[Periodic fever and pancytopenia in a 35-year-old patient]. / Periodisches Fieber und Panzytopenie bei einem 35­jährigen Patienten.

MEDICAL HISTORY AND INITIAL PRESENTATION: A 35-year-old patient with a previous history of persistent episodic fever, sore throat, myalgia, and cephalgia presented for evaluation of pancytopenia. He had no recent travel history, except for a stay in Italy 1 year prior to admission and in Spain several years in the past. DIAGNOSTIC WORKUP: Laboratory evaluation confirmed pancytopenia, agranulocytosis, and elevated infection parameters without indicative serological results en par with lymphadenitis colli. Computed tomography scanning revealed cervical lymphadenopathy, hepatosplenomegaly, and colitis with occult perforation of the sigmoid colon. Bone marrow biopsy showed an infiltration of polyclonal plasma cells. Lymph node biopsy was compatible with necrotizing lymphadenitis. DIAGNOSIS: Polymerase chain reaction analysis of a lymph node specimen confirmed the presence of Leishmania species, thereby enabling the diagnosis of visceral Leishmania. THERAPY COURSE: Treatment with liposomal amphotericin B was initiated. Both fever and lymphadenopathy quickly resolved. CONCLUSION: VL is a clinically pleiotropic, severe disease with fatal outcome if left untreated. It often presents with distinct similarities to hematologic malignancies. Exacerbation can occasionally occur as fulminant macrophage activation syndrome. Disease incidence is globally increasing and has not peaked as yet. A complex interplay between pathogen and the immune system is the key pathophysiological mechanism.

Randomized comparison of prophylactic and minimal residual disease-triggered imatinib after allogeneic stem cell transplantation for BCR-ABL1-positive acute lymphoblastic leukemia.

Minimal residual disease (MRD) after allogeneic stem cell transplantation (SCT) for Ph+ acute lymphoblastic leukemia (ALL) is predictive of relapse. Imatinib administration subsequent to SCT may prevent relapse, but the role of scheduling and its impact on outcome are not known. In a prospective, randomized multicenter trial, we compared the tolerability and efficacy of post-transplant imatinib administered either prophylactically (arm A; n=26) or following detection of MRD (arm B; n=29). Prophylactic imatinib significantly reduced the incidence of molecular recurrence after SCT compared with MRD-triggered imatinib (40% vs 69%; P=0.046). Median duration of PCR negativity was 26.5 and 6.8 months, respectively (P=0.065). Five-year survival in both interventional groups was high (80 and 74.5%), despite premature discontinuation of imatinib in the majority of patients because of poor tolerability. Relapse probability was significantly higher in patients who became MRD positive (P=0.017). In conclusion, post-transplant imatinib results in a low relapse rate, durable remissions and excellent long-term outcome in patients with BCR-ABL1-positive ALL irrespective of whether it is given prophylactically or MRD-triggered. Reappearance of BCR-ABL1 transcripts early after SCT or at higher levels identifies a small subset of patients who do not benefit sufficiently from imatinib, and in whom alternative approaches should be explored.

Analysis of the B cell repertoire against autoantigens in patients with giant cell arteritis and polymyalgia rheumatica.

The analysis of the antibody repertoire of patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) might identify target antigens of the autoimmune response with potential relevance to our understanding of the pathogenesis of the disease and to the development of serodiagnostic tests. To detect such antigens, we screened a cDNA library derived from normal human testis for antigens reacting with IgG antibodies in the 1 : 250 diluted sera of three patients with untreated GCA using SEREX, the serological identification of antigens by recombinant cDNA expression cloning. Of 100 000 clones screened with each serum, six, 28 and six clones, respectively, were positive, representing a total of 33 different antigens. Most of the antigens reacted only with the serum used for identification and/or at a similar frequency with normal control sera. However, lamin C and the nuclear antigen of 14 kD reacted specifically with 32% of GCA/PMR, but with none of the control sera, while human cytokeratin 15, mitochondrial cytochrome oxidase subunit II, and a new gene product were detected preferentially, but not exclusively by sera from GCA/PMR patients. We conclude that patients with GCA/PMR develop antibodies against a broad spectrum of human autoantigens. Antibodies against human lamin C, the nuclear autoantigen of 14 kD as well as human cytokeratin 15, mitochondrial cytochrome oxidase subunit II and the product of a new gene should be investigated further to determine their value as tools for the diagnosis and/or the definition of clinical subgroups of patients with GCA/PMR.

