Survival, neurocognitive function, and health-related quality of life outcomes after rituximab-methotrexate, BCNU, teniposide, and prednisolone for primary CNS lymphoma: Final results of the HOVON 105/ALLG NHL 24 study.

BACKGROUND: Studies on the efficacy of rituximab in primary CNS lymphoma (PCNSL) reported conflicting results. Our international randomized phase 3 study showed that the addition of rituximab to high-dose methotrexate, BCNU, teniposide, and prednisolone (MBVP) in PCNSL was not efficacious in the short term. Here we present long-term results after a median follow-up of 82.3 months. METHODS: One hundred and ninety-nine eligible newly diagnosed, nonimmunocompromised patients with PCNSL aged 18-70 years with WHO performance status 0-3 was randomized between treatment with MBVP chemotherapy with or without rituximab, followed by high-dose cytarabine consolidation in responding patients, and reduced-dose WBRT in patients aged ≤ 60 years. Event-free survival was the primary endpoint. Overall survival rate, neurocognitive functioning (NCF), and health-related quality of life (HRQoL) were additionally assessed, with the IPCG test battery, EORTC QLQ-C30 and QLQ-BN20 questionnaires, respectively. RESULTS: For event-free survival, the hazard ratio was 0.85, 95% CI 0.61-1.18, P = .33. Overall survival rate at 5 years for MBVP and R-MBVP was 49% (39-59) and 53% (43-63) respectively. In total, 64 patients died in the MBVP arm and 55 in the R-MBVP arm, of which 69% were due to PCNSL. At the group level, all domains of NCF and HRQoL improved to a clinically relevant extent after treatment initiation, and remained stable thereafter up to 60 months of follow-up, except for motor speed which deteriorated between 24 and 60 months. Although fatigue improved initially, high levels persisted in the long term. CONCLUSIONS: Long-term follow-up confirms the lack of added value of rituximab in addition to MBVP and HD-cytarabine for PCNSL.

First-line induction chemotherapy with high-dose methotrexate versus teniposide in patients with newly diagnosed primary central nervous system lymphoma: a retrospective, multicenter cohort study.

BACKGROUND: This study aimed to compare the efficacy and safety of high-dose methotrexate (HD-MTX) versus teniposide (TEN) in patients with newly diagnosed immunocompetent primary central nervous system lymphomas (PCNSLs). METHODS: The study included immunocompetent, adult patients with newly diagnosed PCNSL at 22 centers in China from 2007 to 2016. The patients received HD-MTX or TEN as first-line induction therapy. The objective response rate, progression-free survival, and overall survival were analyzed for each patient cohort. RESULTS: A total of 96 patients were eligible: 62 received HD-MTX, while 34 received teniposide. The overall response rate was 73.2% and 72.7% in the MTX and the TEN cohorts, respectively (P = 0.627). The median progression-free survival was 28.4 months [95% confidence interval (CI): 13.7-51.2] in the MTX cohort and 24.3 months (95% CI: 16.6-32.1) in the TEN cohort (P = 0.75). The median overall survival was 31 months (95% CI: 26.8-35.2) in the MTX cohort and 32 months (95% CI: 27.6-36.4) in the TEN cohort (P = 0.77). The incidence of any grade of coagulopathy/deep-vein thrombosis and gastrointestinal disorders was significantly higher in the MTX cohort than in the TEN cohort; no significant difference was found in the incidence of other adverse events between the two cohorts. CONCLUSIONS: This was the first multicenter study using TEN as the main agent compared with HD-MTX in newly diagnosed primary CNS lymphoma. The TEN-based regimen was non-inferior to the HD-MTX-based regimen with similar overall responses. CLASSIFICATION OF EVIDENCE: This study provided Class III evidence that the teniposide-based regimen was non-inferior to high-dose methotrexate - based regimen with similar overall responses and long-time survival in immunocompetent patients with PCNSL.

AL amyloidosis: untangling new therapies.

