To compare mantle-cell lymphomas (MCLs) and follicle-center lymphomas (FCLs) for their features of clinical presentation, response to chemotherapy, and prognosis on the basis of a prospective ...randomized clinical trial.
Patients with MCL and FCL who entered onto the prospective randomized comparison of cyclophosphamide, vincristine, and prednisone (COP) versus prednimustine and mitoxantrone (PmM) followed by a second randomization for interferon (IFN) maintenance versus observation only.
One hundred sixty-five of 234 patients had FCL and 45 of 234 patients had MCL. With FCL, both sexes were equally affected (men, 47%); patients with MCL were predominantly men (78%; P < .0004) and had a higher median age (64 v 53 years; P < .0001). Patients with MCL also had more widespread disease, reflected by the proportion of patients with two or greater extranodal manifestations (43% v 21%; P < .005) and nine or greater involved nodal areas (64% v 45%; nonsignificant NS). Response to chemotherapy was significantly lower in patients with MCL (complete remission CR + partial remission PR, 69% v 88%; P < .05) and occurred at a slower pace. Patients with MCL also had a shorter event-free interval (median, 8 v 24 months; P < .0001) and overall survival (median, 28 v 77 months; P < .0001). In both subtypes, however, patients with less than two residual lymphoma manifestations in remission experienced a relatively good prognosis with an estimated 5-year survival of greater than 60% for MCL and greater than 75% for FCL.
MCL and FCL differ substantially in their features of presentation, response to chemotherapy, and long-term prognosis. The extent of residual disease after completion of chemotherapy discriminates patients with different prognosis and may be used for the stratification of postremission strategies.
In a up-front randomized study, 939 adult patients up to the age of 60 years received a double induction therapy. One course of MAV (mitoxantrone 10 mg/m2 days 4–8, cytarabine 100 mg/m2 continuous ...infusion days 1–8, etoposide 100 m g/m2 days 4–8) was followed by one cycle of MAMAC (cytarabine 1 g/m2, every 12h days 1–5; amsacrine 100 mg/m2 days 1–5). Patients with intermediate risk cytogenetic (IRCG) and a HLA matched sibling received an allogeneic transplantation, those with poor risk cytogenetic (PRCG) were intended to be transplanted from a sibling or unrelated donor. All AML patients without an available donor received the randomly assigned first postremission therapy (PRT) mitoxantrone combined with intermediate-dose cytarabine (I-MAC; total dose 12 g/m2) or high-dose cytarabine (H-MAC; total dose 36 g/m2). As second PRT, patients with t(8;21) received an additional cycle of chemotherapy. An autologous transplantation was scheduled for IRCG and PRCG without an allogeneic donor. The CR rate was 88% for patients with t(8;21), with IRCG 71%, and 50% with PRCG. The 5-year-survival was 21% (95% CI: 16–27%) in the PRCG, 40% (95% CI: 36–45%) in the IRCG and 74% (95% CI: 60–88%) in the t(8;21) group. No difference was observed between the I-MAC and the H-MAC group. In a multivariate analysis, a significant (p<.01 for each parameter) better overall survival was observed in patients under the age of 37 years, blast count <10% at day 15, high myeloperoxidase positivity, low CD34 expression, WBC <15*10^9/L, thrombocytes >50*10^9/L, and IRCG compared to PRCG. The relapse incidence was higher in patients without an allogeneic donor, a Flt3 mutant/wildtype ratio > 0.8 or PRCG. A risk score build out of the sum of the individual hazard ratios (SHR) was able to discriminate two groups for the IRCG with a marked difference in the 5-year-survival (low SHR: 55% 95% CI: 48–62%; high SHR: 33% 95% CI: 28–38%) was well as for the PRCG group (low SHR: 44% 95% CI: 32–56%; high SHR: 13% 95% CI: 7–18%). The risk score identified in this large patient cohort may allow individual tailoring of therapeutic interventions in future AML trials.
This prospective multicenter study was performed to assess the reliability of sentinel lymph node (SLN) biopsy in breast cancer and to analyze factors potentially influencing success rates.
