Diffuse large B-cell lymphoma of Waldeyer's ring has distinct clinicopathologic features: a GELA study.

BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) arising in specific extranodal sites have peculiar clinicopathologic features. PATIENTS AND METHODS: We analyzed a cohort of 187 primary Waldeyer's ring (WR) DLBCLs retrieved from GELA protocols using anthracyclin-based polychemotherapy. RESULTS: Most patients (92%) had stage I-II disease. A germinal center B-cell-like (GCB) immunophenotype was observed in 61%, and BCL2 expression in 55%, of WR DLBCLs. BCL2, BCL6, IRF4 and MYC breakpoints were observed in, respectively, 3 of 42 (7%), 9 of 36 (25%), 2 of 26 (8%) and 4 of 40 (10%) contributive cases. A variable follicular pattern was evidenced in 30 of 68 (44%) large biopsy specimens. The 5-year progression-free survival (PFS) and the overall survival (OS) of 153 WR DLBCL patients with survival information were 69.5% and 77.8%, respectively. The GCB immunophenotype correlated with a better OS (P = 0.0015), while BCL2 expression predicted a worse OS (P = 0.037), an effect overcome by the GCB/non-GCB classification. Compared with matched nodal DLBCLs, WR DLBCLs with no age-adjusted international prognostic index factor disclosed a better 5-year PFS rate (77.5% versus 70.7%; P = 0.03). CONCLUSIONS: WR DLBCLs display distinct clinicopathologic features compared with conventional DLBCLs, with usual localized-stage disease, common follicular features and a high frequency of GCB immunophenotype contrasting with a low rate of BCL2 rearrangements. In addition, they seem to be associated with a better outcome than their nodal counterpart.

[Monoclonal antibodies in hematology in 2009]. / Les anticorps monoclonaux en hématologie en 2009.

Directed against the CD20 antigen on B lymphocytes, rituximab (MabThera) is now incorporated in the first line therapy of symptomatic follicular as well as diffuse large B cell non-Hodgkin's lymphoma and offers superior response and survival rates. 90Y ibritumomab tiuxetan (Zevalin) combines the specificity of rituximab for the CD20 antigen and the therapeutic effect of beta irradiation. Given in monotherapy, it constitutes an interesting alternative therapy for follicular lymphomas in second relapse. Alemtuzumab (MabCampath) recognizes the CD52 antigen and offers encouraging results in chronic lymphocytic leukemia resistant to classical chemotherapy.

[Radiation recall dermatitis after oral cyclophosphamide]. / Le cas clinique du mois. Réaction de rappel d'irradiation induite par l'administration de cyclophosphamide.

Radiation recall dermatitis is an inflammatory skin reaction occurring in a previously irradiated field following the delivery of a promoting agent. It has been described after a number of antineoplastic agents such as gemcitabine, taxanes, anthracyclines. We report the case of a 50-year-old man with metastatic prostate cancer who developed two consecutive radiation recall dermatitis episodes triggered by oral cyclophosphamide. They occurred 4 to 5 weeks after palliative radiotherapy on bone metastasis. Spontaneous resolution was observed within 6 weeks after discontinuation of cyclophosphamide and with local supportive care. To our knowledge this is the first reported case of radiation recall dermatitis after oral cyclophosphamide.

[Monoclonal antibodies and breast cancer. Current therapeutic progress]. / Anticorps monoclonaux et cancer du sein. Actualités thérapeutiques.

About 9,500 new breast cancers are diagnosed in Belgium every year. Improvement of our knowledge of altered molecular events leading to the proliferation of tumor cells has resulted in the development of targeted therapies in subgroups of cancers. One of the first validation of targeted therapy is the anti-HER-2 monoclonal antibody trastuzumab (Herceptin) in patients with overexpression of human epidermal growth factor receptor type 2 (HER2) occurring in 20 to 25% of invasive breast carcinoma. Trastuzumab binds the extracellular juxtamembrane domain and is only active in tumor with HER2 gene amplification detected by fluorescence in situ hybridization (FISH). The results from randomized trials have rapidly lead to the approvement of the drug in the metastatic and then in the adjuvant setting. Another targeted therapy, also approved in the treatment of breast cancer, is the monoclonal antibody bevacizumab with an anti-VEGF (Vascular Endothelial Growth Factor) activity. We will review the benefit of these targeted therapies in breast cancer and their role in the treatment of breast cancer.