Clinical approaches to vaccination in oncology.

Immunotherapy of cancer is still in the early stages of development although almost a century has passed since initial attempts were made to stimulate the immune system in order to destroy malignant cells. Historically, a variety of specific and non-specific immunostimulatory strategies have been administered with only modest clinical success. However, recent advances in tumour immunology, most notably the identification of new tumour antigens and the better understanding of antigen processing and presentation to avoid or break immune tolerance, have paved the way for the development of a variety of novel and specific vaccine approaches. The most important and widely used are whole-cell vaccines, dendritic-cell-based immunotherapy and peptide vaccines. The first wave of clinical trials has revealed that, in general, such vaccination strategies are safe. However, clear examples of clinical responses, especially in conjunction with vaccine-induced immune responses, are still rare. Most clinical trials are too small to allow for comments on the efficacy, and the cohort of patients studied is too heterogeneous with regard to immune status. Therefore, standardised techniques for the accurate assessment of the individual immune phenotype before and during the trial are needed to allow for the identification of the sub-group of patients who will respond favourably to treatment. The precise definition of immune parameters in these patients will then lead the way for optimised treatment procedures that might even be beneficial for a larger group of cancer patients.

Systematic search and molecular characterization of the antigenic targets of myeloma immunoglobulins: a monoclonal IgA from a female patient targeting sperm-specific cylicin II.

The identification of the antigenic stimuli of B-cell neoplasms might be of considerable importance since a causal relationship between these neoplasms and antigenic stimulation has been suggested. To date the identification of such antigens has been erratic and accidental. For a systematic search and molecular characterization of human proteins that are antigenic target structures of myeloma-associated immunoglobulins, we applied SEREX (serological analysis of antigens by recombinant cDNA expression cloning) using a testis cDNA expression library and myeloma proteins from 42 patients. A monoclonal IgA from a female patient was shown to target sperm-specific cylicin II. The specificity of the reaction was confirmed by the characteristic staining of the equatorial belt of human sperm heads by the patient's myeloma protein. Serological analysis of recombinantly expressed cDNAs is a straightforward and high throughput approach for the molecular characterization of the targets of myeloma-associated immunoglobulins. The analysis of the antigenic spectrum of immunoglobulins associated with B-cell neoplasms will provide valuable information for the understanding of the pathogenesis of these diseases.

Gene-modified spontaneous Epstein-Barr virus-transformed lymphoblastoid cell lines as autologous cancer vaccines: mutated p21 ras oncogene as a model.

The transfer of genes coding for tumor antigens (Ags) into Ag-presenting cells is a promising strategy to develop cancer vaccines for patients not limited by major histocompatibility complex restriction. To test whether autologous lymphoblastoid cell lines (LCL) can be used as an alternative to dendritic cells for Ag presentation, we established LCL by spontaneous growth in cyclosporin-containing medium in vitro (SP-LCL). SP-LCL, which have an advantage over B95-8-transfected LCL in that they carry no risk of introducing a new infectious agent when used for vaccination, served as a permanent source for transfection with an episomal Epstein-Barr virus-based expression vector encoding the Ki-ras p21 oncogene carrying a point mutation at codon 12 (muRas) as a model tumor Ag. The ability of muRas-transfected SP-LCL (muRas-LCL) to induce immunoreactivity was determined in vitro. After electroporation with an optimized protocol, muRas-LCL expressed mutated ras peptides for a considerable period of time (at least 8 weeks) on the cell surface. The transfection procedure did not affect the expression of the costimulatory molecules B7.1, intercellular adhesion molecule-1, and leukocyte function associated Ag-3 by SP-LCL. muRas-LCL were able to induce muRas-specific cytotoxic T lymphocytes from three of three healthy donors and one of one patient with pancreatic carcinoma. Our results suggest that the gene transfer of muRas sequences to SP-LCL leads to an endogenous processing of this Ag in the major histocompatibility complex class I pathway and to functional presentation of antigenic peptides to CD8+ T lymphocytes. Autologous SP-LCL can serve as an unlimited renewable source for autologous cellular vaccines and appear to be good candidates as presenters for a wide range of human tumor Ags.