Systemic light chain (AL) amyloidosis is a protein misfolding disorder characterized by the deposition of abnormal immunoglobulin light chains in fibrillary aggregates, resulting in end-organ damage. Several unique challenges face treating physicians, including delayed diagnosis, advanced vital organ involvement, and morbidity with treatment. Aggressive supportive care and risk-adapted application of plasma cell-directed therapies are the cornerstones of management. The therapeutic revolution in multiple myeloma will likely further expand the arsenal against plasma cells. Careful investigation of these agents will be critical to establish their role in this fragile population. The promise of fibril-directed therapies to restore organ function remains despite early disappointments. In this review, we discuss new therapies to tackle AL amyloidosis using a case-based approach.

Identification and Characterization of Alcohol-related Hepatocellular Carcinoma Prognostic Subtypes based on an Integrative N6-methyladenosine methylation Model.

Background: Alcohol consumption increases the risk of hepatocellular carcinoma (HCC), and associated with a high mortality rate and poor prognosis. N6-methyladenosine (m6A) methylations play key roles in tumorigenesis and progression. However, our current knowledge about m6A in alcohol-related HCC (A-HCC) remains elucidated. Herein, the authors construct an integrative m6A model based on A-HCC subtyping and mechanism exploration workflow. Methods: Based on the m6A expressions of A-HCC and in vivo experiment, different prognosis risk A-HCC subtypes are identified. Meanwhile, multiple interdependent indicators of prognosis including patient survival rate, clinical pathological prognosis and immunotherapy sensitivity. Results: The m6A model includes LRPPRC, YTHDF2, KIAA14219, and RBM15B, classified A-HCC patients into high/low-risk subtypes. The high-risk subtype compared to the low-risk subtype showed phenotypic malignancy, poor prognosis, immunosuppression, and activation of tumorigenesis and proliferation-related pathways, including the E2F target, DNA repair, and mTORC1 signalling pathways. The expression of Immunosuppressive cytokines DNMT1/EZH2 was up-regulated in A-HCC patients, and teniposide may be a potential therapeutic drug for A-HCC. Conclusion: Our model redefined A-HCC prognosis risk, identified potential m6As linking tumour progress and immune regulations and selected possible therapy target, thus promoting understanding and clinical applications about A-HCC.

Efficacy and tolerability of VCD chemotherapy in a UK real-world dataset of elderly transplant-ineligible newly diagnosed myeloma patients.

OBJECTIVE: There are limited data on the efficacy and tolerability of VCD chemotherapy in transplant-non-eligible (TNE) newly diagnosed myeloma (NDMM) patients. In this retrospective study, we set out to evaluate this triplet combination in this setting across Thames Valley Cancer Network (UK). METHODS: The primary end point was overall response rate (ORR). Secondary outcomes included event-free survival (EFS), overall survival (OS) and adverse events (AEs). RESULTS: In a total cohort of 158 patients, ORR for total cohort was 72.1%. Median EFS was 10.5 months, and for subgroups by age (<75:11.7 vs ≥75:10.3 months, P = .124), by Charlson Co-morbidity Index (CCI) (<5:11.1 vs ≥5:8.2 months, P = .345). The 4-month landmark analysis showed the following median EFS results: by cumulative bortezomib dose (≥26 mg/m2 : 9.0 months vs <26 mg/m2 : 6.4, P = .13), by cumulative cyclophosphamide dose (≥7000 mg: 9.2 vs <7000 mg: 7.0 months, P = .02) and by cumulative dexamethasone dose (>600 mg: 7.8 vs ≤600 mg: 8.3 months, P = .665). Median OS was 46.9 months. The incidence rate of AE was as follows: any grade (76.8%), ≥G3 (27.1%), ≥G3 haematological AEs (7.9%), any grade infections (31.1%) and ≥G3 infections (11.9%). CONCLUSION: This study demonstrated a good ORR achieved from fixed duration VCD, which was reasonably well tolerated. This was followed by modest median EFS. We envisage that the latter may be improved in this patient group with the use of a higher cumulative bortezomib dose (≥26 mg/m2 ) which showed a trend for improved EFS although without statistical significance (P = .13), and with the use of a higher cumulative cyclophosphamide doses (≥7000 mg, P = .02), subject to tolerability and close monitoring.

Bleomycin, vinblastine and dacarbazine combined with nonpegylated liposomal doxorubicin (MBVD) in elderly (≥70 years) or cardiopathic patients with Hodgkin lymphoma: a phase-II study from Fondazione Italiana Linfomi (FIL).

