Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV.

Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874.

Single-center management of 136 patients with cancer of unknown primary site (CUP syndrome) over a period of 10 years.

BACKGROUND: Cancer of unknown primary site (CUP syndrome) is a particular challenge in oncology which occurs in about 5-10% of cancer patients. Here, we investigated clinicopathological and prognostic factors in patients with CUP syndrome in a retrospective analysis. PATIENTS AND METHODS: 136 patients with CUP syndrome who were treated in our Department of Oncology and Hematology were analyzed over a period of 10 years. Clinical and histopathological characteristics, response to chemotherapy, survival and prognostic factors were investigated in a retrospective analysis. RESULTS: 83 of the patients (61%) received first-line chemotherapy, which induced an overall response rate of 19%. Altogether 37 different chemotherapy regimens were used. Median overall survival of all patients was 7.9 months. In multivariate Cox regression analysis, gender, Karnofsky performance status, treatment modality and extent of disease were identified as independent prognostic factors. CONCLUSIONS: Our analysis showed a poor prognosis for patients with CUP syndrome. The response rate to chemotherapy was low with no significant benefit for any of the investigated cytotoxic agents. Newer diagnostic and therapeutical approaches might contribute to an improvement of prognosis, and their value is currently investigated in prospective studies.

The local cytokine and chemokine milieu within malignant effusions.

BACKGROUND/AIMS: Malignant effusions offer a unique opportunity for the study of interactions between the human immune system and cancer. We have recently demonstrated that malignant effusions are characterized by an accumulation of T cells expressing chemokine receptors such as CCR4, which is commonly found on Th2 cells. In contrast, effector T cells expressing chemokine receptors typical for Th1 cells, such as CCR5, showed a diminished homing into malignant effusions. METHODS: We analyzed concentrations of 12 different cytokines and 9 chemokines within malignant and nonmalignant effusions and investigated cytokine expression by effusion-infiltrating leukocytes. RESULTS: We observed that concentrations of the immunoregulatory cytokine TGF-beta(1) and of angiogenic factors VEGF and IL-8 were markedly increased within effusions caused by malignancies. However, we did not observe signs of a typical Th1 or Th2 milieu. Analyzing concentrations of 9 different chemokines, we found elevated concentrations of the chemokines MDC, eotaxin, I-TAC, and MCP-1 in malignant effusions. Interestingly, tumor-infiltrating leukocytes themselves seemed to contribute strongly to the creation of a distinct cytokine/chemokine pattern within cancer-related effusions. Additional analyses suggested that this cytokine/chemokine milieu might support an enrichment of immunosuppressive leukocytes. CONCLUSION: The local cytokine and chemokine milieu within malignant effusions seems to promote angiogenesis and to block an efficient immune-mediated antitumor response. An elimination of such tumor-promoting influences will be necessary in order to transform local immunotolerance into clinically relevant immune recognition of tumors causing malignant effusions.

A pilot study of docetaxel and trofosfamide as second-line 'metronomic' chemotherapy in the treatment of metastatic non-small cell lung cancer (NSCLC).

BACKGROUND: The aim of this pilot study was to evaluate the efficacy and safety of a chemotherapy containing docetaxel and oral trofosfamide as a 'metronomic' secondline treatment of patients with metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: 21 patients with stage IV disease NSCLC who had progressed under first-line chemotherapy were enrolled. Previous chemotherapy was platinum-based in 15 patients (71.4%), whereas 6 patients (28.6%) had received platinum-free combination chemotherapy. Patients received docetaxel 25 mg/m(2) on days 1, 8, and 15 every 4 weeks plus trofosfamide 50 mg per day. RESULTS: A total of 62 chemotherapy cycles were administered. The median number of cycles per patient was 3. The overall response rate to chemotherapy was 19%, median overall survival was 6.9 months, the median progression-free survival 2.9 months, the 1-year survival rate 28.6%, and the 2-year survival rate 7.1%. No grade IV toxicity was observed. CONCLUSIONS: Our results suggest that the combination of docetaxel and trofosfamide in a metronomic schedule is active and well tolerable as second-line therapy in patients with metastatic NSCLC. The concept of metronomic chemotherapy promises to be a valuable addition to the existing treatment options in NSCLC and warrants further investigation in phase III studies.