In 21 ...departments, SLN biopsy and consecutive axillary lymph node dissection were performed in 814 breast cancer patients. The 80 surgeons involved were free in the choice of lymphography technique. The detection rate and the sensitivity, as well as the impact of lymphography technique, patient selection, technical procedure and learning curves, were evaluated.
The blue dye technique was used in 137 patients, radiocolloid in 169 patients, and combined blue dye/radiocolloid in 508 patients. The identification rate for the sentinel node was 83.9% for the entire group and showed a significant dependence on the lymphography technique (blue dye, 71.6%; radiocolloid, 78.8%; combined blue dye and radiocolloid, 89.6%). The overall sensitivity in detecting lymph node metastases was 91.3%. Immunostaining for cytoceratine revealed micrometastases in 19 (5.1%) of 374 patients in whom H/E staining was negative. The combined subdermal/peritumoral injection of the colloid showed a significantly higher identification rate than subdermal or peritumoral injection alone (96.8%, 84.6%, 78.6%; p < 0.001). There was also a significant higher detection rate in cases of SLN biopsy performed prior to lumpectomy, compared to SLN biopsy following lumpectomy (94.7% versus 82.8%; p < 0.001). Furthermore, there was a close correlation between the number of performed examinations and the detection rate.
SLN mapping predicts the axillary lymph node status accurately. Learning curves and several technical features influence the detection rate significantly. However, the false negative rate was independent of experience and injection technique.
Between 1996 and 2003, 994 patients aged under 60 years with de novo AML received a double induction chemotherapy consisting of MAV (mitoxantrone 10 mg/m2 day 4–8, Ara-C 100 mg/m2 continuous infusion ...day 1–8, etoposide 100 mg/m2 day 4–8) and MAMAC after an interval of at least 14 days (Ara-C 1 g/m2 q. 12 hrs day 1–5, amsacrine 100 mg/m2 day 1–5). A cytogenetic high risk profile (complex aberrations, −5/del(5q), −7/del(7q), hypodiploid karyotypes other than −5, −7, −X, −Y, abnl3q, abnl1q, abnl12p, t(6;9), t(9;22), t(9;11), +11, +13, +21, +22) was present in 252 patients (de novo AML N=160, prior MDS N=41, and secondary AML N=51). 119 out of 252 (47%) were in complete remission after 2 induction cycles. 35 (14%) additional patients showed complete remission after a further cycle. Patients with a HLA matched sibling donor (N=37) or an unrelated donor (N=34) received an allogeneic transplantation as consolidation therapy. The conditioning protocol consisted of 12 Gy TBI and cyclophosphamide. Cyclosporine and methotrexate were used as GvH prophylaxis. The actuarial survival at 5 years is 42% (CI: 26%–58%) in the related donor group and 53% (CI: 36%–70%) in the unrelated donor group. The disease free survival at 5 years is 40% (CI: 24%–56%) in the related group and 43% (CI: 26%–60%) in the unrelated group (for both, p=ns). In conclusion, the results after unrelated donor transplants are comparable with those after related donor transplants in patients with high risk AML. These data of the AML'96 study will be compared with the experience of our current upfront concept using allogeneic transplantation in aplasia after the 1st or 2nd induction cycle in high risk AML.
The information obtained by conventional cytogenetics (CC) in human leukemias is sometimes limited, in particular by complex karyotypes with many marker chromosomes. While CC is restricted to ...metaphases with a good quality, interphase fluorescence in situ hybridization (I-FISH) is also capable of analyzing specific anomalies in the interphase nuclei. Comparative genomic hybridization (CGH) gives additional information about the imbalanced karyotype changes in the whole genome. The aim of this study was to assess the contribution of CGH to the unraveling of complex GTG karyotypes, which are difficult to evaluate by banding analysis, and to compare these results with those by CC and FISH. Thirteen bone marrow samples and one sample obtained from peripheral blood of 13 leukemia patients were examined by CC, FISH and CGH. The GTG banding analysis showed complex karyotypes with many marker chromosomes. The most frequent abnormalities were numerical and structural aberrations on chromosomes 5 and 7. In 12 of the 14 samples, the CGH analysis was able to detect chromosomal imbalances with losses of material on chromosome 5 and 7 as the most frequent aberrations. In all 14 samples, additional FISH analyses were performed. For most of the studied neoplasias, a close correlation between CC, FISH and CGH data was observed. CGH was considerably helpful in adding additional information to classical karyotyping, if the low quality or number of metaphases was insufficient for a reliable CC analysis. Even in cases where whole chromosome painting could be applied, it added information on the breakpoints of the observed rearrangements. In only 2 of the studied 14 samples, neither CGH nor I-FISH could improve the result of karyotyping. CGH, nevertheless, can be regarded as a powerful additional technique in leukemias with unsuccessful CC, incomplete, or complex karyotypes with many marker chromosomes. A systematic analysis by three techniques such as CC, FISH and CGH guarantees an optimal genetic characterization of the neoplasias.