This phase-II study assessed activity and toxicity of substituting conventional doxorubicin with nonpegylated liposomal doxorubicin in the conventional ABVD regimen for the treatment of elderly or cardiopathic patients with HL. Stage I-IIA and IIB-IV patients were treated with three courses of MBVD plus radiotherapy, or six courses of MBVD, respectively, plus radiotherapy limited to bulky or residual disease areas. The primary endpoints were CR rate and the rate of cardiac events. Forty-seven patients were enrolled. Median age was 75 years, 13 had stage I-II disease. Overall, CR was achieved by 36 patients (77%, 95% CI: 62-88), 100% and 68% in stage I-II and III-IV, respectively. With a median follow-up of 40 months (IQR: 36-45). Three-year overall survival (OS) and progression-free survival (PFS) were 70% and 43%, respectively. Cardiac events grades 3-5 were reported in two patients. In conclusion, MBVD's activity and safety profile was comparable to historical ABVD data.

Upfront bortezomib, lenalidomide, and dexamethasone compared to bortezomib, cyclophosphamide, and dexamethasone in multiple myeloma.

OBJECTIVES: At our center, patients with multiple myeloma (MM) were treated upfront with bortezomib, cyclophosphamide, and dexamethasone (VCD) until cyclophosphamide was replaced with lenalidomide in the combination (VRD). These treatments have never been compared head-to-head in large real-life patient material. METHOD: A retrospective analysis of patients treated with VRD and VCD in the first line, both with and without subsequent high-dose treatment (HDT) and autologous stem cell transplantation. A total of 681 patients were included, 117 receiving VRD (71 with, 46 without HDT) and 564 receiving VCD (351 with, 213 without HDT). RESULTS: Overall response rate (≥partial response) was higher with VRD compared to VCD in the entire VRD group (98% vs 88%, P < 0.001) and in the non-HDT group (98% vs 79%, P < 0.001). Progression-free survival (PFS) at 18 months was longer with VRD compared to VCD in the entire VRD group, the non-HDT group and the HDT group (88% vs 63%, 82% vs 32% and 91% vs 73%, respectively). Overall survival at 18 months was better for VRD-treated patients in the entire VRD group (95% vs 89%, P = 0.048). CONCLUSION: Upfront VRD gives better responses and longer PFS compared to VCD in MM patients with or without subsequent HDT.

Anorectal involvement in a patient with multiple myeloma.

Multiple myeloma is a neoplastic proliferation of monoclonal plasma cells. Symptomatic gastrointestinal involvement is uncommon. We report the case of a 45-year-old patient admitted with an anorectal polypoid lesion, which progressed to colonic obstruction. Investigation revealed a secondary plasmacytoma associated with multiple myeloma. We discuss the characteristics of this rare entity with poor prognosis, its clinical implications and treatment options.

Myoinositol as a Biomarker in Recurrent Glioblastoma Treated with Bevacizumab: A 1H-Magnetic Resonance Spectroscopy Study.

BACKGROUND: Antiangiogenic treatment of glioblastomas with Bevacizumab lacks predictive markers. Myoinositol (MI) is an organic osmolyte, with intracellular concentration changes depending on the extracellular osmolality. Since Bevacizumab markedly reduces tumor edema and influences the tumor microenvironment, we investigated whether the MI concentration in the tumor changes during therapy. METHODS: We used 1H-magnetic resonance spectroscopy to measure the MI concentrations in the tumor and contralateral control tissue of 39 prospectively recruited patients with recurrent glioblastomas before and 8-12 weeks after starting therapy. 30 patients received Bevacizumab and 9 patients were treated with CCNU/VM26 as control. We performed a survival analysis to evaluate MI as a predictive biomarker for Bevacizumab therapy. RESULTS: MI concentrations increased significantly during Bevacizumab therapy in tumor (p < .001) and control tissue (p = .001), but not during CCNU/VM26 treatment. For the Bevacizumab cohort, higher MI concentrations in the control tissue at baseline (p = .021) and higher differences between control and tumor tissue (delta MI, p = .011) were associated with longer survival. A Kaplan-Meier analysis showed a median OS of 164 days for patients with a deltaMI < 1,817 mmol/l and 275 days for patients with a deltaMI > 1,817 mmol/l. No differences were observed for the relative changes or the post treatment concentrations. Additionally calculated creatine concentrations showed no differences in between subgroups or between pre and post treatment measurements. CONCLUSION: Our data suggest that recurrent glioblastoma shows a strong metabolic reaction to Bevacizumab. Further, our results support the hypothesis that MI might be a marker for early tumor cell invasion. Pre-therapeutic MI concentrations are predictive of overall survival in patients with recurrent glioblastoma treated with Bevacizumab.

