Changes in the expression and function of adhesion molecules on the surface of cancer cells are important characteristics in the development of gastrointestinal malignancies and might be used in the future as prognostic factors or as new targets for diagnostic and therapeutic approaches. In esophageal cancer a down-regulation of the E-cadherin receptor and the cytoplasmic protein alpha-catenin is associated with tumor dedifferentiation, infiltrative growth and lymph-node metastasis. In gastric cancer a reduction of E-cadherin expression due to gene mutations is restricted to diffuse-type tumors while the occurrence of the CD44-standard and the CD44-9v isoform is significantly related to a higher tumor-induced mortality and a shorter survival time. The CD44-6v isoform is predominantly expressed by intestinal-type gastric carcinomas, giving these tumor cells the ability to perform lymph-node metastasis. In pancreatic cancer the expression of integrin adhesion receptors is significantly altered during the malignant transformation while a loss of the E-cadherin receptor can generate dedifferentiation and invasiveness of pancreas carcinoma cells. There is increasing evidence that integrin receptors as well as different isoforms of the CD44 receptor are altered following the malignant transformation of colonic mucosa into adenomas and invasive carcinomas. The expression of the CD44-6v isoform seems to be associated with an adverse prognosis in colorectal cancer due to the development of tumor metastases. A strong correlation has been observed between the expression of the 67-kDa laminin receptor and the degree of differentiation, the invasive phenotype and the metastatic abilities af colorectal cancer cells. Analyzing the expression of the E-cadherin receptor showed that this receptor may serve as an independent prognostic marker in Dukes' stage B colorectal cancer to identify patients with poor prognosis and designate them for intensive adjuvant therapy and clinical observation after curative surgical tumor treatment.

With short intensive chemotherapy mainly based on HDMTX, fractionated alkylators and HDAC outcome of Burkitt’s NHL and mature B-ALL (B-ALL) in adults could be improved substantially to CR rates of 80% and overall survival (OS) of 50–70% (Hoelzer et al, Blood, 1996). Further intensification - namely increase of MTX dose - failed to improve these results. Therefore the German Multicenter Study Group for Adult ALL (GMALL) invented in 2002 a new protocol for mature B-ALL/Burkitt and other high-grade NHL, namely primary mediastinal (med) DLBCL, including 6x Rituximab® 375 mg/m2 before each chemo cycle and two R maintenance cycles. In addition 2 cycles based on HDAC 2 g /m2 were included. HDMTX was 1,5 g/m2 in the protocol for younger pts (<55 yrs). Older pts (>55 yrs) received a dose reduced regimen without HDAC and with MTX at 500 mg/m2. 227 pts with Burkitt (27=Burkitt-like), B-ALL or med DLBCL aged between 16 and 78 enrolled between 09/02 and 12/06 were evaluable for response after the first two cycles. The median age was 36 yrs for Burkitt, 46 for B-ALL and 35 for med DLBCL; 18%, 41% and 12% were older than 55 yrs respectively. The subgroups were characterised as follows: 115 Burkitt (stage III–IV 52%, extranodal inv. 78%, aaIPI >1 47%), 70 B-ALL, 42 med DLBCL (stage III–IV 55%, extranodal inv. 71%, aaIPI >1 61%). The CR rate was 90% in Burkitt, 83% in B-ALL and 69% in med DLBCL; death under therapy occurred in 3%, 11% and 0% respectively. The overall survival at 3 yrs was 91% for Burkitt, 79% for B-ALL and 90% for med DLBCL in pts at the age of 15–55 yrs and 84%, 39% and 67% (N=5) respectively in pts >55 yrs. CNS relapses were observed in 3 out of 22 older CR patients with B-ALL whereas in younger pts the CNS relapse rate was 0. CNS relapses are among the reasons for inferior outcome in elderly B-ALL in contrast to elderly pts with Burkitt or med DLBCL. CNS relapse rate may hopefully be reduced by inclusion of an intermediate dose ARAC cycle in the elderly B-ALL. There was no difference in OS between pts with Burkitt (92%) vs Burkitt-like NHL (86%). Since no prognostic factors could be identified in younger pts, there was no need for SCT in CR1. Major grade III/IV toxicity was hematological (28–37%) and mucositis (36%, 37%, 28% in cycles A1, B1, C1 respectively). Compared to the previous GMLL trial B-NHL90 (without Rituximab) with 270 pts the OS of 272 patients (including LBL, LCAL, DLBCL) at 3 yrs improved significantly from 54% to 80% (p<.0001) overall, 56% to 85% (p<.0001) in younger and 39% to 65% (p=.01) in older pts. In this largest prospective study of adult Burkitt’s lymphoma/leukemia and med DLBCL the combination of Rituximab and 6 short intensive chemo cycles was feasible and lead to an OS of 90% in NHL and 79% in mature B-ALL in the younger patient cohort. Even in older pts with Burkitt’s NHL survival was 84%. The further aim is now to reduce toxicity, namely mucositis.

