH and DCIS, adjacent to invasive ductal carcinoma (IDC), to screen these potential precursor lesions for whole genomic chromosomal imbalances. Laser-microdissection was used to select pure cell populations from the sections. Isolated DNA was amplified by degenerate oligonucleotide primed PCR (DOP-PCR) and further processed for CGH analysis. Investigating multiple samples (n = 25) from four patients we found an average of 5.6 +/- 0.9 (mean +/- SEM) chromosomal imbalances already present in DH. In the twelve DCIS lesions an average of 10.8 (+/- 0.9) aberrations was identified with 14.8 (+/- 0.8) aberrations in the four adjacent IDC lesions. The increasing number of chromosomal changes in parallel with the histopathological sequence corroborate the hypothesis, that the carcinomas may have developed through a sequential progression from normal to proliferative epithelium and eventually into carcinoma. However, heterogeneous results were identified in the multiple samples per entity from the same patient, demonstrated mainly in the DCIS samples in the chromosomal regions 6p, 9p, 11q, 16p and 17q, in the DH samples by 3p, 16p and 17q. This heterogeneous findings were most pronounced within the DH and was less in the DCIS and IDC samples. The only aberration consistently found in all samples-even in all DH sample-was amplification of the 20q13 region. Our results demonstrate, that the applied combination of laser-microdissection, DOP-PCR and CGH, may serve to analyse breast carcinogenesis pathways in suitable histological material. However, so far, it is unclear how to handle heterogeneous results and these make identification of relevant changes more difficult. Setting a threshold and evaluating only those chromosomal changes which are present in a majority of samples may be one possibility. This involves however, the risk that infrequent but possibly significant aberrations may be missed. Figures on http://www.esacp.org/acp/2000/20-1/aubele. htm.

Breast Neoplasms↗
PubMed2000

Evaluation of c-erbB-2 overexpression and Her-2/neu gene copy number heterogeneity in Barrett's adenocarcinoma.

Amplification of the Her-2/neu gene is accompanied by overexpression of its cell surface receptor product, c-erbB-2 protein. To investigate the degree of intratumoural heterogeneity we applied immunohistochemistry in primary Barrett's adenocarcinoma (BCA) (n = 6) and dysplasia adjacent to the carcinoma (n = 4). In addition, fluorescence in situ hybridisation (FISH) was performed in primary BCA (n = 5) and dysplastic areas (n = 4). For an objective evaluation digital image analysis and laser scanning microscopy were used. Five of six BCA showed a marked intratumoral heterogeneous staining pattern ranging from areas in which the tumour cells were negative or faintly positive to tumour areas with a strong staining of the entire membrane. Among the two dysplastic areas also a heterogeneous staining pattern was observed. FISH analysis revealed marked heterogeneity of intratumoral gene copy number changes in all BCA showing populations with different fractions of cells with polysomy, low level amplification and high level amplification. One dysplasia showed a minor population with Her-2/neu signal clusters. In conclusion, we observed marked intratumoural heterogeneity of c-erbB-2 protein overexpression and Her-2/neu gene copy number in the majority of the primary BCA analyzed. Digital image analysis and laser scanning microscopy were helpful in quantifying the variations in protein expression and DNA copy number in individual tumour cells. The observed heterogeneity could hamper the exact diagnostic determination of the c-erbB-2 status in small biopsies and possibly influence the effectiveness of a potential c-erbB-2 targeting therapy. Figures on http://www.esacp.org/acp/2000/20-1/walch.htm+ ++.

Adenocarcinoma↗
PubMed2000

Positron emission tomography using [(18)F]Fluorodeoxyglucose for monitoring primary chemotherapy in breast cancer.

PURPOSE: To address the role of positron emission tomography (PET) using [(18)F]fluorodeoxyglucose (FDG) to monitor primary (neoadjuvant) chemotherapy in patients with locally advanced breast cancer. PATIENTS AND METHODS: Quantification of regional FDG uptake of the breast acquired after the first and second courses of chemotherapy was compared with the baseline scan in 22 patients with a total of 24 breast carcinomas. To evaluate the predictive value of PET imaging, histopathologic response after completion of chemotherapy classified as gross residual disease (GRD) or minimal residual disease (MRD) served as the gold standard. RESULTS: Significant differences in tracer uptake between nonresponding tumors (GRD) and responding lesions (MRD) were observed (P <.05) as early as after the first course of chemotherapy. Tracer uptake showed little change in tumors with GRD found later in pathologic analysis but decreased sharply to the background level in most tumors with MRD. After the first course, all responders were correctly identified (sensitivity 100%, specificity 85%) by a standardized uptake value decrease below 55% of the baseline scan. At this threshold, histopathologic response could be predicted with an accuracy of 88% and 91% after the first and second courses of therapy, respectively. CONCLUSION: This study demonstrates that in patients with advanced breast cancer undergoing primary chemotherapy, FDG-PET differentiates responders from nonresponders early in the course of therapy. This may help improve patient management by avoiding ineffective chemotherapy and supporting the decision to continue dose-intensive preoperative chemotherapy in responding patients.

Adult↗