[Isolated tumor cells in bone marrow predicts reduced survival in lymph node-negative non-small-cell lung cancer]. / Isolierte Tumorzellen im Knochenmark sagen ein verkürztes Uberleben bei lymphknotennegativem nicht-kleinzelligen Bronchialkarzinom vorher.

BACKGROUND: It became recently evident that isolated tumor cells undetectable by conventional tumor staging are frequently present in bone marrow of patients with apparently localized non-small cell lung cancer (NSCLC). The clinical relevance of this minimal hematogenous tumor cell dissemination is under vigorous debate. METHODS: For tumor cell detection in the bone marrow we used monoclonal antibody CK2 against the epithelial intermediate filament protein cytokeratin 18. The influence of a positive bone marrow finding on clinical outcome was studied in 139 patients with NSCLC postoperatively staged as pT1-4, pN0-2, M0, R0 after a median follow up of 66 months (48-74). FINDINGS: Cytokeratin-18-positive cells in bone marrow were demonstrated in 83 (59.7%) patients at the time of primary surgery and in 6 of 12 representative patients analyzed twice 3-18 months after surgery. In patients without histopathological lymph node metastases (pN0; n = 66) the occurrence of > or = 2 tumor cells in bone marrow at primary surgery was a strong and independent predictor for overall survival (p = 0.007) in univariate analysis. The multivariate analysis showed a 2.8 times increased risk for shorter survival in patients with disseminated tumor cells versus patients without such cells. Four of the six patients with a positive CK status after surgery developed a tumor recurrence 11-44 months after the operation, while in none of the patients with a negative bone marrow at all times intervals showed a tumor relapse. CONCLUSIONS: Minimal residual bone marrow involvement is an independent prognostic factor for overall survival in patients with node-negative NSCLC, which may help to identify patients in need of an adjuvant systemic therapy. The postoperative persistence or re-appearance of tumor cells in bone marrow indicates that these are not only shredded cells but rather represent true micrometastasis.

Myasthenia gravis: selective enrichment of antiacetylcholine receptor antibody production in untransformed human B cell cultures.

B cells producing antibodies against the acetylcholine receptor (AchR) play a central role in the pathogenesis of myasthenia gravis (MG). Although anti-AchR autoantibodies have been studied extensively, not much is known about autoimmune B cells and their antigen-driven activation. This has mainly been due to difficulties in establishing and maintaining untransformed antigen-specific B cells in vitro. In this study, we show that highly enriched B cells from peripheral blood and thymus of MG patients can be maintained in culture over a period of 4 weeks when grown on the AchR-expressing rhabdomyosarcoma cell line TE671 together with an anti-CD40 stimulus and lymphokines. Anti-AchR antibody secretion could be detected in the majority of B cell cultures on TE671 cells up to 4 weeks. In contrast, B cells cultured on CDw32-transfected L cells binding anti-CD40 antibodies (the CD40 system) produced only small amounts of anti-AchR antibodies at single time points, whereas the overall IgG production was higher than on TE671 cells. The expression of the relevant autoantigen on the adherent cell line in addition to other growth stimuli could account for this difference and may provide a useful tool for investigating antigen-dependent B cell activation in MG and other B cell-mediated autoimmune conditions.

Disseminated tumor cells in lymph nodes as a determinant for survival in surgically resected non-small-cell lung cancer.