[Current treatment of follicular lymphoma]. / Traitements actuels du lymphome folliculaire.

After diffuse large B-cell lymphoma, follicular lymphoma is the most frequent non-Hodgkin's lymphoma. It remains incurable, except for localized diseases. Advanced disease has to be treated only in the presence of clinical and/or biology aggressiveness. These patients should be treated by rituximab (Mab-Thera) associated to polychemotherapy comprising cyclophosphamide, vincristine and prednisone. After this therapy, the benefit of rituximab in maintenance has to be confirmed. Autologous stem cell transplantation is now reserved for young patients in first relapse. Allogenic stem cell transplantation is also an interesting option. The other therapeutic options comprise radio-immunotherapy with 90Y ibritumomab tiuxetan (Zevalin) and bortezomib (Velcade).

[How I treat... Acute myeloid leukemia in older patients with good performance status]. / Comment je traite...La leucémie myéloblastique aiguë (LMA) du sujet âgé en bon état général.

This article describes the treatment of acute myeloid leukemia in older patients with good performance status, and then discusses briefly some future therapeutic perspectives.

Storage iron kinetics. VII. A biologic model for reticuloendothelial iron transport.

The processing of erythrocyte iron by the reticuloendothelial cell has been characterized by kinetic measurements of blood radioactivity made after the intravenous injection of heat-damaged erythrocytes labeled with (59)Fe and of transferrin-bound (55)Fe. The early reticuloendothelial release of iron, a matter of hours, was calculated from the plasma turnover rate of (55)Fe and the plasma reappearance of (59)Fe. Late release was calculated from the ratio of the cumulative incorporation of both tracers into the circulating red cell mass over a period of 2 wk. There was an initial processing period within the reticuloendothelial cell, after which radioiron either rapidly returned to circulation (t(1/2) 34 min) or was transferred to a slowly exchanging pool of storage iron within the reticuloendothelial cell (t(1/2) release to plasma of 7 days). These pathways were of equal magnitude in the normal dog. Reticuloendothelial release of iron was largely independent of the pre-existing plasma iron level or transferrin saturation. Diurnal fluctuations in the plasma iron level were shown to be the result of a variable partitioning of iron between the early and late release phases. Acute inflammation resulted in a prompt and marked increase in the fraction of iron stored (late phase), whereas depletion of iron stores resulted in a marked increase in early release.

Non-infusional vs intravenous consolidation chemotherapy in elderly patients with acute myeloid leukemia: final results of the EORTC-GIMEMA AML-13 randomized phase III trial.

In this trial, acute myeloid leukemia patients (pts) aged 61-80 years received MICE (mitoxantrone, etoposide and cytarabine) induction chemotherapy in combination with different schedules of granulocyte colony-stimulating factor administration. Pts in complete remission were subsequently randomized for two cycles of consolidation therapy: mini-ICE regimen (idarubicin, etoposide and cytarabine) given according to either an intravenous (i.v.) or a 'non-infusional' schedule. Among the 346 pts randomized for the second step, 331 pts received consolidation-1 and 182 consolidation-2. A total of 290 events (255 relapses, 35 deaths in first CR) have been reported. The median follow-up was 4.4 years. No significant differences were detected in terms of disease-free survival (median 9 vs 10.4 months, P=0.15, hazard ratio (HR) =1.18, 95% confidence interval (CI) 0.94-1.49) - primary end point - and survival (median 15.7 vs 17.8 months, P=0.19, HR=1.17, 95% CI 0.92-1.50). In the 'non-infusional' arm grade 3-4 vomiting (10 vs 2%; P=0.001) and diarrhea (10 vs 4%; P=0.03) were higher than in the 'i.v.' arm, whereas time to platelet recovery >20 x 10(9)/l (median: 19 vs 23 days; P=0.02) and duration of hospitalization (mean: 15 vs 27 days; P<0.0001) was shorter. The 'non-infusional' consolidation regimen resulted in an antileukemic effect similar to the intravenous regimen, which was less myelosuppressive and associated with less hospitalization days.