Preparation and in vitro-in vivo evaluation of teniposide nanosuspensions.

Teniposide (TEN) is a potent, broad spectrum antitumor agent, especially for cerebroma. But the application in clinic was limited because of its poor solubility. In this paper, teniposide nanosuspensions drug delivery system (TEN-NSDDS) for intravenous administration was developed for the first time. Specifically, TEN nanosuspensions were prepared by an anti-solvent sonication-precipitation method and evaluated in comparison with teniposide injection (VUMON) in vitro and in vivo. TEN nanosuspensions prepared showed rod-like morphology and the size was 151 ± 11 nm with a narrow poly dispersion index 0.138 determined by dynamic light scattering. The obtained TEN nanosuspensions were physically stable at least 10 days at 4°C. And the freeze-drying preparations were stable during 3 months. The cytotoxicity of TEN nanosuspensions were considerable to that of VUMON against U87MG and C6 cells in vitro. When tested in rats bearing C6 tumors, the TEN concentration in the tumors treated by the nanosuspensions was more than 20 times than that by the TEN solution at 2h. The TEN nanosuspensions exhibited significant tumor growth inhibition. Overall, the results suggested that nanosuspensions was an alternative formulation for teniposide to be administered intravenously, and it would be a promising formulation in clinic.

Institutional review of primary non-hodgkin lymphoma of the female genital tract: a 33-year experience.

OBJECTIVE: The aim of this is to provide an updated review of the literature and to report our institutional experience with this rare gynecologic malignancy. METHODS: The medical records of patients with diagnosis of non-Hodgkin lymphoma of the female genital tract from 1980 to 2013 at the Yale-New Haven Hospital were reviewed retrospectively. Histological classification and staging were determined by the World Health Organization and Ann Arbor systems, respectively. Kaplan-Meier was used to calculate the survival. RESULTS: There were 36 patients with diagnosis of non-Hodgkin lymphoma of the female genital tract and followed for a median of 61 months (0-361 months). The median age of diagnosis was 44 years (19-87 years), and 76% (n = 28) were classified as stage IV.Of these, 4 patients were asymptomatic on presentation, and 13 were identified incidentally during surgery/radiography (n = 9), on prenatal ultrasound (n = 1), and on Papanicolaou test (n = 3). The location of the disease included the ovary (n = 6), uterine corpus and cervix (n= 9), vagina (n = 1), a pelvic mass (n = 7), isolated pelvic/para-aortic lymph nodes (n = 3), and/or multiple sites (n = 9). There were 6 cases that were concomitant with other gynecologic malignancies.Diffuse large B-cell lymphoma (n= 18) was the most common histologic type. A total of 28 patients underwent surgery. Combination chemotherapy was used in 34 patients, with concomitant radiation therapy in 7 and stem cell transplantation in 3. A total of 5 patients had recurrent disease.The overall median survival from the diagnosis of lymphoma was 70 months (0.3-361 months) with a 91% 1-year survival, 86% 5-year survival, and a 79% 10-year survival. CONCLUSIONS: Our report is the largest published single-institution experience of this disease. It demonstrates a more favorable prognosis and proposes that with early diagnosis and appropriate therapy, radical gynecologic surgery can be avoided.

Higher LRRFIP1 expression in glioblastoma multiforme is associated with better response to teniposide, a type II topoisomerase inhibitor.