PURPOSE: In recent years, the detection of even a few tumor cells in lymph nodes of patients with surgically resected non-small-cell lung cancer (NSCLC) became possible with immunohistochemical staining procedures. Tumor cells in lymph nodes have been shown to be associated with an increased rate of early recurrence. However, the prognostic significance of this minimal tumor cell spread for overall survival remains unclear. PATIENTS AND METHODS: We used the epithelium-specific monoclonal antibody Ber-EP4, which recognizes the 17-1A antigen (also called EGP40 or Ep-CAM), to discover small tumor cell deposits (< or = three cells) in 565 regional lymph nodes judged as tumor-free by conventional histopathology in patients with NSCLC staged as pT1-4, pN0-2, M0, R0. In a prospective analysis, we studied the influence of the detected tumor cells on the cancer recurrence rate and survival of 117 patients. RESULTS: Ber-EP4-positive cells were found in 27 of 125 patients (21.6%). After an observation period of 64 months, patients with disseminated tumor cells had reduced disease-free survival (P < .0001) and overall survival (P = .0001) rates in univariate analyses (logrank test). Multivariate analysis (Cox model) showed a 2.7 times increased risk for tumor relapse and a 2.5 times increased risk for shorter survival in patients with disseminated tumor cells compared with patients without such cells. Patients without any evidence of histopathologic and immunohistochemical lymph node involvement had an overall survival rate of 78%. CONCLUSION: The immunohistochemical detection of disseminated tumor cells in lymph nodes of patients with completely resected NSCLC is an independent prognostic factor for overall survival.

Isolated tumor cells in bone marrow predict reduced survival in node-negative non-small cell lung cancer.

BACKGROUND: It recently became evident that isolated tumor cells undetectable by conventional tumor staging are frequently present in bone marrow of patients with apparently localized non-small cell lung cancer (NSCLC). The clinical relevance of this minimal hematogenous tumor cell dissemination is under vigorous debate. METHODS: For tumor cell detection in the bone marrow, we used monoclonal antibody CK2 against the epithelial intermediate filament protein cytokeratin 18. The influence of a positive bone marrow finding on clinical outcome was studied in 139 patients with NSCLC postoperatively staged as pT1-4, pN0-2, M0, and R0 after a median follow-up of 66 months (range 48 to 74 months). RESULTS: Cytokeratin-18-positive cells in bone marrow were demonstrated in 83 (59.7%) patients at the time of primary surgery and in 6 of 12 representative patients analyzed twice 3 to 18 months after surgery. In patients without histopathological lymph node metastases (pN0; n = 66), the occurrence of 2 or more tumor cells in bone marrow at primary surgery was a strong and independent predictor for overall survival (p = 0.007) in univariate analysis. The multivariate analysis showed a 2.8 times increased risk for shorter survival in patients with disseminated tumor cells versus patients without such cells. Four of the 6 patients with a positive cytokeratin status after surgery developed a tumor recurrence 11 to 44 months after the operation, while none of the patients with a negative bone marrow at all time intervals showed a tumor relapse. CONCLUSIONS: Minimal residual bone marrow involvement is an independent prognostic factor for overall survival in patients with node-negative NSCLC, which may help to identify patients in need of an adjuvant systemic therapy. The postoperative persistence or reappearance of tumor cells in bone marrow indicates that these are not only shed cells but rather represent true micrometastasis.

Serum levels of macrophage-derived protein MRP-8/14 are elevated in active multiple sclerosis.

Serum concentrations of two macrophage-derived calcium-binding proteins, MRP-8 and MRP-8/14, were studied in 28 patients with relapsing multiple sclerosis (MS). Serum levels were determined with a commercially available sandwich ELISA and the one-tailed Mann-Whitney U test was used for statistical analysis. Median serum levels of MRP-8/14 were significantly higher in MS patients (5150 ng/ml) compared to 26 healthy controls (1482 ng/ml) and significantly higher in MS patients within an acute relapse (6690 ng/ml) compared to MS patients with stable disease (3050 ng/ml). MRP-8 levels were not elevated in MS patients. These results may indicate an early activation of macrophages in the formation of demyelinating MS plaques. In addition, increased serum levels of MRP-8/14 may prove to be a useful paraclinical disease activity parameter in MS patients.