[Current therapeutic progress in oncology: the development of targeted therapies]. / Actualités thérapeutiques en oncologie: l'essor des thérapeutiques ciblées.

Over the last decades, significant advances were make in basic research as concerns the malignant transformation of normal cells. As a result, new targets for treatment were identified. "Targeted therapies" indicates that treatments are directed against specific molecular targets that play a major role in the activation of cell division and in the growth and dissemination of tumors. In particular, targeted therapies were developed against epithelial growth factor receptors and angiogenesis. We can expect specifise therapies against many other targets in the near future. Several drugs have obtained a marketing license. Predictive factors for tumor response and long term outcome should be developed for a better selection of the patient population who will benefit from these treatments. New imaging techniques are under development in order to assess the molecular response to these new approaches.

[Chemotherapy of ovarian cancer: state of the art]. / Traitement chimiotérapique actuel du cancer de l'ovaire.

Epithelial ovarian cancer is frequently diagnosed at advanced-stage disease and chemotherapy is nearly always required. Optimally debulked patients may need adjuvant chemotherapy while, most of the time this chemotherapy will be given to those with advanced-stage disease. Also relapses will be treated differently whether they occur early or late in the course of the disease. This paper reviews medical treatment modalities according to stage based on published data. Maintenance and consolidation treatments are also discussed. Finally a brief insight into new therapeutic tools is also given.

[Targeted therapies in breast cancer: current status and perspectives]. / Actualités thérapeutiques en oncologie sénologique: place actuelle et perspectives des traitements ciblés.

The introduction of targeted therapies has largely modified the treatment strategies in oncology. Two targets are currently used for defining the systemic treatment of breast cancer: hormone receptors and HER2 overexpression. Trastuzumab, a monoclonal antibody, is the only registered antiHER2 treatment in Belgium. The association of trastuzumab with chemotherapy is now the recommended adjuvant treatment for early breast cancer overexpressing HER2. Other antiHER2 medications are available and some will probably be registered soon. Angiogenesis is another potential target for improving the treatment results. The CHU Liège, as a reference center for the systemic treatment of solid tumors, participates in many international trials in order to validate these new approaches. The highest quality of care is required to be in compliance with the conduct of these clinical trials. Another benefit for the patient is the easy access to last generation medical treatments, generally not accessible in our health care system in Belgium outside of clinical trials.

[Current therapies in hematology]. / Actualités thérapeutiques en hématologie.

This article focuses on recent advances in four important areas of hematology: aggressive lymphomas, allogeneic hematopoietic stem cell transplantation, multiple myeloma, and molecular therapy of cancer.

Infections after allogeneic hematopoietic stem cell transplantation with a nonmyeloablative conditioning regimen.

Hematopoietic cell transplantation (HCT) following nonmyeloablative conditioning (NMSCT) may be associated with a reduced risk of infection compared to standard allogeneic HCT. We retrospectively analyzed incidence and risk factors of infection in 62 patients undergoing NMSCT with low-dose TBI +/- fludarabine and postgrafting CsA and MMF. The proportion of patients with any infection was 77%, but the majority of infectious events occurred beyond day 30. Donor other than sibling, older age, early disease and male gender were significant risk factors. The incidence of bacteremia was 55% at 1 year and the number of bacteremic episodes was 0.9 per patient (0.08 before day 30). The risk of bacteremia increased with older age and the use of a donor other than an HLA-identical sibling, but not with neutropenia. The incidence of infections other than bacteremia correlated with the use of corticosteroids. The risk of CMV infection increased with high-risk CMV serology, and risk of CMV disease with high-risk CMV serology, older age, first transplantation and a diagnosis of lymphoma. In conclusion, after NMSCT, infections are not frequent in the first 30 days post transplant but careful long-term monitoring is necessary thereafter.

[Hic et Nunc. Naevus or melanoma?]. / Hic et Nunc. Naevus ou mélanome?

