Choroidal and adnexal extranodal marginal zone B-cell lymphoma: presentation, imaging findings, and therapeutic management in a series of nine cases.

PURPOSE: To describe the clinical and imaging presentation, pitfalls in the diagnosis of choroidal extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), as well as the therapeutic management and prognosis. METHODS: A retrospective case review of nine choroidal MALT lymphomas was performed. Initial clinical presentation and imaging findings of these histologically confirmed cases of lymphoma were analyzed. Treatment methods, time to diagnosis, systemic work-up, and treatment prognosis were assessed. RESULTS: Initial presentation was essentially blurred vision. The features described on examination were: anterior and posterior scleritis, iridocyclitis, choroidal infiltration, and exudative retinal detachment. Fluorescein and indocyanine green angiography as well as ultrasonography and optic coherence tomography provided arguments in favor of the diagnosis. Biopsy sites included conjunctiva, Tenon's capsule, deep scleral tissue, episclera, lacrimal gland, and choroid. Treatment mostly consisted of a combination of chemotherapy and radiotherapy. The mean time to diagnosis was 12 months. CONCLUSIONS: Owing to the insidious onset of these tumors and their ability to simulate other conditions, the diagnosis is commonly delayed. The prognosis is generally good and treatment is effective in the case of localized lymphoma.

[Breast conserving surgery in locoregional treatment of breast carcinoma after Hodgkin lymphoma]. / Traitement conservateur dans la prise en charge locorégionale du cancer du sein après lymphome de Hodgkin.

PURPOSE: To report characteristics and outcome of breast cancer after irradiation for Hodgkin lymphoma with special focus on breast conservation surgery. PATIENTS AND METHODS: Medical records of 72 women who developed either ductal carcinoma in situ or stage I-III invasive carcinoma of the breast after Hodgkin lymphoma between 1978 and 2009 were retrospectively reviewed. RESULTS: Median age at Hodgkin lymphoma diagnosis was 23 years old. Median total dose received by the mediastinum was 40 Gy, mostly by a mantle field technique. Breast cancer occurred after a median time interval of 21 years. Ductal invasive carcinoma and ductal carcinoma in situ represented respectively 71% and 19% of the cases. Locoregional treatment for breast cancer consisted of mastectomy with or without radiotherapy in 39 patients and of lumpectomy with or without adjuvant radiotherapy in 32 patients. The isocentric lateral decubitus radiation technique was used in 17 patients after breast conserving surgery (57%). With a median follow-up of 7 years, 5-year overall survival rate and locoregional control rate were respectively 74.5% and 82% for invasive carcinoma and 100% and 92% for in situ carcinoma. Thirteen patients died of progressive breast cancer and contralateral breast cancer was diagnosed in ten patients (14%). CONCLUSIONS: Breast conserving treatment can be an option for breast cancers that occur after Hodgkin lymphoma despite prior thoracic irradiation. It should consist of lumpectomy and adjuvant breast radiotherapy with use of adequate techniques, such as the lateral decubitus isocentric position.

Modeling of response to endocrine therapy in a panel of human luminal breast cancer xenografts.

Resistance to endocrine therapy is a major complication of luminal breast cancer and studies of the biological features of hormonal resistance are limited by the lack of adequate preclinical models. The aim of this study is to establish and characterize a panel of primary human luminal breast carcinoma xenografts, and to evaluate their response to endocrine therapies. Four hundred and twenty-three tumor fragments obtained directly from patients have been grafted in the interscapular fatpad of Swiss nude mice. After stable engraftment with estradiol supplementation, xenografted tumors have been validated by conventional pathology and immunohistochemistry examination, and additional molecular studies. In vivo tumor growth and response to different endocrine treatments were evaluated. We have engrafted 423 tumors including 314 ER+ tumors, and 8 new luminal breast cancer xenografts have been obtained (2.5%). Tumor take was much lower for luminal tumors than for non-luminal tumors (2.5 vs. 24.7%, P < 0.0001), and was associated with two independent criteria, i.e., ER status (P < 0.0001) and a high grade tumor (P = 0.05). Histological and immunohistochemical analyses performed on patient's tumors and xenografts showed striking similarities in the tumor morphology as well as in the expression level of ER, PR, and HER2. Response to hormone therapy, evaluated in 6 luminal models, showed different sensitivities, thus exhibiting heterogeneity similar to what is observed in the clinic. We have established a panel of primary human luminal breast cancer xenografts, recapitulating the biological and clinical behaviors of patient tumors, and therefore suitable for further preclinical experiments.