Synergistic immunomodulatory effects of interferon-beta1b and the phosphodiesterase inhibitor pentoxifylline in patients with relapsing-remitting multiple sclerosis.

Subcutaneous application of interferon-beta1b (IFN-beta1b) is an established therapy for patients with relapsing-remitting multiple sclerosis (RRMS), but early side effects are still a major concern. In vitro studies with myelin basic protein (MBP)-specific T-cell lines revealed a synergistic suppressive effect of IFN-beta1b and the phosphodiesterase inhibitor pentoxifylline (PTX) on proliferation and the production of tumor necrosis factor-alpha (TNF-alpha), lymphotoxin (LT), and interferon-gamma (IFN-gamma). In an initial, open labeled prospective trial, the cytokine messenger RNA (mRNA) expression of blood mononuclear cells from MS patients, receiving either IFN-beta1b alone or in combination with oral PTX, was determined by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Patients treated with IFN-beta1b alone reported more side effects during the first 3 months of treatment and had upregulated TNF-alpha as well as IFN-gamma mRNA expression during the first month, which was not detected in patients receiving both drugs. A synergistic effect of both drugs was observed on the upregulation of interleukin (IL)-10 mRNA, which was accompanied by an increase in IL-10 serum levels. Both in vitro and in vivo data suggest that co-treatment of IFN-beta1b with PTX is a promising approach to correct the disturbed cytokine balance in MS patients.

[Simultaneous immunocytochemical detection of tumor cells in lymph nodes and in bone marrow of patients with resectable bronchial carcinomas]. / Simultaner immunzytochemischer Nachweis von Tumorzellen in Lymphknoten und im Knochenmark von Patienten mit resektablen Bronchialkarzinomen.

Despite an apparently curative resection more than 50% of patients with non-small cell carcinomas (NSCLC) will relapse after surgery. Therefore, it has to be assumed that in a substantial number of patients a tumor cell dissemination has occurred already at the time of surgery. In a prospective study we analyzed the extend of an early regional tumor cell dissemination into lymph nodes and/or a systemic tumor cell dissemination into the bone marrow in 91 patients with completely resected NSCLC by using sensitive immunocytochemical techniques. A tumor cell dissemination limited to the regional lymph nodes was detected in 14 (15.4%) patients. A systemic dissemination of tumor cells into the bone marrow alone in 10 (11.1%) patients. In 6 patients (6.6%) both body compartments were involved by immunocytochemistry. The detection of a nodal and a systemic tumor cell dissemination was associated with a significantly shortened disease free survival (p = 0.002 and p = 0.05, respectively). A Cox regression analysis demonstrated that the detection of tumor cells by immunocytochemistry is an independent prognostic factor (p = 0.018). In conclusion the detection of disseminated tumor cells by immunocytochemistry is an useful prognostic parameter, which underlines the requirement of a multimodal therapeutic strategy in these patients.

Expression of MHC molecules and ICAM-1 on non-small cell lung carcinomas: association with early lymphatic spread of tumour cells.

Early microdissemination of tumour cells determines the prognosis of patients with apparently localised non-small cell lung cancer (NSCLC). Monoclonal antibodies to epithelial antigens can now be used to detect single carcinoma cells present in mesenchymal secondary organs such as bone marrow or lymph nodes. The present study was designed to obtain insights into the potential role of the immune system in lymphatic and haematogenous microdissemination of NSCLC cells. Using immunohistochemical staining of primary NSCLC, we assessed the expression pattern of molecules mediating an efficient cellular immune response, that is, MHC class I and class II antigens and the intercellular adhesion molecule-1 (ICAM-1). All 58 patients evaluated were staged as free of overt metastases by conventional clinico-pathological screening. Isolated tumour cells in bone marrow or lymph nodes were identified with mAb CK2 to cytokeratin component No. 18 and mAb BerEp-4 to glycoproteins of 34 and 39 kd present on epithelial cells, respectively. MHC class I expression on primary tumours was reduced or absent in 6/10 (60.0%) patients with isolated cancer cells in lymph nodes as compared to 6/33 tumours (18.1%) without such tumour cell dissemination (P = 0.01). MHC class II molecules on primary tumours were detected in 1/10 (10.0%) patients with micrometastases to regional lymph nodes and in 10/33 (30.3%) patients without such a tumour cell spread. None of the 10 patients with nodal microdissemination expressed ICAM-1 on their primary NSCLC, while such expression was detectable in 12/33 (36.4%) patients without this dissemination (P = 0.01). In contrast, the detection of tumour cells in bone marrow was not correlated to the expression of any of these immunoregulatory molecules. Our data suggest that escape caused by deficient expression of MHC class I antigens and ICAM-1 on tumour cells may support homing or survival of disseminated tumour cells in lymphoid tissue.