In Wallonia, the incidence of cutaneous melanoma has steadily increased over the past decades. Hopefully, the early diagnosis made at the premetastatic stage has benefited from great advances both in the clinical and laboratory fields. Thanks to the "Groupement Oncologique Universitaire Wallonie-Liège" (GOUWL) organization, some efforts are currently made in order to better frame and normalize the management of cancer patients. Some medical staffs involved in prospective clinical research bring by their own experience further practical insights for the benefit to the patients. In this field, Belgium is not destituted. We report a brief review of the contribution of the Mosan Study Group of Pigmentary Tumors (GMETP) at the University Hospital of Liège.

Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy--the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon Group.

PURPOSE AND METHODS: Optimization of remission-induction and postremission therapy in elderly individuals with acute myeloid leukemia (AML) was the subject of a randomized study in patients older than 60 years. Remission-induction chemotherapy was compared between daunomycin (DNR) 30 mg/m2 on days 1, 2, and 3 versus mitoxantrone (MTZ) 8 mg/m2 on days 1, 2, and 3, both plus cytarabine (Ara-C) 100 mg/m2 on days 1 to 7. Following complete remission (CR), patients received one additional cycle of DNR or MTZ chemotherapy and were then eligible for a second randomization between eight cycles of low-dose (LD)-Ara-C 10 mg/m2 subcutaneously every 12 hours for 1 2 days every 6 weeks or no further treatment. RESULTS: A total of 242 patients was randomized to DNR and 247 to MTZ. Median age of both study groups was 68 years. Secondary AML was documented in 26% and 25% of patients in either arm. The probability of attaining CR was greater (P = .069) with MTZ (47%) than with DNR (38%). Median duration of neutropenia was 19 (DNR) and 22 days (MTZ). The greater response rate to MTZ therapy correlated with reduced occurrence of chemotherapy resistance (32% v 47%, P = .001). With a median follow-up of 6 years, 5-year disease-free survival (DFS) is 8% in each arm. Overall survival estimates are not different between the groups (6% v 9% at 5 yrs). Poor performance status at diagnosis, high WBC count, older age, secondary AML, and presence of cytogenetic abnormalities all had an adverse impact on survival. Secondary AML and abnormal cytogenetics predicted for shorter duration of CR. Among complete responders, 74 assessable patients were assigned to Ara-C and 73 to no further therapy. Actuarial DFS was significantly longer (P = .006) for Ara-C-treated (13% [SE = 4.0%] at 5 years) versus nontreated patients (7% [SE = 3%]), but overall survival was similar (P = .29): 18% (SE = 4.6%) versus 15% (SE = 4.3%). Meta-analysis on the value of Ara-C postremission therapy confirms these results. CONCLUSION: In previously untreated elderly patients with AML, MTZ induction therapy produces a slightly better CR rate than does a DNR-containing regimen, but it has no significant effect on remission duration and survival. Ara-C in maintenance may prolong DFS, but it did not improve survival.

Soluble CD23 and other receptors (CD4, CD8, CD25, CD71) in serum of patients with chronic lymphocytic leukemia.