Previous studies from this laboratory indicated that microRNA-21 (miR-21) contributes to chemoresistance of glioblastoma multiforme (GBM) cells to teniposide, a type II topoisomerase inhibitor. We also showed that LRRFIP1 is a target of miR-21. In this study, we found that higher baseline LRRFIP1 expression in human GBM tissue (n=60) is associated with better prognosis upon later treatment with teniposide. Experiments in cultured U373MG cells showed enhanced toxicity of teniposide against U373MG cells transfected with a vector that resulted in LRRFIP1 overexpression (vs. cells transfected with control vector). Experiments in nude mice demonstrated better response of LRRFIP1 overexpressing xenografts to teniposide. These findings indicate that high baseline LRRFIP1 expression in GBM is associated with better response to teniposide, and encourage exploring LRRFIP1 as a target for GBM treatment.

Pathologic risk-based adjuvant chemotherapy for unilateral retinoblastoma following enucleation.

BACKGROUND: There are no standardized diagnostic or treatment guidelines for patients with advanced unilateral retinoblastoma. MATERIALS AND METHODS: Patients with advanced unilateral retinoblastoma were prospectively treated after enucleation using a risk-based protocol. Patients were assigned to low risk (LR), intermediate risk (IR), or high risk (HR) based on pathology. LR patients underwent observation. IR patients received 4 courses of chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VDC). In the HR group, patients received 3 courses of VDC alternating with 3 courses of vincristine, carboplatin, and etoposide (VCE) and irradiation when indicated. RESULTS: Fifty patients with advanced unilateral retinoblastoma were treated (LR, n=36; IR, n=7; HR, n=7). All eyes were Reese-Ellsworth group V. All bone scans (n=81), lumbar punctures (n=16), and bone marrow aspirates (n=16) were negative. Chemotherapy was well tolerated. Grades 3/4 hematologic toxicities were seen in all patients; grades 3/4 nonhematologic toxicities were seen in half the patients. Only one patient in the HR group received radiation therapy. All patients were alive at the time of analysis with no signs of disease recurrence. Median follow-up was 3.4 years (range, 0.8 to 6.4 y). CONCLUSIONS: Patients with nonmetastatic unilateral retinoblastoma undergoing primary enucleation can be cured with a graduated intensity approach based on pathology.

Reversal of multidrug resistance by mitochondrial targeted self-assembled nanocarrier based on stearylamine.

Multidrug resistance (MDR) remains one of the major challenges for successful chemotherapy. Herein, we tried to develope a mitochondria targeted teniposide loaded self-assembled nanocarrier based on stearylamine (SA-TSN) to reverse MDR of breast cancer. SA-TSN was nanometer-sized spherical particles (31.59 ± 3.43 nm) with a high encapsulation efficiency (99.25 ± 0.21%). The MDR in MCF-7/ADR cells was obviously reduced by SA-TSN, which mainly attributed to the markedly reduced expression of P-gp, increased percentages in G2 phase, selectively accumulation in mitochondria, decrease of mitochondrial membrane potential, and greatly improved apoptosis. The plasma concentration of teniposide was greatly improved by SA-TSN, and the intravenously administered SA-TSN could accumulate in the tumor site and penetrate into the inner site of tumor in MCF-7/ADR induced xenografts. In particular, the in vivo tumor inhibitory efficacy of SA-TSN in MCF-7/ADR induced models was more effective than that of teniposide loaded self-assembled nanocarrier without stearylamine (TSN) and teniposide solution (TS), which verified the effectiveness of SA-TSN in reversal of MDR. Thereby, SA-TSN has potential to circumvent the MDR for the chemotherapy of breast cancer.

