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4Department of Radiology, University of Erlangen, Erlangen, Germany. ystemic multifocal fibrosclerosis is a rare disorder of unknown cause and is characterized by multiple fibrous lesions occurring with a variety of combined manifestations. Clinical variants include retroperitoneal fibrosis, Riedel’s thyroiditis, sclerosing cholangitis, mediastinal fibrosis, and orbital pseudotumor [1, 2]. An accurate diagnosis is based on tissue biopsy and pathologic examination. We describe a case of systemic multifocal fibrosclerosis with extensive bone involvement that was detected on MRI, gallium-67 scanning, and bone scintigraphy, with only subtle changes on conventional radiography.

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%; p0.001). 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%; p0.001). 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.

Background: Chromosomal abnormalities are one of the most important prognostic factors in acute myeloid leukemia (AML). However, only a limited number of patients have such informative chromosomal abnormalities. The prognostic value of immunophenotyping in this disease is still unclear. Methods: Seven hundred and eighty-three newly diagnosed AML patients treated in the German SHG-AML trials in 1991 and 1996 were analyzed with a panel of 33 antibodies. Expression was correlated to overall survival, complete remission-rate, and complete remission duration, and tested in a multivariate analysis including other clinical and biological markers. Results: With a median follow-up of 4.3 years, patients with AML blasts negative for CD9, CD11b, CD13, CD34, and CD41, or positive for CD15, CD33, CD38, CD64, and MPO had superior overall survival. This effect was associated with a significantly higher complete remission rate (CD13, CD34, CD41, and CD64) or a longer complete remission duration (CD9, CD11b, and CD64). Cox-regression analysis, including cytogenetic, morphologic, and biologic parameters showed CD9, CD13, CD34, and CD64 as independent factors for overall survival. These markers were used for a prognostic score. Patients were pooled in three groups with highly significant differences of overall survival. The prognostic relevance of this score was confirmed in patients with normal karyotype and/or in younger patients < 60 years. Conclusions: Immunophenotyping is not only helpful for diagnosis but is of independent significance for prognosis, and may be useful for risk stratification in AML patients. Cytometry Part B (Clin. Cytometry) 53B: 11‐19, 2003. © 2003 Wiley-Liss, Inc. Key terms: acute myeloid leukemia AML; immunophenotyping; prognosis; risk factors; statistics; retrospective study; multicenter study

This paper reports the case of a patient with a composite lymphoma consisting of nodular sclerosing Hodgkin's disease and peripheral T-cell lymphoma. The Hodgkin and Reed-Sternberg (HRS) cells harboured the Epstein-Barr virus (EBV) and displayed a type II EBV latency (LMP1(+)/EBNA2(-)), whereas the neoplastic T-cells were EBV-negative. Four years later, the patient presented with a relapse of the peripheral T-cell lymphoma. In situ hybridization revealed numerous EBV-carrying lymphocytes, which were shown to be polyclonal B-cells with a latency III pattern of EBV gene expression (LMP1(+)/EBNA2(+)). This observation suggests that impairment of EBV-specific immunity in the micro-environment of T-cell lymphomas may facilitate the outgrowth of EBV-carrying B-lymphocytes and emphasizes the importance of determining the phenotype of EBV-infected cells, particularly when studying T-cell lymphomas. The results further suggest that the HRS cells and neoplastic T-cells were of different clonal origins. The detection of EBV-carrying cell populations admixed with the neoplastic T-cells at primary presentation and at relapse raises the possibility that the growth of the T-cell lymphoma was dependent on the presence of such cells.

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.

Functioning as a B-cell growth and differentiation factor, interleukin-6 (IL-6) may play an important role in the pathophysiology of B-cell tumors. The capacity for IL-6 secretion was evaluated in 58 patients with various B-cell leukemias/lymphomas and in four patients with Castleman's disease (CMD). Cell populations from various sites including peripheral blood, bone marrow, lymph nodes, and osteolytic bone lesions were cultured and tested for spontaneous or IL-1 beta/TNF alpha-induced IL-6 production in a sensitive bioassay. No significant IL-6 levels were released by the tumor cells in any of the B-cell leukemias or lymphomas tested, including hairy cell leukemia (HCL) and B-cell chronic lymphocytic leukemia (B-CLL). In contrast, purified malignant plasma cells were found to secrete IL-6, strengthening the idea that an autocrine pathway for growth regulation in multiple myeloma (MM) exists. For the first time, in several patients with CMD, peripheral blood cells were shown to produce extremely high levels of IL-6, the pathogenetic significance of which remains to be elucidated. However, similar observations were very occasionally made in MM patients. Therapy with corticosteroids strongly inhibited this IL-6 production. These data provide evidence for autocrine and possibly an additional paracrine regulatory loop in plasma cell neoplasias and CMD.

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 (p50*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.

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.