We measured the soluble (s) receptors CD23, CD8, CD4, interleukin-2 receptor (IL-2R, CD25), and transferrin receptor (TfR, CD71), in normal serum and in patients with chronic lymphocytic leukemia (CLL) and evaluated them in relation to clinical and biological parameters of the disease, as well as serum immunoglobulin E (IgE). Compared to 31 normal individuals, 42 CLL patients had increased levels of sCD23 (98.4 +/- 127.7 versus 0.9 +/- 0.3 U/ml, p < 0.001), sIL-2R (6080 +/- 7030 versus 1420 +/- 640 pg/ml, p < 0.001), sTfR (12,100 +/- 11,250 versus 5000 +/- 1050 ng/ml, p < 0.001), and sCD8 (510 +/- 191 versus 234 +/- 89 U/ml, p < 0.001), but normal sCD4 levels. Mean sCD23 levels remained normal in patients with non-Hodgkin's lymphoma (other than small lymphocytic), Hodgkin's disease, hairy cell leukemia, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), multiple myeloma, or solid tumors. Advancing Rai clinical stage was associated with a progressive elevation of sCD23 (p < 0.001), while sCD8 (p < 0.05), sIL-2R (p < 0.001), and sTfR (p < 0.005) were highest in stage 2 patients. Discriminant analysis confirmed the value of soluble receptor determinations in the clinical evaluation of CLL patients. sCD23 correlated with sIL-2R (p < 0.001) and sTfR (p < 0.05) but not with sCD4 or sCD8, and displayed an inverse relationship with serum IgE (NS) and total gamma-globulin (p < 0.05). sIL-2R correlated with sCD23 (p < 0.001), sTfR (p < 0.001), sCD4 (p < 0.01), and sCD8 (p < 0.01). The lymphocyte count correlated with serum lactate dehydrogenase (LDH) (p < 0.05), sCD23 (p < 0.001) and sIL-2R (p < 0.01) but not sTfR, sCD8, or sCD4. Chemotherapy produced consistent reductions of sCD23 levels in two responding patients. We conclude that: (i) sCD23 is considerably elevated in CLL, correlates with the tumor mass and clinical stage, and could be helpful in monitoring these patients; and (ii) sIL-2R, sCD8, and sTfR levels are less specifically increased and could be influenced by other factors such as immune activation and erythropoiesis.

Multicenter randomized phase II trial of idarubicin vs mitoxantrone, combined with VP-16 and cytarabine for induction/consolidation therapy, followed by a feasibility study of autologous peripheral blood stem cell transplantation in elderly patients with acute myeloid leukemia.

To compare the antileukemic efficacy of idarubicin and mitoxantrone in elderly patients with acute myeloid leukemia (AML) and to evaluate the feasibility of autologous transplantation using PBSC after consolidation in those with a good performance status, 160 patients (median age 69 years), with AML at diagnosis, 118 of them with de novo AML and 42 with AML secondary to myelodysplastic syndrome or toxic exposure (sAML), received induction treatment with idarubicin, 8 mg/m2/day or mitoxantrone, 7 mg/m2/day, on days 1, 3, and 5, both combined with VP-16, 100 mg/m2/day on days 1 to 3 and cytarabine (araC), 100 mg/m2/day, on days 1 to 7. G-CSF, 5 microg/kg/day, was administered after chemotherapy in patients aged more than 70 years. Patients in complete remission (CR) received one course of consolidation using the same schedule as for induction except the araC administration was shortened to 5 days. Some patients younger than 70 years were then scheduled for autologous stem cell harvest on days 5 to 7 of G-CSF, 5 microg/kg/day, initiated after hematopoietic recovery from consolidation. Autologous transplantation was performed following an additional chemotherapy conditioning. Ninety-five patients (59%) achieved CR, without significant difference between the idarubicin (56% CR) and mitoxantrone (63% CR) group. There was also no significant difference in CR rate between de novo AML (63%) and secondary AML (55%) (P = 0.12). Patients aged < 70 years had 67% CR, while patients aged > or = 70 years had 49% (P = 0.02). There was no significant difference in the duration of aplasia between the two arms. Median time to neutrophil recovery was 22 days in patients who received G-CSF following induction and 27 days in patients who did not (P = 0.006). Severe extrahematologic toxicities of induction did not differ between the two arms and included sepsis (39%), diarrhea (13%), hyperbilirubinemia (8%), hemorrhage (6%) and vomiting (6%). Overall, 14 patients (9%), died from toxicity of induction. First consolidation was administered in 74 patients of whom seven (9%) died from toxicity. Nineteen patients have received transplantation. Median time to recovery of neutrophils > 0.5 x 10(9)/l was 13 days and of platelets > 50 x 10(9)/l 43 days following consolidation. There were two toxic deaths. Median disease-free survival and survival from time of achieving CR of non transplanted patients are 6 and 7 months respectively without difference between the two arms. Fourteen transplanted patients relapsed at a median of 5 months post-transplant. We conclude that this regimen is well tolerated and has a good efficacy to induce CR, without a significant difference in efficacy and toxicity between idarubicin and mitoxantrone. Intensive postinduction, including transplantation, is feasible; however, this procedure did not seem to prevent early relapse in the majority of patients. Neither the high rate of CR nor consolidation nor transplant procedure in a selected group of patients did translate into improved DFS and/or survival.