Adjuvant chemotherapy after complete resection of non-small cell lung cancer.

INTRODUCTION: In non-small cell lung cancer (NSCLC) surgical resection is the treatment of choice in stages I and II of the disease; but even of this selected group of patients, almost half suffer recurrence following complete resection, usually in the form of distant metastases. The role of adjuvant systemic chemotherapy has been investigated extensively in the last two decades. METHODS: Selective literature review of randomized phase III trials. RESULTS AND DISCUSSION: There is currently no indication for adjuvant chemotherapy in patients with stage IA disease, whereas the role of adjuvant chemotherapy for stage IB disease remains controversial. To treat a patient with stage IB disease should be an individualized decision depending on age, tumor size, vascular invasion, and patient preference. Adjuvant chemotherapy is now the standard of care after complete resection of stage II-IIIA NSCLC. Patients considered for adjuvant chemotherapy should be under 75 years of age, have no contraindications to cisplatin-based chemotherapy, and should be in a good performance status after surgery. Currently the standard adjuvant chemotherapy regimen is a combination containing cisplatin and vinorelbine.

A phase II study of irinotecan (CPT-11) and carboplatin in patients with limited disease small cell lung cancer (SCLC).

PURPOSE: The aim of this phase II trial was to evaluate the efficacy and safety of a combination chemotherapy containing irinotecan (CPT-11) and carboplatin as first-line treatment of patients with small cell lung cancer (SCLC). PATIENTS AND METHODS: From December 2002 to May 2004 61 patients with limited disease (IASLC classification) were enrolled who were not suitable for concurrent chemo-radiotherapy. Eighteen of the 61 patients (29.5%) had malignant pleural or pericardial effusion and 4 patients (6.6%) had involved supra- or infraclavicular lymph nodes. Patients received irinotecan 50mg/m(2) on days 1, 8 and 15 and carboplatin AUC 5 on day 1, every 4 weeks. RESULTS: A total of 233 chemotherapy cycles were administered. The median number of cycles per patient was 4. The overall response rate to chemotherapy on an intention-to-treat basis was 64%. The median overall survival was 13.8 months, the median disease-free survival 8.0 months, the 1-year survival rate 53.5%, and the 2-year survival rate 17.9%. Haematological and non-hematogical toxicities were low (CTC-grade 3 neutropenia 14.8%, grade 3 thrombocytopenia 5.2%, grade 3/4 anemia 5.1%, grade 3 nausea/vomiting 5.1%, grade 3 diarrhea 3.6%, grade 3 alopecia 3.6% of pts). CONCLUSION: The results suggest that the combination of irinotecan (CPT-11) and carboplatin is active and well tolerable in patients with limited disease SCLC who were not suitable for concurrent chemotherapy.

Cancer-testis antigens are commonly expressed in multiple myeloma and induce systemic immunity following allogeneic stem cell transplantation.

Immunotherapies using cancer-testis (CT) antigens as targets represent a potentially useful treatment in patients with multiple myeloma (MM) who commonly show recurrent disease following chemotherapy. We analyzed the expression of 11 CT antigens in bone marrow samples from patients with MM (n=55) and healthy donors (n=32) using reverse transcriptase-polymerase chain reaction (RT-PCR). CT antigens were frequently expressed in MM with 56% (MAGEC2), 55% (MAGEA3), 35% (SSX1), 20% (SSX4, SSX5), 16% (SSX2), 15% (BAGE), 7% (NY-ESO-1), and 6% (ADAM2, LIPI) expressing the given antigen. Importantly, CT antigens were not expressed in healthy bone marrow. Analyzing patients with MM (n=66) for antibody responses against MAGEA3, SSX2, and NY-ESO-1, we found strong antibody responses against CT antigens preferentially in patients who had received allogeneic stem cell transplantation (alloSCT). Antibody responses against NY-ESO-1 correlated with NY-ESO-1-specific CD4+ and CD8+ T-cell responses against peptide NY-ESO-1(51-62) and CD4+ responses against NY-ESO-1(121-140) in 1 of these patients. These allogeneic immune responses were not detectable in pretransplantation samples and in the patients' stem cell donors, indicating that CT antigens might indeed represent natural targets for graft-versus-myeloma effects. Immune responses induced by alloSCT could be boosted by active CT antigen-specific immunotherapy, which might help to achieve long-lasting remissions in patients with MM.

