Phase 2 study of pegylated liposomal doxorubicin plus cyclophosphamide, vincristine/vindesine, and prednisone in newly diagnosed PTCL: 8-year results.

BACKGROUND: Pegylated liposomal doxorubicin (PLD) is a liposome-encapsulated form of doxorubicin with equivalent efficacy and less cardiotoxicity. This phase 2 study evaluated the efficacy and safety of the PLD-containing CHOP regimen in newly diagnosed patients with aggressive peripheral T-cell lymphomas (PTCL). METHODS: Patients received PLD, cyclophosphamide, vincristine/vindesine, plus prednisone every 3 weeks for up to 6 cycles. The primary endpoint was the objective response rate at the end of treatment (EOT). RESULTS: From September 2015 to January 2017, 40 patients were treated. At the EOT, objective response was achieved by 82.5% of patients, with 62.5% complete response. As of the cutoff date (September 26, 2023), median progression-free survival (mPFS) and overall survival (mOS) were not reached (NR). The 2-year, 5-year, and 8-year PFS rates were 55.1%, 52.0%, and 52.0%. OS rate was 80.0% at 2 years, 62.5% at 5 years, and 54.3% at 8 years. Patients with progression of disease within 24 months (POD24) had worse prognosis than those without POD24, regarding mOS (41.2 months vs NR), 5-year OS (33.3% vs 94.4%), and 8-year OS (13.3% vs 94.4%). Common grade 3-4 adverse events were neutropenia (87.5%), leukopenia (80.0%), anemia (17.5%), and pneumonitis (17.5%). CONCLUSION: This combination had long-term benefits and manageable tolerability, particularly with less cardiotoxicity, for aggressive PTCL, which might provide a favorable benefit-risk balance. CLINICALTRIALS.GOV IDENTIFIER: Chinese Clinical Trial Registry, ChiCTR2100054588; IRB Approved: Ethics committee of Fudan University Shanghai Cancer Center (Date 2015.8.31/No. 1508151-13.

Clinical significance of TP53 mutations in adult T-cell leukemia/lymphoma.

Adult T-cell leukaemia/lymphoma (ATL) patients have a poor prognosis. Here, we investigated the impact of TP53 gene mutations on prognosis of ATL treated in different ways. Among 177 patients, we identified 47 single nucleotide variants or insertion-deletions (SNVs/indels) of the TP53 gene in 37 individuals. TP53 copy number variations (CNVs) were observed in 38 patients. Altogether, 67 of 177 patients harboured TP53 SNVs/indels or TP53 CNVs, and were categorized as having TP53 mutations. In the entire cohort, median survival of patients with and without TP53 mutations was 1·0 and 6·7 years respectively (P < 0·001). After allogeneic haematopoietic stem cell transplantation (HSCT), median survival of patients with (n = 16) and without (n = 29) TP53 mutations was 0·4 years and not reached respectively (P = 0·001). For patients receiving mogamulizumab without allogeneic HSCT, the median survival from the first dose of antibody in patients with TP53 mutations (n = 27) was only 0·9 years, but 5·1 years in those without (n = 42; P < 0·001). Thus, TP53 mutations are associated with unfavourable prognosis of ATL, regardless of treatment strategy. The establishment of alternative modalities to overcome the adverse impact of TP53 mutations in patients with ATL is required.

Ambulatory high-dose methotrexate administration as central nervous system prophylaxis in patients with aggressive lymphoma.

High-dose methotrexate (HD-MTX) at 3 g/m2 is one of the strategies for central nervous system (CNS) prophylaxis in the first-line treatment of aggressive lymphomas, especially in diffuse large B cell lymphoma patients with high-risk CNS-International Prognostic Index. The objective of our study was to retrospectively analyze the safety of 2 cycles of systemic HD-MTX administered as an ambulatory regimen. Between January 2013 and December 2016, 103 patients were carefully selected on 6 criteria, including age < 60, albumin > 34, performance status 0 or 1, normal renal and hepatic functions, good understanding of practical medical guidance, and no loss of weight. Strict procedures of HD-MTX infusion were observed including alkalinization, urine pH monitoring, and leucovorin rescue. Renal and hepatic functions were monitored at days 2 and 7. MTX clearance was not monitored. Toxicities and grades of toxicity were collected according to the NCI-CTCAE (version 4.0). Among the 103 selected patients, 92 (89%) patients successfully completed the planned 2 cycles of HD-MTX on an outpatient basis. Eleven patients completed only 1 cycle, 3 because of lymphoma progression and 8 because of toxicity including 3 grade II hepatotoxicity, 2 grade I/II renal toxicity, 1 grade III neutropenia, 1 active herpetic infection, and 1 grade III ileus reflex. Reported adverse events (AE) included 92 (84%) grade I/II and 18 (16%) grade III/IV. Grade III hepatotoxicity, mostly cytolysis, was the most frequent AE observed with 8 (8%) events. Grade III/IV hematologic toxicities concerned 9 patients with 8 grade III/IV neutropenia and 1 thrombocytopenia. Renal toxicity was rare, mild, and transient, observed with 4 (4%) grade I/II events. Ambulatory administration of HD-MTX at 3 g/m2 without MTX clearance monitoring is safe with strict medical guidance. It requires careful selection of patients before administration, and a renal and hepatic monitoring after the administration.