Changes in the expression and function of adhesion molecules on the surface of cancer cells are important characteristics in the development of gastrointestinal malignancies and might be used in the future as prognostic factors or as new targets for diagnostic and therapeutic approaches. In esophageal cancer a down-regulation of the E-cadherin receptor and the cytoplasmic protein alpha-catenin is associated with tumor dedifferentiation, infiltrative growth and lymph-node metastasis. In gastric cancer a reduction of E-cadherin expression due to gene mutations is restricted to diffuse-type tumors while the occurrence of the CD44-standard and the CD44-9v isoform is significantly related to a higher tumor-induced mortality and a shorter survival time. The CD44-6v isoform is predominantly expressed by intestinal-type gastric carcinomas, giving these tumor cells the ability to perform lymph-node metastasis. In pancreatic cancer the expression of integrin adhesion receptors is significantly altered during the malignant transformation while a loss of the E-cadherin receptor can generate dedifferentiation and invasiveness of pancreas carcinoma cells. There is increasing evidence that integrin receptors as well as different isoforms of the CD44 receptor are altered following the malignant transformation of colonic mucosa into adenomas and invasive carcinomas. The expression of the CD44-6v isoform seems to be associated with an adverse prognosis in colorectal cancer due to the development of tumor metastases. A strong correlation has been observed between the expression of the 67-kDa laminin receptor and the degree of differentiation, the invasive phenotype and the metastatic abilities af colorectal cancer cells. Analyzing the expression of the E-cadherin receptor showed that this receptor may serve as an independent prognostic marker in Dukes' stage B colorectal cancer to identify patients with poor prognosis and designate them for intensive adjuvant therapy and clinical observation after curative surgical tumor treatment.

No abstract

Summary:over, plasma factors (eg paraprotein) may also have some impact. In summary, the Isolex 50 provides a high Immunomagnetic separation with anti-CD34 monopurity of CD34 ؉ cells and depletion of tumor cells was clonal antibodies and paramagnetic microbeads has efficient. However, calculated and experimental purging been used to enrich hematopoietic stem cells from efficiencies are not necessarily identical. human bone marrow (BM) or mobilized peripheral Keywords: immunomagnetic separation; CD34 + hematoblood mononuclear cells (PBMNC). The introduction of poietic cells; peripheral blood mononuclear cells; tumor this technique also constitutes a new principle of tumor cell purging; breast cancer cells; cloning assay cell purging. The efficiency in terms of purging tumor cells from PBMNC was evaluated in seven different experiments. Mobilized (chemotherapy and G-CSF) PBMNC were collected from patients with solid tumors Autologous reinfusion of peripheral blood mononuclear (n = 6) and multiple myeloma (n = 1) by leukapheresis cells (PBMNC) after high-dose chemotherapy constitutes using an automated MNC separation system and conan important alternative to autologous bone marrow transtaminated with 1% (n = 5) or 10% (n = 2) tumor cells plantation in patients with hematologic malignancies or from different epithelial cell lines being CD34-negative.solid tumors. 1-6 The cell mixture was sensitized with anti-CD34 (9C5)There are multiple advantages of PBMNC reinfusion vs antibodies and sheep anti-mouse IgG1 paramagnetic autologous bone marrow transplants. The collection promicrospheres and enriched for CD34 ؉ cells using an cedure with a central i.v. line is much easier abrogating any Isolex 50 magnetic separator. Purity of CD34 ؉ cells was need for general anesthesia for the donor. Hematological studied by flow cytometry (FACScan) and tumor cell reconstitution in the recipient is faster 4-7 which contributes depletion was evaluated by comparative human tumor to applicability of high-dose protocols. cloning assays (HTCA) containing methylcellulose and Although the rate of tumor cell contamination in agar. We achieved a median purity of CD34 ؉ cells of PBMNC has been reported to be significantly lower than 85.9% (range 69.8-92.9%) and a median yield of 48.1% in bone marrow transplants 8 the circulation of tumor cells (range 21.0-85.2%). From these data in each case the in the PBMNC transplant remains a major concern regardestimated log depletion of tumor cells was calculated ing the prognosis of patients. [9][10][11][12][13][14][15][16] Brenner et al 15 showed and compared with the experimentally achieved with genetic markers that residual tumor cells in autologous (HTCA) log depletion (log ⌬ depletion = log experibone marrow transplants can contribute to disease recurmental depletion − log calculated depletion). In our rence. Moreover, mobilization of hematopoietic stem cells experiments we achieved a median depletion of 2.75 log into peripheral blood by applying chemotherapy followed (range 1.55-3.69 log). When corr...