BACKGROUND AND OBJECTIVE: Many environmental and genetic factors influence the development of chemoresistance. The goal of this study was to characterize the genetic variation in the ABCB1, GSTM1, GSTT1 and GSTP1 genes, as well as the haplotype structure in the ABCB1 gene. METHODS: Variants in these genes were studied in 109 healthy controls and 93 breast cancer cases, both of Caucasian origin. The cases were analyzed in relation to TP53 mutation status and response to doxorubicin. Both single and multiple single nucleotide polymorphism analyses were performed. RESULTS: Chi-square analyses revealed a significant association between TP53 mutation status and both the GA genotype of ABCB1 exon 11 (Ser400Asn) and the GG genotype of GSTP1 (Ile105Val; P
An update of the adjuvant trial on osteosarcoma in Sweden comparing patients receiving natural interferon (IFN) alpha with a high-dose chemotherapy group and a nonadjuvant group is presented. The overall survival for the IFN group is 49%, for the chemotherapy group 54%, and for the nonadjuvant group 35%. Trial evaluation was complicated by group differences with respect to various clinicopathologic features of prognostic significance. The role of IFN in the treatment of osteosarcoma can still not be established.
Antitumor activity of carcinoma-reactive BR96-doxorubicin conjugate against human carcinomas in athymic mice and rats and syngeneic rat carcinomas in immunocompetent rats.
The internalizing monoclonal antibody BR96 was conjugated to the anticancer drug doxorubicin (DOX) using an acid-labile hydrazone bond to DOX and a thioether bond to the monoclonal antibody. The resulting conjugate, termed BR96-DOX, binds to a tumor-associated Lewis(y) antigen that is abundantly expressed on the surface of human carcinoma cells. BR96-DOX binds to RCA, a human colon carcinoma cell line, and BN7005, a transplantable colon carcinoma induced in a Brown Norway (BN) rat by 1,2-dimethyl-hydrazine. BR96-DOX produces cures of established s.c. RCA human colon carcinomas in athymic mice and rats. BR96-DOX also cured both s.c. and intrahepatic BN7005 tumors in immunocompetent BN rats. Unconjugated DOX, given at its maximum tolerated dose, and matching doses of nonbinding IgG-DOX conjugate were not active against RCA or BN7005 carcinomas. An anticonjugate antibody response was produced in BN rats treated with BR96-DOX. However, this could be largely prevented by administering the immunosuppressive drug deoxyspergualin. These results confirm the concept of antibody-directed therapy in models in which the targeted antigen is expressed both in normal tissues and tumors. The findings in BN7005 further demonstrate efficacy of BR96-DOX therapy in a model in which the tumor is syngeneic and the host is immunocompetent.
Biological roles and prognostic values of the epithelial-mesenchymal transition-mediating transcription factors Twist, ZEB1 and Slug in diffuse large B-cell lymphoma.
To evaluate the biological roles and prognostic significance of the epithelial-mesenchymal transition (EMT)-mediating transcription factors (TFs) Twist, ZEB1 and Slug in patients with diffuse large B-cell lymphoma (DLBCL). EMT has been shown to enhance solid tumour metastasis, invasion, and proliferation.
Expression of Twist, ZEB1 and Slug was evaluated immunohistochemically in eight samples from reactive lymphoid tissues and in diagnostic samples from 102 DLBCL patients treated with curative intent with R-CHOP-type chemotherapy. ZEB1 and Slug expression correlated with adverse disease presentation. However, cytoplasmic Slug expression was linked to a favourable disease outcome, whereas nuclear expression of ZEB1 indicated an adverse outcome.
This study shows that an EMT-like process occurs in lymphomas. Of the TFs investigated, ZEB1 seems to be the main one associated with adverse clinical presentation and clinical outcome. Surprisingly, Slug expression in cytoplasm was linked to a favourable prognosis. Further studies are needed to evaluate whether inhibition of ZEB1 could serve as a therapeutic target.