Downregulation of VEGF-A, STAT5 and AKT in acute myeloid leukemia blasts of patients treated with SU5416.

In acute myeloid leukemia (AML), autocrine or paracrine activation of receptor tyrosine kinases such as c-kit and FLT3 contributes to proliferation and apoptosis resistance of leukemic blasts. This provided the rationale for a multicenter clinical trial in patients with refractory AML with SU5416, a small molecule kinase inhibitor which blocks phosphorylation of c-kit, FLT3, VEGFR-1, VEGFR-2 (KDR) and VEGFR-3. The levels of VEGF mRNA expression were investigated in peripheral blood leukemic blasts taken from AML patients before and during treatment with SU5416. Rapid down regulation of VEGF was observed in AML blasts from 72% (13 of 18) of patients analysed. Patients initially expressing high VEGF-levels had a stronger downregulation and a higher clinical response rate (mean 865-fold, n = 10, P = 0,01) than patients initially expressing low VEGF-levels (mean four-fold, n = 8). These results suggest that abnormal high VEGF expression is downregulated by SU5416 treatment, and furthermore that decreases in VEGF mRNA levels may provide an early marker of therapeutic response with anti-angiogenic therapy. Additionally, protein expression of STAT5 and AKT was assessed by western blotting in these patient samples, as well as in the leukemia cell line, M-07e, treated in vitro with SU5416 as a model system. In the AML patient samples, parallel downregulation of both STAT5 and AKT was observed in several cases (STAT5 in four of 15; AKT in three of six examined patients). These effects were confirmed with the cell line M-07e after incubation with SU5416 in vitro using concentrations that are achievable in patients. In summary, our data show suppression of the expression of VEGF and key signal transduction intermediates in AML blasts during treatment with SU5416.

Expression of cancer-testis antigens as possible targets for antigen-specific immunotherapy in head and neck squamous cell carcinoma.

Cancer-Testis (CT) antigens are by definition expressed in tumor but not in healthy tissue except testis and might represent ideal targets for antigen-specific immunotherapy. Here, we present the first comprehensive analysis of CT antigen expression in patients with head and neck squamous cell carcinoma (HNSCC). Tumor samples (N = 51), and adjacent healthy tissue from patients with HNSCC were analyzed for the expression of 23 genes designated CT antigens using RT-PCR. Patient sera (N = 39) were screened for IgG antibody responses against NY-ESO-1, MAGEA3, and SSX2. According to their expression pattern antigens were divided into four groups. ADAM2, LIP1, SLLP1, AKAP3, CTAGE, ZNF165, CAGE, and FTHL17 were expressed in tumor and healthy tissue at comparable frequencies. NY-TLU-57, GAGE1, SAGE1 were expressed more frequently in tumor samples than in healthy tissues. TPTE, LDHC, SPO11 were expressed neither in tumor samples nor in healthy tissue. 9 CT antigens were expressed only in the tumor tissue and may represent ideal candidates for active immunotherapy in HNSCC: MAGEA3 was expressed in 72%, SSX1 in 45%, MAGEC2 in 33%, MAGEC1 in 28%, BAGE in 17%, SSX2 in 16%, SCP1 in 12%, NY-ESO-1 in 6%, and HOM-TES-85 in 4% of cases. 86% of tumor samples expressed at least one, 69% expressed at least two, and 43% expressed at least three of these antigens. Three patients showed an antibody response against NY-ESO-1. In conclusion, we demonstrate here that HNSCC frequently express CT antigens. Furthermore, a relatively high percentage of tumors express more than one CT antigen opening the perspective for polyvalent antigen-specific immunotherapy.