Establishment and characterisation of a new breast cancer xenograft obtained from a woman carrying a germline BRCA2 mutation.

BACKGROUND: The BRCA2 gene is responsible for a high number of hereditary breast and ovarian cancers, and studies of the BRCA2 biological functions are limited by the lack of models that resemble the patient's tumour features. The aim of this study was to establish and characterise a new human breast carcinoma xenograft obtained from a woman carrying a germline BRCA2 mutation. METHODS: A transplantable xenograft was obtained by grafting a breast cancer sample into nude mice. The biological and genetic profiles of the xenograft were compared with that of the patient's tumour using histology, immunohistochemistry (IHC), BRCA2 sequencing, comparative genomic hybridisation (CGH), and qRT-PCR. Tumour response to standard chemotherapies was evaluated. RESULTS: Histological profile identified the tumour as a basal-like triple-negative breast cancer. Targeted BRCA2 DNA sequencing of the xenograft showed the presence of the mutation previously identified in the carrier. Comparative genomic hybridisation array profiles of the primary tumour and the xenograft revealed a high number of similar genetic alterations. The therapeutic assessment of the xenograft showed sensitivity to anthracyclin-based chemotherapy and resistance to docetaxel. The xenograft was also highly sensitive to radiotherapy and cisplatin-based treatments. CONCLUSIONS: This study describes a new human breast cancer xenograft obtained from a BRCA2-mutated patient. This xenograft provides a new model for the pre-clinical drug development and for the exploration of the drug response biological basis.

[High risk of cardiac dysfunction after treatment of secondary acute myeloid leukemia following chemotherapy and radiotherapy for breast cancer]. / Risque élevé de dysfonction cardiaque des leucémies aiguës myéloïdes secondaires à un cancer du sein.

Secondary acute myeloid leukaemia (AML) occurring after breast cancer is a rare long-term complication of the chemo- and/or radiation therapy required to treat breast cancer. The usually recognized curative option of these secondary AML includes courses of anthracycline-based chemotherapy followed by haematopoietic stem cell transplantation (HSCT). Cardiac dysfunction during AML treatment of these patients previously treated with anthracyclines for breast cancer has not been reported to date. We evaluated the evolution of cardiac function in seven patients treated with anthracyclines and/or autologous or allogeneic bone marrow transplantation for secondary AML occurring after breast cancer. All of the patients who received a cumulative anthracycline dose above the cardiac toxicity threshold developed cardiac symptoms during AML chemotherapy courses. Moreover, four of the five transplanted patients developed severe heart failure among which two were fatal. Thus, the risk of severe cardiac dysfunction after treatment of secondary AML following breast cancer must be taken in account as part of the therapeutic strategy of those patients. As discussed here, an accurate evaluation of risk factors, the use of sensitive detection tests and of cardioprotective drugs as well as that of non-cardiotoxic chemotherapy might decrease the occurrence and severity of this life-threatening complication.

CD44 targeting reduces tumour growth and prevents post-chemotherapy relapse of human breast cancers xenografts.

CD44 is a marker of tumour-initiating cells and is upregulated in invasive breast carcinoma; however, its role in the cancer progression is unknown. Here, we show that antibody-mediated CD44-targeting in human breast cancer xenografts (HBCx) significantly reduces tumour growth and that this effect is associated to induction of growth-inhibiting factors. Moreover, treatment with this antibody prevents tumour relapse after chemotherapy-induced remission in a basal-like HBCx.

Multifocal neuropathy due to plasma cell infiltration of peripheral nerves in multiple myeloma.

Patients with multiple myeloma (MM) can manifest a variety of neurologic complications. The authors report two patients who had development of a multifocal neuropathy related to infiltration of peripheral nerves by malignant plasma cells as the only manifestation of a relapse of MM, which was considered in full remission.

Protein toxins: intracellular trafficking for targeted therapy.

The immunotoxin approach is based on the use of tumor-targeting ligands or antibodies that are linked to the catalytic (toxic) moieties of bacterial or plant protein toxins. In this review, we first discuss the current state of clinical development of immunotoxin approaches describing the results obtained with the two toxins most frequently used: diphtheria and Pseudomonas toxin-derived proteins. In the second part of the review, a novel concept will be presented in which the roles are inverted: nontoxic receptor-binding toxin moieties are used for the targeting of therapeutic and diagnostic compounds to cancer or immune cells. The cell biological basis of these novel types of toxin-based therapeutics will be discussed, and we will summarize ongoing preclinical and clinical testing.