The nuclear DNA content of 148 high-grade soft tissue sarcomas of the extremities and trunk was determined by flow cytometry, using tumor material from paraffin-embedded tissue. The patients were part of a prospective randomized clinical trial on the efficacy of adjuvant single-agent chemotherapy with doxorubicin. Chemotherapy did not improve the metastasis-free survival (MFS). After a median follow-up time of 48 months (range, 2 to 97), a multivariate analysis of prognostic factors for developing metastatic disease was performed. DNA aneuploidy was found to be an independent prognostic risk factor in addition to histologic malignancy grade IV, intratumoral vascular invasion, tumor size over 10 cm, and male sex. Patients with none or one risk factor had a 5-year MFS of 79%, with two risk factors 65%, with three risk factors 43%, and with four and five risk factors 0%. About one half (78 of 148) of the patients with three factors or less belonged to a group with a MFS over 60%. The combination of different risk factors, including DNA aneuploidy, seems to be a useful prognostic model for soft tissue sarcomas, which could be of value to select high-risk patients for further trials with adjunctive therapy.
Central nervous system (CNS) relapse in non-Hodgkin lymphoma (NHL) carries a very poor prognosis. Risk factors and outcome have been studied in aggressive B-cell lymphomas, but very little is known about the risk in peripheral T-cell lymphoma (PTCL). We aimed at analyzing risk factors for CNS involvement at first relapse or progression, as well as the outcome of these patients, in a large population-based cohort of patients with PTCL. Twenty-eight out of 625 patients (4.5%) developed CNS disease over time. In multivariable analysis, disease characteristics at diagnosis independently associated with an increased risk for later CNS involvement were involvement of more than 1 extranodal site (hazard ratio [HR], 2.60; 95% confidence interval [CI], 1.07-6.29; P = .035) and skin (HR, 3.51; 95% CI, 1.26-9.74; P = .016) and gastrointestinal involvement (HR, 3.06; 95% CI, 1.30-7.18; P = .010). The outcome of relapsed/refractory patients was very poor, and CNS involvement was not associated with a significantly worse outcome compared with relapsed/refractory patients without CNS involvement in multivariable analysis (HR, 1.6; 95% CI, 0.96-2.6; P = .074). The results from the present study indicate that CNS relapse in PTCL occurs at a frequency similar to what is seen in aggressive B-cell lymphomas, but the poor outcomes in relapse are largely driven by systemic rather than CNS disease.
The first chemotherapy study of soft tissue sarcoma (STS) by the Scandinavian Sarcoma Group was started in 1981 (SSG I). It evaluated the single agent adjuvant doxorubicin in a randomized setting in patients with high-grade STS. No improvement was noted in the overall survival or disease-free survival rate. More intense chemotherapy was thereafter (1991-1994) evaluated in a phase 2 study, introducing ifosfamide and a continuous infusion of etoposide with growth factor (SSG X). The response rate of previously untreated patients was high (42%), but complete remissions were few. Analysis of patients undergoing surgery after preoperative chemotherapy suggested an increased survival. A recent meta-analysis of adjuvant chemotherapy for localized resectable STS in adults, including the SSG I trial, indicated a better disease-free survival and possibly improved overall survival (Thierny et al. 1997). At present, we are studying whether such a benefit can be shown in patients with high-risk prognostic criteria by giving adjuvant ifosfamide and doxorubicin treatment after primary surgery (SSG XIII). In the latter SSG study, started on July 1, 1998, the adjuvant therapy is evaluated in a phase 2 study in selected patients with high-grade STS and other unfavorable prognostic factors.
A clinicopathological retrospective study of 131 patients with primary bone lymphoma: a population-based study of successively treated cohorts from the British Columbia Cancer Agency.
Primary bone lymphoma (PBL) is a distinct clinicopathological entity. Although PBL has been reviewed in several small studies, few reflect recent improvements in primary treatment.
We used the British Columbia Cancer Agency Lymphoid Cancer Database to identify all patients with PBL (1983-2005). All were staged in a uniform manner and treated with era-specific protocols.
We identified 131 patients with a median age of 63 years (18-87). One third had disease in long bones and another one third had disease in the spine, of which half presented with spinal cord compression. Patients with diffuse large-cell lymphoma (DLCL) (n=103, 79%) had 5- and 10-year overall survivals (OS) of 62% and 41%, respectively. Multivariate analysis identified three prognostic groups: ageor=60 with IPI 0-3 (n=23) and age>or=60 with IPI 4-5 (n=33), with markedly different 5-year OS of 90%, 61% and 25%, respectively (P