Patients with solid tumors treated with high-temperature whole body hyperthermia show a redistribution of naive/memory T-cell subtypes.

An activation of the immune system might contribute to the therapeutic effect of whole body hyperthermia (WBH) in cancer patients. We explored immune and endocrine responses in patients undergoing high-temperature WBH. Identical parameters were investigated in a separate group of healthy volunteers undergoing physical exercise to rule out effects of sympathetic activation. Lymphocyte subpopulations, lymphocytic expression of a range of adhesion molecules, and serum concentrations of a variety of hormones and cytokines were assessed in cancer patients undergoing high-temperature (60 min at 41.0-41.8 degrees C) WBH (n = 25) and in a separate group of healthy volunteers (n = 10) performing strenuous physical exercise. WBH induced an increase in human growth hormone (hGH), ACTH, and cortisol as well as in TNF-alpha, IL-6, IL-8, and IL-12R. We observed an increase in natural killer (NK) cells and CD56+ NK T cells shortly after initiation of WBH. In contrast, we found a decrease in T cells expressing L-selectin (CD62L) or alpha4beta7 integrin adhesion molecules mediating homing to lymphatic tissues. Accordingly, we observed a decrease in CD45RA+CCR7+ naive and CD45RA-CCR7+ central memory T cells. Numbers of CD45RA-CCR7- memory effector and CD45RA+CCR7 terminally differentiated T cells, on the other hand, remained unchanged. No comparable changes were observed in the group of healthy volunteers. In conclusion, patients with solid tumors treated with WBH show an increase in NK and NK T cells. In a later phase, plasma concentrations of IL-8, hGH, and cortisol increase, correlated with an influx of neutrophils into the peripheral blood. The alterations in T-cell populations suggest that WBH may induce naive and central-memory T cells to enter lymphatic tissue to await antigen exposure and effector T cells to migrate into peripheral tissues to exert their effector function. Although the exercise group may not be an appropriate control to proof the effect of WBH, these changes were not seen in the healthy volunteers performing physical exercise.

Pharmacogenetics of extraordinary responses to 5-FU/cisplatin chemotherapy in advanced gastric cancer -- report of 2 cases.

BACKGROUND: Gastric cancer is often diagnosed in the metastatic stage, and only 10% of patients survive for as long as 2 years. Current chemotherapy regimens show significant treatment-related toxicities. It is crucial to identify the patients that will benefit most from certain chemotherapy regimens in order to avoid unnecessary side effects. PATIENTS AND METHODS: 2 patients with advanced gastric cancer repeatedly received 5-FU/cisplatin combination chemotherapy. Genomic DNA was extracted from tumor tissue and mononuclear blood cells. Genotype analysis of genes of metabolizing and DNA repair enzymes was carried out using a PCR-RFLP technique. Direct sequencing was used to identify mutations of the gene dihydropyrimidine dehydrogenase (DPD). RESULTS: Prolonged survival of 51 and 29 months, respectively were observed in our 2 patients. Both patients were positive for genotypes of thymidylate synthase -- the target enzyme of 5-FU -- that are associated with improved drug response. DPD variants connected with increased toxicity were not observed. However, both patients also showed genotypes in cisplatin metabolizing enzymes which enhance the effect of the drug. CONCLUSION: Genotype analysis in drug metabolizing enzymes of 5-FU and cisplatin provide a possible explanation for extraordinary therapy effects observed in 2 patients with advanced gastric cancer.

Pretreatment vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) serum levels in patients with metastatic non-small cell lung cancer (NSCLC).