Detection of disseminated lung cancer cells in lymph nodes: impact on staging and prognosis.

BACKGROUND: A major reason for the high incidence of tumor recurrences in patients with apparently resectable non-small cell lung cancer is presumably early tumor cell dissemination, which is clearly underestimated by current staging procedures. METHODS: In this prospective study we assessed the frequency and prognostic significance of early lymphatic tumor cell spread to regional lymph nodes staged as tumor free by conventional histopathology by applying an immunohistochemical assay using monoclonal antibody Ber-Ep4. RESULTS: Ber-Ep4 positive cells were demonstrated in 27 (21.6%) of 125 patients and in 35 (6.2%) of 565 lymph nodes, respectively. Immunohistochemical analysis resulted in an up-staging in 24 of 27 patients. In patients previously staged as having pN0 disease, tumor cells were detected in 11/70 cases (15.7%). Univariate and multivariate survival analysis showed that the detection of minimal nodal tumor cell dissemination was associated with a reduced disease-free survival (log rank test, p = 0.0001; Cox regression model, p = 0.001). CONCLUSIONS: The use of immunohistochemistry enables one to identify many patients with regional tumor cell dissemination at the time of operation. These patients might benefit from an adjuvant therapeutic regimen.

[The significance of regional lymphatic tumor cell dissemination in patients with resectable non-small cell bronchial carcinoma. Results of a prospective study]. / Bedeutung der regionalen lymphatischen Tumorzelldisseminierung bei Patienten mit resektablem nicht-kleinzelligem Bronchialcarcinom. Ergebnisse einer prospektiven Studie.

Encountering the high incidence of tumor recurrences in patients with apparently resectable non-small cell lung cancer it has to be assumed that in many patients already at the time of surgery a tumor cell dissemination has occurred, which is underestimated by current staging procedures. We therefore conducted a prospective study to assess the frequency and prognostic significance of a nodal tumor cell dissemination by using an immunohistochemical assay. Disseminated epithelial cells were demonstrated in 35 (6.2%) out of 565 lymph nodes staged as tumor free by conventional histopathology and in 27 (21.6%) out of 125 patients, respectively. In pN0 patients disseminated tumor cells were detected in 11/70 (15.7%) cases. In patients staged as pN1 and pN2 by conventional histopathology a tumor cell dissemination to additional lymph nodes was demonstrated by immunohistochemistry in 4/25 (16.0%) and in 12/30 (40.0%) patients, respectively (p = 0.019). Independent from tumor staging univariate survival analysis showed that the detection of a nodal tumor cell dissemination was associated with a reduced disease-free survival (p < 0.001). Multivariate analysis demonstrated that the detection of such cells is an independent prognostic parameter (p = 0.005). In conclusion, the use of immunohistochemistry enables to identify many patients with a widespread regional tumor cell dissemination at the time of surgery. This finding could represent a new criterion for an adjuvant therapeutic regime.

Immunohistochemical assessment of individual tumor cells in lymph nodes of patients with non-small-cell lung cancer.