Chemotherapy for brain metastases from small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) accounts for approximately 20% of all cases of lung cancer. It tends to disseminate early in the course of its natural history and to grow quickly. Approximately 10% to 18% of patients present with brain metastases (BM) at the time of initial diagnosis, and an additional 40% to 50% will develop BM some time during the course of their disease. OBJECTIVES: The aim of this review was to evaluate the effectiveness and toxicity of systemic chemotherapy for the treatment of BM from SCLC. SEARCH METHODS: We searched the Cochrane Lung Cancer Review Group Specialised Register (July 2011), CENTRAL (2011, Issue 5), PubMed (1966 to July 2011), EMBASE (2005 to July 2011), LILACS (1982 to July 2011) and the International Clinical Trial Registry Platform (ICTRP). SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing systemic chemotherapy (single agent or combination chemotherapy) with another chemotherapy regimen, palliative care, whole brain radiotherapy or any combination of these interventions for the treatment of BM as the only site of progression. DATA COLLECTION AND ANALYSIS: Data extraction and 'Risk of bias' assessment were carried out independently by two review authors. As the included studies evaluated three different treatment modalities meta-analysis was not possible. MAIN RESULTS: Three RCTs, involving 192 participants, met inclusion criteria for this review. No significant differences for overall survival (OS) were reported in any of the trials: in the first trial, 33 patients received whole brain radiation therapy and no significant difference was found between patients treated with topotecan and those not treated with topotecan. In a second trial, in which 120 patients were randomized to receive teniposide with or without brain radiation therapy, the authors reported that the median progression-free survival (brain-specific progression-free survival (PFS)) was 3.5 months in the combined modality arm and 3.2 in the teniposide alone arm. In a third trial, comparing sequential and concomitant chemoradiotherapy (teniposide plus cisplatin) in 39 participants, the survival difference between the two groups was not statistically significant. While the first trial reported no significant difference in PFS, the second RCT found a significant difference favoring combined therapy group. The second trial also found that patients receiving chemoradiotherapy (teniposide plus whole brain radiotherapy) had a higher complete response rate than those receiving only the topoisomerase inhibitor. AUTHORS' CONCLUSIONS: Given the paucity of robust studies assessing the clinical effects of treatments, available evidence is insufficient to judge the effectiveness and safety of chemotherapy for the treatment of BM from SCLC. Published studies are insufficient to address the objectives of this review. According to the available evidence included in this review, chemotherapy does not improve specific brain PFS and OS in patients with SCLC. The combined treatment of teniposide and brain radiation therapy contributed to outcome in terms of increased complete remission and shorter time to progression (though not OS).

miR-20a targets BNIP2 and contributes chemotherapeutic resistance in colorectal adenocarcinoma SW480 and SW620 cell lines.

Chemotherapy is an important treatment for colorectal adenocarcinoma cancer; however, colorectal adenocarcinoma cells often develop resistance to chemotherapeutic drugs, leading to relapse and poor patient prognosis. The development of drug resistance is often a multifactor process, which involved several genes and cellular mechanisms. microRNAs are endogenous small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. In the present study, we investigated the possible role of microRNAs in regulating drug sensitivity of colorectal adenocarcinoma cells SW620 and SW480. Using microRNA expression arrays and quantitative reverse transcriptase (RT)-PCR, we found that SW620 cells exhibited elevated miR-20a expression compared with SW480 cells. In addition, these two cell lines displayed different sensitivities to the chemotherapeutic drugs fluorouracil, oxaliplatin, and teniposide. Modulation of miR-20a altered the sensitivity of SW620 and SW480 cells to these drugs; knockdown of miR-20a sensitized SW620 cells to chemotherapeutic agents, whereas overexpression of miR-20a in SW480 cells resulted in chemoresistance. Endogenous BNIP2 mRNA and BNIP2 protein levels were inversely related to miR-20a levels as detected by quantitative RT-PCR and western blot analysis. Fluorescence reporter assays showed a direct interaction between miR-20a and the BNIP2 3'UTR. Taken together, our findings suggested that miR-20a may play a role in colorectal adenocarcinoma cancer cell drug resistance and may be a therapeutic target against chemotherapy drug resistance in colorectal adenocarcinoma.

Cytogenetic and molecular analysis of MLL rearrangements in acute lymphoblastic leukaemia survivors.