PURPOSE: In the present study, we investigated the prognostic value of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9 serum levels in patients with metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: From September 1999 to June 2001, pretreatment serum levels of VEGF and MMP-9 were analysed in 194 patients of a randomized phase III trial with enzyme-linked immunoassays. RESULTS: Patients with a VEGF serum level higher than the median serum level (10,995 pg/ml) had a significantly shorter overall survival than those with a lower serum level (P=0.04). The MMP-9 serum level did not correlate with survival. In a multivariate Cox regression analysis, only the pretreatment serum level of VEGF, the Karnofsky performance status, and the presence of bone metastases were identified as independent prognostic factors. CONCLUSIONS: The pretreatment VEGF serum level was identified as independent prognostic factor in this study and may help to assess individual risk and treatment profiles in patients with metastatic NSCLC.

Peripheral T cells of patients with B cell non-Hodgkin's lymphoma show a shift in their memory status.

BACKGROUND: Tumor-infiltrating T cells have a positive influence on the clinical course of B cell non-Hodgkin's lymphoma (NHL). T cells in the peripheral blood of patients with B cell NHL, however, have so far rarely been examined. METHODS: Using flow cytometry we examined lymphocyte subpopulations and numbers of naïve/memory T cell subtypes among peripheral T cells of patients with B cell NHL (N=22), patients with metastasized solid tumors (N=27), and healthy controls (N=20). In addition, we analyzed the intracellular content of effector molecules granzyme B and perforin and expression of the T cell receptor zeta chain. RESULTS: We observed increased percentages of potentially highly cytotoxic CD8+CD56+ T cells in the peripheral blood of patients with NHL. Both, patients with NHL and patients with solid tumors showed a much higher expression of the chemokine receptors CCR4 and CCR5 on their T cells than healthy controls, suggesting a polarization of their T cells following stimulation with antigen and/or cytokines in vivo. Furthermore, patients with B cell NHL and patients with solid tumors had far lower percentages of naïve CD45RA+CCR7+ T cells than healthy controls and, in the case of CD4+ T cells, patients with solid tumors. In contrast, patients with B cell NHL showed markedly increased levels of memory effector CD45RA-CCR7- CD4(+) T cells when compared to healthy controls and patients with metastasized solid tumors. Patients with NHL also showed elevated levels granzyme B within CD8(+) T cells, indicating that the increase in memory effector cells was of functional relevance. CONCLUSIONS: These findings indicate a marked shift in the composition of peripheral T cells of patients with B cell NHL from naïve to memory effector-type cells.

Serum levels of Magic Roundabout protein in patients with advanced non-small cell lung cancer (NSCLC).

BACKGROUND: Magic Roundabout (MR; ROBO 4) is a recently discovered gene which encodes a protein that derived its name form the structural homology with the roundabout family of genes. Genes of the roundabout family comprise neuronal-specific cell surface receptors that are involved in axon guidance. MR in contrast showed endothelial specificity in vitro and in vivo using immunohistochemistry and in situ hybridisation. The putative role of MR as an endothelial analogue of Roundabout in angiogenesis makes it an attractive target for anti-angiogenic cancer therapy. PATIENTS AND METHODS: Using specific antibodies against MR peptide, we screened pretreatment sera from 193 patients with advanced non-small cell lung cancer (NSCLC) for MR-protein levels. RESULTS: Patients with serum levels of MR-protein lower than median (E(450 nm) = 0.652) had a median survival of 41.0 weeks whereas those with a higher serum level had a considerably shorter median survival of 32.4 weeks (P = 0.05). The pretreatment serum level of MR-protein achieved no significance in a univariate Cox regression analysis. CONCLUSIONS: This is the first study to present clinical data that link MR expression with outcome in patients with NSCLC, whether the correlation of pretreatment serum levels of MR and survival can be attributed to MR dependent angiogenesis remains to be investigated.

Dicentric (19;21)(p13;p13), a novel chromosomal abnormality occurring in a case of Philadelphia chromosome-positive acute lymphoblastic leukemia.

