Rituximab (IDEC-C2B8

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M166V, S534N, I543V) displayed significantly reduced DPD activity. The rare combination of the highly conserved mutation sites M166V and S534N was additionally found in one of the other patients. DPD enzyme activity was low, but yet within normal range. The K259E mutation did not provoke a decrease in DPD function in a heterozygous individual. Based on the protein structure of crystalline pig DPD and the deduced homology models, we have additionally investigated the amino acid positions in their three-dimensional network which correspond to the five missense mutations discovered in the patients.

This phase II trial assessed the toxicity and efficacy of irinotecan plus docetaxel in cisplatin-pretreated oesophageal cancer. Irinotecan 160 mg m À2 plus docetaxel 65 mg m À2 once every 3 weeks led to severe myelosuppression in four patients, all of whom experienced neutropenic fever. After amendment of this regimen, 24 patients (male/female ¼ 18/6; median age ¼ 58.5 years; ECOG performance status 0/1/2 ¼ 9/11/4) with advanced oesophageal cancer (adenocarcinoma/epidermoid carcinoma ¼ 13/11) received irinotecan 55 mg m À2 plus docetaxel 25 mg m À2 on days 1, 8 and 15 of a 28-day cycle. Serious adverse events occurred in five patients, one with lethal outcome (pneumonia). Haematological toxicity X31 was rare, whereas nonhaematological toxicity X31 was noted in nine out of 24 patients (asthenia in five patients, diarrhoea in three patients, nausea/emesis in two patients, constipation in one patient). Median survival time was 26 (range 2 -70) weeks. Response rate, assessed according to the WHO criteria, was 12.5% (95% CI 2.7 -32.4%); rate of disease stabilisation (partial remission and stable disease) was 33.3% (95% CI 15.6 -55.3%) with a median duration of 18.5 (range 16 -51) weeks. Although the nonhaematological toxicity proved to be considerable, weekly irinotecan plus docetaxel is feasible and shows some activity in extensively pretreated patients with oesophageal cancer. British Journal of Cancer (2003) Owing to early lymphogenic and haematogenous spread, most patients with oesophageal cancer are diagnosed with advanced disease. These patients receive multimodal treatment if the tumour is deemed to be resectable, or systemic chemotherapy if palliation is the goal. Cisplatin has been the mainstay of chemotherapy and chemoradiotherapy protocols during the last decade (Herskovic et al, 1992;Bleiberg et al, 1997). In case of resistance to cisplatin-based therapy, no evidence-based recommendations regarding second-line treatment exist, but many patients ask for more than measures of best supportive care. Thus, there is a need for tolerable and active protocols beyond cisplatin-based therapy. Irinotecan and taxanes proved to induce remissions in oesophageal cancer (Ilson et al, 1998(Ilson et al, , 1999 although single-agent docetaxel revealed only moderate activity (Heath et al, 2002). The combination of irinotecan and docetaxel has been investigated in phase I studies in patients with pretreated solid tumours (Adjei et al, 2000;Couteau et al, 2000). The recommended phase II dose on this schedule was irinotecan 160 mg m À2 followed by docetaxel 65 mg m À2 administered every 3 weeks (Adjei et al, 2000). This phase II trial was designed to assess the activity and toxicity of the combination of irinotecan plus docetaxel in cisplatin-pretreated relapsed or refractory oesophageal cancer. METHODS Patient populationPatients with histologically confirmed adenocarcinoma or epidermoid carcinoma of the oesophagus were enrolled at a single site (Klinikum rechts der Isar, Technical University of Munich). Eligible patients with...

A t(2;5) (p23;q35) chromosomal translocation can be found in a high percentage of anaplastic large-cell lymphomas (ALCL). This genetic abnormality leads to the expression of the NPM-ALK fusion protein, which encodes a constitutively active tyrosine kinase that plays a causative role in lymphomagenesis. Employing a modified infection/transplantation protocol utilizing an MSCVbased vector, we were able to reproducibly induce two phenotypically different lymphoma-like diseases dependent on the retroviral titers used. The first phenotype presented as a polyclonal histiocytic malignancy of myeloid/macrophage origin with a short latency period of 3-4 weeks. Clinically, the diseased mice showed rapidly progressive wasting, lymphadenopathy and pancytopenia. Mice displaying the second phenotype developed monoclonal B-lymphoid tumors with a longer latency of approximately 12-16 weeks, primarily involving the spleen and the bone marrow, with less extensive lymph node but also histologically evident extranodal organ infiltration by large immature plasmoblastic cells. The described retroviral mouse model will be useful to analyse the role of NPM-ALK in lymphomagenesis in vivo and may contribute to the development of new treatment options for NPM-ALK induced malignancies.

Twenty-eight cases of monocytoid B-cell lymphoma of lymph nodes and 16 lymph node metastases of primary gastric lymphomas, mostly low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type were investigated morphologically and immunohistochemically. Both groups showed the same morphological and immunohistochemical features: diagnostically important sites of infiltration were the sinuses and the marginal zones. The tumour cells were either medium-sized or small. The cytoplasm stained grey with Giemsa and was sometimes rather pale. In imprints the grey colour of the cytoplasm was a characteristic feature. The medium-sized cell type was more frequent; in one third of the cases it was combined with a prominent lymphoplasmacytic component from the same clone, and it resembled the monocytoid B-cells of the sinuses. The small cell type was less common, was not combined with a lymphoplasmacytic component and more closely resembled marginal zone cells. The difference was underlined by the negative reaction with the monoclonal antibody Ki-B3 in the small cell type, which, conversely, was positive in the medium-sized cell type and in the monocytoid B-cell reaction of the sinuses. Both of these cell types, however, showed a granular reaction with the new monoclonal antibody Ki-Mlp. The morphological and immunohistochemical parallels are arguments in favour of the assumption that monocytoid B-cell lymphoma is the nodal equivalent of low-grade B-cell lymphoma of MALT type. This is further supported by the fact that in nine of our 28 cases of monocytoid B-cell lymphoma, lymphomas were found simultaneously or subsequently in organs of the MALT. Monocytoid B-cell lymphoma must be differentiated from an infiltration that occurs in the form of clusters of monocytoid B-cells in other low-grade B-cell lymphomas, especially in immunocytoma with a high content of epithelioid cells.

Pathomorphological examination of trephine biopsies of the bone marrow (BM) represents a standard method for the diagnosis and staging of hematologic neoplasms and other disorders involving the BM. The increasing knowledge about the genetic basis and biology of hematologic neoplasms, as well as the recently proposed WHO classification system, provide the framework for an accurate diagnosis. Although conventional morphology remains the gold standard for paraffin-embedded BM trephines, immunohistochemical stainings have become an integral part of the diagnostic workup. Antibodies suitable for paraffin sections are generally applicable to BM trephines, but modifications of staining protocols may be necessary due to the alternative fixatives and decalcification procedures used for BM biopsies. The indications for immunostainings range from confirmation and classification of lymphoma involvement, subclassification of acute leukemias, and estimating blast counts in myelodysplastic and myeloproliferative syndromes to characterization of BM involvement in nonhematologic neoplasms. Although subtyping of NHL in the BM is more difficult from the point of morphology, classification of the entities that frequently involve the BM, especially the small B-cell lymphomas, can easily be achieved with the help of immunohistochemistry. In this review, we try to summarize the current state of the art in BM immunohistochemistry for the diagnosis of hematologic disorders. Moreover, diagnostic algorithms and useful antibody panels are proposed for a rational and cost-effective approach.

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