The stem cell mobilizing capacity of patients with acute myeloid leukemia in complete remission correlates with relapse risk: results of the EORTC-GIMEMA AML-10 trial.

Variable numbers of CD34+ cells can be harvested from the blood of AML patients in CR after G-CSF supported mobilization following consolidation chemotherapy. We hypothesized that a decreased ability to mobilize stem cells reflects a chemotherapy-induced reduction in the number of normal and leukemic stem cells. We therefore analyzed whether the mobilizing capacity of these patients was of prognostic significance. 342 AML-patients in first CR received daily G-CSF from day 20 of the consolidation course and underwent 1-6 aphereses to obtain a minimum dose of 2 x 10(6) CD34+ cells/kg. Afterwards they were randomized for autologous bone marrow (BM) or blood SCT. As a surrogate marker for the mobilizing capacity, the highest yield of CD34+ cells of a single apheresis was adopted. Patients could be categorized into four groups: no harvest (n = 76), low yield (<1 x 10(6) CD34+/kg; n = 50), intermediate yield (1-6.9 x 10(6) CD34+ cells/kg; n = 128) and high yield (> or = 7 x 10(6) CD34+ cells/kg; n = 88). The median follow-up was 3.4 years; 163 relapses and 16 deaths in CR were reported. Autologous blood or BM SCT was performed in 36%, 64%, 81% and 88%, respectively, of the patients assigned to the no harvest, low, intermediate and high CD34+ yield group. The 3-year disease-free survival rate was 46.7%, 65.0%, 50.4% and 26.9% (P = 0.0002) and the relapse incidence was 47.5%, 30.1%, 43.1% and 71.9% (P < 0.0001). Multivariate Cox's proportional hazards model showed that the CD34+ yield was the most important independent prognostic variable (P = 0.005) after cytogenetics. Patients with the highest mobilizing capacity have a poor prognosis due to an increased relapse incidence.

[Anemia by self-injury: the Lasthenie de Ferjol syndrome]. / L'anémie par spoliation sanguine volontaire: le syndrome de Lasthénie de Ferjol.

Patients with factitious disorders need to be ill and to defy physicians. These syndromes are difficult to diagnose because of the permanent disorder appearing inside the therapeutic relation. The case of a young woman who presents with a factitious anemia, also called Lasthenie de Ferjol syndrome, shows the complexity of such psychosomatic symptoms.

Comparative cytokine production by in vitro stimulated mononucleated cells from cord blood and adult blood.

Cord blood transplantations successfully reconstituted hemopoiesis in patients treated with myeloablative therapies. These transplantations were associated with a low rate of acute graft-versus-host disease (aGVHD), a major life-threatening complication of allo-transplantation. The physiopathology of aGVHD implies the recognition of host alloantigens by donor T cells but also involves a cytokine cascade. In this cascade, interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma) produced by donor T cells and monocytes/macrophages play a major effector role. Therefore, we investigated whether the lower percentage of aGVHD in cord blood transplants could be related to a lower ability to produce these cytokines in vitro compared with adult blood. Mononucleated cells (MNCs) isolated from term cord blood and adult peripheral blood were stimulated with a combination of lipopolysaccharide and phytohemaglutinin and incubated for 96 hours. Levels of IL-1beta, IL-2, IL-3, IL-4, IL-6, TNF-alpha, IFN-gamma, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured in the supernatants after various times of incubation. The productions of IL-1beta, IL-6, and GM-CSF were similar in stimulated cord and adult blood and IL-3 levels, though lower and delayed in cord blood, were not statistically different. On the other hand, we found markedly lower levels of IFN-gamma, TNF-alpha, and IL-4 in cord blood throughout the incubation period. The stimulated levels of IL-2 were similar in cord and adult samples throughout the first 48 hours of incubation but became significantly lower in cord blood after 72 and 96 hours. We suggest that the cytokine production pattern that characterizes cord blood could provide an explanation for the lower occurence of aGVHD following cord blood transplants.