We report on a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia, who acquired a novel chromosomal abnormality, a dic(19;21)(p13;p13), during relapse of the disease. The cytogenetic result was confirmed by fluorescence in situ hybridization using alpha-satellite and library probes specific for chromosomes 19 and 21, respectively, as well as a chromosome 19q13.1-specific DNA probe. In our case, the dic(19;21) represents a secondary genetic change and was associated with disease progression and poor prognosis.

Characterization of effusion-infiltrating T cells: benign versus malignant effusions.

PURPOSE: While naïve T cells circulate between peripheral blood and lymph nodes, memory effector T cells acquire certain surface molecules that enable them to travel to peripheral tissues and exert their effector function. We analyzed whether deficient numbers of effector-type T cells within the malignant effusion might contribute to tumor escape from immunosurveillance. EXPERIMENTAL DESIGN: We analyzed the expression of a broad range of adhesion molecules and chemokine receptors (CD62L, CD56, CCR4, CCR5, CCR7, CXCR3, CLA, and integrin alpha 4 beta 7) on tumor-associated lymphocytes in effusions and peripheral blood lymphocytes of patients with malignant ascites (n = 11) or malignant pleural effusion (n = 16). A tumor-associated lymphocyte:peripheral blood lymphocyte ratio was calculated as an indicator for homing of lymphocytes into the effusions and was compared with patients with nonmalignant ascites (n = 17). RESULTS: Patients with malignancies show an increased enrichment of T cells expressing the phenotype of "naïve" (CD62L+ and CD45RA+CCR7+), "central memory" (CD45RA-CCR7+), and type 2-polarized (CCR4+) T cells within their effusions. In contrast, enrichment of "effector"-type (CD45RA-CCR7- or CD45RA+CCR7-) and presumably type 1-polarized T cells (CCR5+) at the tumor site is deficient. The same is true for natural killer cells and potentially cytotoxic CD56+ T cells. CONCLUSIONS: Here we show for the first time that patients with malignant effusions show a deficient enrichment of T cells expressing the phenotype of type-1-polarized effector T cells at the tumor site. This mechanism is likely to contribute to the escape of tumor cells from immunosurveillance.

Deletion of chromosome 15 represents a rare but recurrent chromosomal abnormality in myelocytic malignancies.

We report on three cases with myelocytic malignancies cytogenetically characterized by a deletion of chromosome 15 occurring as the sole cytogenetic aberration. The deletions were defined as del(15) (q12q21) (two cases) and del(15)(q11q21) (one case). Cytogenetic analysis was supplemented by fluorescence in situ hybridization (FISH) using a chromosome 15 specific whole chromosome painting probe and probes hybridizing to the UBE3A gene on 15q11~q13, the PML gene on 15q22, and the telomeric region of 15q. Hereby, an interstitial deletion of 15q including UBE3A, but not PML and the telomeric region of 15q could be demonstrated. Two of our patients were diagnosed as acute myelocytic leukemia (AML) with bone marrow dysplasia classified as AML-M6 and AML-M4, respectively, according to the French-American-British classification; the third patient suffered from a chronic myelomonocytic leukemia (CMMoL). In two cases, the aberration was found at the time of primary diagnosis, whereas the third case showed the del(15) only during relapse of leukemia. Both cases with acute leukemia did not adequately respond to intensive chemotherapeutic treatment and died 13 and 11 months, respectively, after primary diagnosis. Our findings and the data of five previously published cases with an isolated del(15) indicate that: 1) del(15) represents a rare but recurrent abnormality in myelocytic hemopathies; 2) in our cases, del(15) was interstitial and included the region 15q11~q13/UBE3A, but not 15q22/PML and the telomeric region of 15q as shown by FISH; 3) del(15) occurs frequently in disorders with myelodysplastic or myeloproliferative features and may therefore affect early hematopoietic progenitor cells; and 4) del(15) may occur during disease progression and is often associated with an unfavorable prognosis.

Expression of CEACAM1 in adenocarcinoma of the lung: a factor of independent prognostic significance.