Ex vivo expansion of megakaryocyte precursor cells in autologous stem cell transplantation for relapsed malignant lymphoma.

To evaluate the impact of ex vivo expanded megakaryocyte (MK) progenitors on high-dose chemotherapy-induced thrombocytopenia, we conducted a phase II study in 10 patients with relapsed lymphoma. Two fractions of peripheral blood progenitor cells (PBPC) were cryopreserved, one with enough cells for at least 2 x 10(6) CD34+ cells/kg and a second obtained after CD34+ selection. Ten days before autologous stem cell transplantation, the CD34+ fraction was cultured with MGDF+SCF for 10 days. After BEAM (BCNU, cyclophosphamide, cytarabine, and melphalan) chemotherapy, patients were reinfused with standard PBPC and ex vivo expanded cells. No toxicity was observed after reinfusion. The mean fold expansion was 9.27 for nucleated cells, 2 for CD34+ cells, 676 for CD41+ cells, and 627 for CD61+ cells. The median date of platelet transfusion independence was day 8 (range: 7-12). All patients received at least one platelet transfusion. In conclusion, ex vivo expansion of MK progenitors was feasible and safe, but this procedure did not prevent BEAM-induced thrombocytopenia. Future studies will determine if expansion of higher numbers of CD34+ cells towards the MK-differentiation pathway will translate into a functional effect in terms of shortening of BEAM-induced thrombocytopenia.

Distinct experimental efficacy of anti-Fas/APO-1/CD95 receptor antibody in human tumors.

Ligation of the Fas receptor (FasR) is a key step in apoptosis induction. Using a series of human tumor cells (SNB19, SNB79, 143N2, and SHEP), we observed a distinct efficacy of human anti-FasR antibody with an apparent correlation with Fas cell surface antigen expression. In contrast, all cells studied expressed detectable FasR mRNA transcripts. For all anti-FasR antibody-sensitive tumor cells, we showed a similar efficacy of Mab according to dose fractionation and injection site. We showed that, when injected into nude mice bearing human osteosarcoma 143N2, neuroblastoma SHEP, prostatic cancer PAC120, and the two glioblastomas SNB19 and SNB79, anti-FasR Mab induces significant inhibition of the growth rate of 143N2, SHEP, and PAC120 tumors, but has no efficacy on SNB19 and SNB79 tumors, with a relationship between in vitro and in vivo sensitivity to anti-FasR antibody. Altogether, these results suggest the antitumor potential of anti-FasR antibody in human neoplasms.

Mitochondrion as a novel target of anticancer chemotherapy.

Mitochondrial membrane permeabilization is a critical event in the process leading to physiologic or chemotherapy-induced apoptosis (programmed cell death). This permeabilization event is, at least in part, under the control of the permeability transition pore complex (PTPC). Oncoproteins from the Bcl-2 family and tumor suppressor proteins from the Bax family interact with PTPC to inhibit or facilitate membrane permeabilization, respectively. Conventional chemotherapeutic agents elicit mitochondrial permeabilization in an indirect fashion by induction of endogenous effectors that are involved in the physiologic control of apoptosis. However, an increasing number of experimental anticancer drugs, including lonidamine, arsenite, betulinic acid, CD437, and several amphipathic cationic alpha-helical peptides, act directly on mitochondrial membranes and/or on the PTPC. Such agents may induce apoptosis in circumstances in which conventional drugs fail to act because endogenous apoptosis induction pathways, such as those involving p53, death receptors, or apical caspase activation, are disrupted. However, stabilization of the mitochondrial membrane by antiapoptotic Bcl-2-like proteins reduces the cytotoxic potential of most of these drugs. Targeting of specific PTPC components may overcome this Bcl-2-mediated apoptosis inhibition. One strategy involves cross-linking of critical redox-sensitive thiol groups within the PTPC; another involves the use of ligands to the mitochondrial benzodiazepine receptor. Thus, the design of mitochondrion-targeted cytotoxic drugs may constitute a novel strategy for overcoming apoptosis resistance.

Is mantle cell lymphoma a sex-related disease?

Mantle cell lymphomas are characterized by a male predominance with a range between 55 and 65 years (sex ratio M/F of 6.5). When the sex ratio of patients having mantle cell lymphoma was compared to that of each of the subtypes of non-Hodgkin's lymphomas, it was significantly higher in all cases except Burkitt's and lymphoblastic T-cell lymphomas. These observations suggest a possible relation between the chromosome X and mantle cell lymphomas which has to be explored.