PURPOSE: This prospective study was designed to evaluate the prognostic relevance and biologic characteristics of a minimal lymphatic tumor load in non-small-cell lung cancer (NSCLC). METHODS: Frozen-tissue sections from 391 regional lymph nodes of 72 patients with completely resected NSCLCs, who were staged as free of metastases (pT1-3, pN0,M0,R0) by clinical tumor staging procedures and histopathologic examinations, were studied. For tumor-cell detection, we applied the alkaline phosphatase-antialkaline phosphatase (APAAP) immunostaining technique with monoclonal antibody Ber-Ep4 against two glycoproteins of 34 and 49 kd present of the surface and cytoplasm of epithelial cells. RESULTS: Individual Ber-Ep4-positive cells were detected in 11 of 72 (15.2%) cancer patients, while positive staining was consistently absent in all sections from control nodes of 24 noncarcinoma patients. No correlation between a positive lymph node finding and either the size or differentiation grade of the primary tumor or the presence of micrometastatic tumor cells in bone marrow assessed by immunocytochemistry with antikeratin monoclonal antibody CK2 was observed. Following a median observation time of 26.0 months (range, 15 to 39), patients with lymph node micrometastases showed a significantly shorter disease-free survival duration than node-negative patients (log-rank test, P = .005). The independence of this prognostic significance was demonstrated by a multivariate analysis (Cox regression model, P = .005). CONCLUSION: Our results provide evidence that the presence of single lung carcinoma cells in lymph nodes is an independent indicator of the disseminatory capacity of an individual primary tumor. Immunohistochemical assessment of micrometastases in lymph nodes is recommended for current tumor staging in NSCLC, as it might lead to better stratification of patients for adjuvant therapy.

Radical systematic mediastinal lymphadenectomy in non-small cell lung cancer: a randomized controlled trial.

The value of radical systematic lymphadenectomy in the treatment of bronchial carcinoma is controversial. In a randomized controlled clinical trial, radical lymphadenectomy was compared with conventional node dissection in 182 patients with non-small cell lung cancer. Comparison of short-term results revealed a significantly longer operating time in those undergoing systematic lymphadenectomy, but overall morbidity and mortality rates were comparable between groups. However, there were complications associated with radical lymphadenectomy such as prolonged air leakage and haemorrhage. Interim analysis of results at a median follow-up of 26.8 months showed no significant influence of radical lymphadenectomy on local recurrence-free interval, metastasis-free interval or cancer-related survival. In conclusion, radical systematic lymphadenectomy is a safe operation that leads to a better staging of non-small cell lung cancer, but its prognostic benefit is questionable.

Expression of major histocompatibility class I and class II antigens and intercellular adhesion molecule-1 on operable non-small cell lung carcinomas: frequency and prognostic significance.

Major histocompatibility complex (MHC) antigens and adhesion molecules, such as the intercellular adhesion molecule-1 (ICAM-1), appear to play an important role in the immunological recognition and destruction of tumour cells. We, therefore, examined the expression patterns of these proteins on primary tumours of 91 patients with operable non-small cell lung cancer (NSCLC). Applying immunohistochemistry with monoclonal antibody (MAb) W6/32 against a common framework determinant of HLA class I antigens revealed a deficient expression in 33.0% of the cases analysed, while neo-expression of either HLA class II antigens (MAb TAL.1B5) or ICAM-1 (MAb PA3.58-14) was observed in 26.4 or 29.7% of tumours, respectively. Analysis of consecutive tumour specimens indicated that HLA antigens and ICAM-1 were frequently coexpressed. With regard to clinicopathological risk factors, we could demonstrate a preferential expression of those markers in patients with locally restricted and well-differentiated tumours or no lymph node metastases, which was more pronounced in adenocarcinomas than in squamous cell carcinomas. In contrast, the presence versus the absence of HLA antigens and ICAM-1 was not correlated with the rate of tumour recurrence or overall survival in patients with NSCLC. In conclusion, the co-ordinated expression of immunologically relevant cell surface molecules on primary NSCLC is a frequent event that correlates with distinct parameters of favourable prognosis. However, we have no evidence that the immune response facilitated by these molecules can effectively influence the clinical course of the disease.