Myeloid cells can mediate tumor cell cytotoxicity via certain receptors for immunoglobulins. Among the different Fc receptors, the high-affinity IgG receptor (Fc gamma RI, CD64) is a promising ...trigger molecule because it is selectively expressed on effector cells, including monocytes/macrophages and granulocyte colony-stimulating factor (G-CSF)-primed neutrophils. In vitro, a bispecific antibody (BsAb) (MDX-210, constructed by chemically cross-linking F(ab') fragments of monoclonal antibody (mAb) 520C9 to HER-2/neu and F(ab') fragments of mAb 22 to Fc gamma RI) mediated effective lysis of HER-2/neu overexpressing breast cancer cell lines. HER-2/neu (c-erbB2) is overexpressed in approximately 30% of breast and ovarian carcinomas and is a target for immunotherapy in clinical trials. In vitro assays showed Fc gamma RI-positive neutrophils to constitute a major effector cell population during G-CSF therapy. Based on these preclinical data and a preceding study at Dartmouth (New Hampshire) with a single dose of MDX-210 alone, a combination of G-CSF and MDX-210 is tested in a phase I study in breast cancer patients. In this study, patients receiving G-CSF are treated with escalating single doses of MDX-210. This therapy was generally well tolerated by the treated patients, some of whom reacted with fever and short periods of chills, which were temporally related to elevated plasma levels of IL-6 and TNF-alpha. After MDX-210 application, a transient decrease in the total white blood count and absolute neutrophil count (ANC) was observed. During G-CSF application, isolated neutrophils were highly cytotoxic in the presence of MDX-210 in vitro. These data indicate a potential role for G-CSF and BsAb in immunotherapy.
Oesophageal atresia (OA) with or without tracheoesophageal fistula (TOF) are rare anatomical congenital malformations whose cause is unknown in over 90% of patients. A genetic background is ...suggested, and among the reported genetic defects are copy number variations (CNVs). We hypothesized that CNVs contribute to OA/TOF development. Quantifying their prevalence could aid in genetic diagnosis and clinical care strategies. Therefore, we profiled 375 patients in a combined Dutch, American and German cohort via genomic microarray and compared the CNV profiles with their unaffected parents and published control cohorts. We identified 167 rare CNVs containing genes (frequency<0.0005 in our in-house cohort). Eight rare CNVs - in six patients - were de novo, including one CNV previously associated with oesophageal disease. (hg19 chr7:g.(143820444_143839360)_(159119486_159138663)del) 1.55% of isolated OA/TOF patients and 1.62% of patients with additional congenital anomalies had de novo CNVs. Furthermore, three (15q13.3, 16p13.3 and 22q11.2) susceptibility loci were identified based on their overlap with known OA/TOF-associated CNV syndromes and overlap with loci in published CNV association case-control studies in developmental delay. Our study suggests that CNVs contribute to OA/TOF development. In addition to the identified likely deleterious de novo CNVs, we detected 167 rare CNVs. Although not directly disease-causing, these CNVs might be of interest, as they can act as a modifier in a multiple hit model, or as the second hit in a recessive condition.
We report the clearly observed tunneling magnetoresistance at 5 K in magnetic tunnel junctions with Co-doped ZnO as a bottom ferromagnetic electrode and Co as a top ferromagnetic electrode prepared ...by pulsed laser deposition. Spin-polarized electrons were injected from Co-doped ZnO to the crystallized Al2O3 and tunnelled through the amorphous Al2O3 barrier. Our studies demonstrate the spin polarization in Co-doped ZnO and its possible application in future ZnO-based spintronics devices.
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