Efficacy of autologous stem cell transplantation in mantle cell lymphoma: a 3-year follow-up study.

This study was designed to evaluate the efficacy of therapeutic intensification with autologous stem cell transplantation (ASCT) for mantle cell lymphomas (MCL) in terms of response rate, duration of response, and event-free and overall survivals. Twenty-four patients with confirmed MCL responding to chemotherapy received a high-dose chemo-radiotherapy regimen followed by ASCT. Transplantation was performed during first-line therapy in nine cases, second-line in 13 cases and third-line in two cases. The source of hematopoietic stem cells was peripheral blood for 19 cases. At the time of ASCT, eight patients were in complete remission (33%). Seventeen of the 24 cases received an intensified regimen with TBI and seven received the BEAM or the BEAC regimen. After transplantation, 19 patients were in CR (79%). Nine of these were alive in continued CR at a median follow-up of 34 months, while seven relapsed at a median of 18 months. One patient died from Pneumocystis carinii interstitial pneumonitis and five patients developed secondary malignancies. With a median follow-up after transplantation of 34 months, the 3-year event-free survival was 55% and the 3-year overall survival was 68%. These results indicate that therapeutic intensification with ASCT might be an effective treatment for mantle cell lymphomas. Bone Marrow Transplantation (2000) 25, 251-256.

Low-grade stage III-IV follicular lymphoma: multivariate analysis of prognostic factors in 484 patients--a study of the groupe d'Etude des lymphomes de l'Adulte.

PURPOSE: To identify the prognostic factors that influence overall survival (OS) in patients with stage III-IV follicular lymphomas and evaluate the clinical usefulness and the prognostic value of the International Prognostic Index (IPI). PATIENTS AND METHODS: Four hundred eighty-four patients with Ann Arbor stage III-IV follicular lymphomas treated in two phase III trials from 1986 to 1995 were screened for this study. All histologic slides were reviewed by two hematopathologists. The influence of the initial parameters on survival was defined by univariate (log-rank test) and multivariate (Cox model) analyses. RESULTS: The poor prognostic factors for OS (age > 60 years, "B" symptom(s), > or = two extranodal sites, stage IV disease, tumor bulk > 7 cm, at least three nodal sites > 3 cm, liver involvement, serous effusion-compression or orbital/epidural involvement, and erythrocyte sedimentation rate > 30 mm/h) that were significant in univariate analysis were subjected to multivariate analysis. Three factors remained significant: B symptom(s) (risk ratio = 1.80), age greater than 60 years (risk ratio = 1.60), and at least three nodal sites greater than 3 cm (risk ratio = 1.71). When the IPI was applied to these patients, the score was 1, 2, 3, and 4-5 in 49%, 39%, 11%, and 2%, respectively, and it was significant for progression-free survival (P =.002) and OS (P =.0001). CONCLUSION: Three prognostic factors for poor OS were identified: B symptoms, age greater than 60 years, and at least three nodal sites greater than 3 cm. The IPI was prognostic for OS, but in this population, a very low number of patients belonged to the high-risk groups.

Arsenite induces apoptosis via a direct effect on the mitochondrial permeability transition pore.

The molecular mode of action of arsenic, a therapeutic agent employed in the treatment of acute promyelocytic leukemia, has been elusive. Here we provide evidence that arsenic compounds may act on mitochondria to induce apoptosis. Arsenite induces apoptosis accompanied by a loss of the mitochondrial transmembrane potential (Delta Psim). Inhibition of caspases prevents the arsenite-induced nuclear DNA loss, but has no effect on the Delta Psim dissipation and cytolysis induced by arsenite. In contrast, Bcl-2 expression induced by gene transfer prevents all hallmarks of arsenite-induced cell death, including the Delta Psim collapse. PK11195, a ligand of the mitochondrial benzodiazepine receptor, neutralizes this Bcl-2 effect. Mitochondria are required in a cell-free system to mediate arsenite-induced nuclear apoptosis. Arsenite causes the release of an apoptosis-inducing factor (AIF) from the mitochondrial intermembrane space. This effect is prevented by the permeability transition (PT) pore inhibitor cyclosporin A, as well as by Bcl-2, which is known to function as an endogenous PT pore antagonist. Arsenite also opens the purified, reconstituted PT pore in vitro in a cyclosporin A- and Bcl-2-inhibitible fashion. Altogether these data suggest that arsenite can induce apoptosis via a direct effect on the mitochondrial PT pore.