PURPOSE: To evaluate the prognostic relevance of CEACAM1 and sialyl Lewis X expression in adenocarcinomas of the lung. PATIENTS AND METHODS: Paraffin wax sections of 93 patients with adenocarcinomas of the lung who underwent surgery between 1990 and 1995 were immunohistochemically investigated using monoclonal anti-CEACAM1 and sialyl Lewis X antibodies. The clinical course of all patients was followed up for a minimum of 5 years. RESULTS: Sixty-one tumors were classified as CEACAM1-positive, and 32 were classified as CEACAM1-negative. Patients with CEACAM1-positive tumors had a significantly poorer overall (P =.00025) and relapse-free (P =.00029) survival than those with CEACAM1-negative tumors. Only three patients did not express the sialyl Lewis X glycotope, whereas 90 tumors (97%) were sialyl Lewis X-positive. In multivariate Cox regression analysis, next to tumor stage and sex, only the expression of CEACAM1 was a significant independent prognostic factor for survival. CONCLUSION: Expression of CEACAM1 was an independent prognostic factor in our patient population and can be used to stratify patients with adenocarcinomas of the lung into low-risk and high-risk groups. In contrast, the expression of sialyl Lewis X was of no prognostic relevance because it was expressed in 97% of all investigated tumors, and most likely has no influence on the function of CEACAM1 in this tumor entity.

Prolonged inhibition of von Willebrand factor-cleaving protease after splenectomy in a 22-year-old patient with acute and plasma refractory thrombotic thrombocytopenic purpura.

We report a 22-year-old woman with acute, plasma refractory thrombotic thrombocytopenic purpura (TTP) in whom splenectomy led to consistent stabilization of platelet counts, but who showed complete inhibition of vonWillebrand factor-cleaving protease (VWF-cp) after 6 months of follow up. Persistent protease deficiency and resolved clinical and haematological TTP symptoms resulted in the transient appearance of unusually large VWF multimers in the patient plasma. As low but significant protease activity (10%) was first detectable as late as 9 months after splenectomy, we conclude tentatively that, at least in a subgroup of patients with acquired TTP, the beneficial effect of splenectomy is not exclusively due to the removal of splenic B lymphocytes producing an inhibitor of VWF-cp.

Biliary transport of irinotecan and metabolites in normal and P-glycoprotein-deficient mice.

PURPOSE: The extensive and unpredictable biliary excretion of CPT-11 and its metabolites, SN-38 and SN-38 glucuronide (SN-38G) may contribute to the wide interpatient variability reported in the disposition and gastrointestinal toxicity of CPT-11. We studied the role of P-glycoprotein (P-gp) in in vivo biliary excretion of CPT-11, SN-38 and SN-38G in mice lacking mdr1-type P-gp [ mdr1a/1b(-/-)] in the presence of the multidrug resistance (MDR) reversal agent, PSC833. METHODS: Wild-type (Wt) and mdr1a/1b(-/-) mice ( n=3 or 4) were treated intragastrically with PSC833 (50 mg/kg) or vehicle 2 h prior to i.v. CPT-11 dosing (10 mg/kg), and bile samples were collected. RESULTS AND CONCLUSIONS: P-gp was found to play an important role in CPT-11 biliary excretion, as there was a significant (40%, P<0.05) decrease in its biliary recovery in 90 min in mdr1a/1b(-/-) mice (6.6+/-0.6% dose) compared with Wt mice (11+/-1.2%). This also implied a major role of other undetermined non-P-gp-mediated mechanism(s) for hepatic transport of CPT-11, which was inhibited by PSC833 (1.8+/-0.8% with PSC833, 6.6+/-0.6% without PSC833) in mdr1a/1b(-/-) mice. SN-38 and SN-38G biliary transport was unchanged in mice lacking P-gp after vehicle treatment, indicating a lack of P-gp mediation in their transport. PSC833 significantly reduced (56-89%) SN-38 and SN-38G biliary transport in Wt and mdr1a/1b(-/-) mice, suggesting that PSC833 may be a candidate to modulate biliary excretion of SN-38 with potential use in reducing CPT-11 toxicity.