The successful treatment of paediatric malignancies by multimodal therapy has improved outcomes for children with cancer, especially those with acute lymphoblastic leukaemia (ALL). Second malignant neoplasms, however, represent a serious complication after treatment. Depending on dosage, 2-12% of patients treated with topoisomerase II inhibitors and/or alkylating agents develop treatment-related acute myeloid leukaemia characterized by translocations at 11q23. Our goal was to study MLL rearrangements in peripheral lymphocytes using cytogenetic and molecular methods in order to evaluate the late effects of cancer therapy in patients previously treated for childhood ALL. Chromosomal rearrangements at 11q23 were analysed in cytogenetic preparations from 49 long-term ALL survivors and 49 control individuals. Patients were subdivided depending on the inclusion or omission of topoisomerase II inhibitors (VP-16 and/or VM-26) in their treatment protocol. The statistical analysis showed significant (P = 0.007) differences between the frequency of translocations observed for the groups of patients and controls. These differences were also significant (P = 0.006) when the groups of patients (independent of the inclusion of topoisomerase II inhibitors) and controls were compared (P = 0.006). The frequencies of extra signals, however, did not differ between groups of patients and controls. Several MLL translocations were detected and identified by inverse polymerase chain reaction, followed by cloning and sequencing. Thirty-five patients (81%) presented putative translocations; among those, 91% corresponded with t(4;11) (q21;q23), while the other 9% corresponded with t(11;X), t(8;11)(q23;q23) and t(11;16). Our results indicate an increase in MLL aberrations in childhood ALL survivors years after completion of therapy. The higher frequency in this cohort might be associated with therapy using anti-tumoural drugs, independent of the inclusion of topoisomerase II inhibitors. Even though the biological significance of these rearrangements needs further investigation, they demonstrate a degree of genome instability, indicating the relevance of cytogenetic and molecular studies during the follow-up of patients in complete clinical remission.

High numbers of tumor-associated macrophages have an adverse prognostic value that can be circumvented by rituximab in patients with follicular lymphoma enrolled onto the GELA-GOELAMS FL-2000 trial.

PURPOSE: High amounts of intratumoral macrophages have been shown to correlate with poor prognosis in patients with follicular lymphoma (FL) treated with chemotherapy without rituximab. We tried to establish whether intratumoral macrophage count (MC) definitely is able to predict the outcome of FL patients in the rituximab era. PATIENTS AND METHODS: We analyzed immunohistochemical CD68 expression in 194 FL patients from the FL-2000 trial, randomly assigned to receive cyclophosphamide, doxorubicin, etoposide, prednisolone, and interferon (CHVP-I) or rituximab plus CHVP-I. Immunohistochemistry was performed on paraffin sections using anti-CD68 KP1 antibody, and stained macrophages were scored on high-power field (hpf) in either intrafollicular (IF) or extrafollicular (EF) areas. RESULTS: For IF MC, the best cutoff point was estimated at 10 macrophages/hpf. Low IF MC was significantly associated with a better event-free survival (EFS; P = .011). However, this effect was observed only in the CHVP-I arm (P = .012) and not in the rituximab plus CHVP-I arm. Using a cutoff of 15 IF MC, we found no significant association with EFS. For EF MC, fewer than 22 macrophages/hpf were associated with better EFS in the CHVP-I arm (P = .02) but not in the rituximab plus CHVP-I arm. CONCLUSION: These results show that MC can predict outcome of FL patients and that rituximab is able to circumvent the unfavorable outcome associated with high MC.

Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA).

The purpose of this study is to compare our standard chemotherapy regimen (CHVP [cyclophosphamide, doxorubicin, teniposide, and prednisone]) plus interferon with 4 courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by high-dose therapy with autologous stem cell transplantation (ASCT) in treatment-naive patients with advanced follicular lymphoma. Four hundred one patients were included from July 1994 to March 2001: 209 received 12 cycles of CHVP plus interferon alpha for 18 months (CHVP-I arm) and 192 received 4 cycles of CHOP followed by high-dose therapy (HDT) with total body irradiation and ASCT (CHOP-HDT arm). Overall response rates were similar in both groups (79% and 78% after induction chemotherapy, respectively). One hundred thirty-one of the 150 patients eligible for HDT underwent transplantation (87%). Intent-to-treat analysis after a median follow-up of 7.5 years showed that there was no difference between the 2 arms for overall survival (P = .53) or event-free survival (P = .11). Patients with a complete response at the end of the induction therapy had a statistically longer event-free survival and overall survival (P = .02 and < .001, respectively). After long-term follow-up, our study showed that there was no statistically significant benefit in favor of first-line high-dose therapy in patients with follicular lymphoma. High-dose therapy should be reserved for relapsing patients.