Prognosis of patients with adult T-cell leukemia/lymphoma in Japan: A nationwide hospital-based study.

Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm and is classified into four subtypes (acute, lymphoma, chronic, and smoldering) according to the Shimoyama classification, established in 1991 through several nationwide surveys based on the clinical diversity of patients diagnosed in 1983-1987 in Japan. Thereafter, no such studies have been conducted. Recently, we conducted a nationwide hospital survey using the method of the 1980s studies, collected baseline data on 996 ATL patients diagnosed in 2010-2011 from 126 hospitals, and reported their unique epidemiological characteristics. Here, we report the follow-up results of registered ATL patients with the goal of evaluating current prognoses and treatment modalities as of 2016-2017. Of 770 evaluable patients, 391 (50.8%) had acute-type, 192 (24.9%) had lymphoma-type, 106 (13.8%) had chronic-type, and 81 (10.5%) had smoldering-type ATL. The initial therapy regimens used for acute/lymphoma-type ATL were vincristine, cyclophosphamide, doxorubicin and prednisone, followed by doxorubicin, ranimustine, and prednisone and then by vindesine, etoposide, carboplatin, and prednisone (VCAP-AMP-VECP)-like in 38.5/41.7% and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like in 14.6/13.7% of patients. Allogeneic hematopoietic stem cell transplantation was used to treat 15.9/10.4% of acute/lymphoma-type ATL patients. The 4-year survival rates (the median survival time, days) for acute-, lymphoma-, unfavorable chronic-, favorable chronic-, and smoldering-type ATL were 16.8% (252), 19.6% (305), 26.6% (572), 62.1% (1937), and 59.8% (1851), respectively. The 4-year survival rates for acute- and lymphoma-type ATL improved compared with those reported in 1991, but those for chronic- and smoldering-type ATL were not. Further efforts are warranted to develop more efficient therapeutic strategies to improve the prognosis of ATL in Japan.

Rituximab-PECC induction followed by 90 Y-ibritumomab tiuxetan consolidation in relapsed or refractory DLBCL patients who are ineligible for or have failed ASCT: results from a phase II HOVON study.

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) after, or ineligible for, autologous stem cell transplantation (ASCT) have a dismal prognosis. This phase II study evaluated treatment with R-PECC (rituximab, prednisolone, etoposide, chlorambucil, lomustine), every 28 days for 4 cycles in 62 patients, followed by radio-immunotherapy consolidation with 90 Y-ibritumomab tiuxetan in responsive patients. Primary endpoints were failure-free survival (FFS) and incidence of grade ≥3 adverse events from start of 90 Y-ibritumomab tiuxetan. The overall response rate after R-PECC was 50%. Twenty-nine of 31 responsive patients proceeded to 90 Y-ibritumomab tiuxetan. Five out of 15 partial remission patients converted to complete remission after 90 Y-ibritumomab tiuxetan. One-year FFS and overall survival (OS) from start of 90 Y-ibritumomab tiuxetan was 52% (95% confidence interval [CI], 33-68%) and 62% (95% CI, 42-77%), respectively. One-year FFS and OS from start of R-PECC was 28% (95% CI, 17-39%) and 49% (95% CI, 36-61%), respectively. Toxicities of R-PECC and 90 Y-ibritumomab tiuxetan were mainly haematological. In conclusion, for relapsed DLBCL patients the largely oral R-PECC regimen achieves promising response rates, combined with an acceptable safety profile. Consolidation with 90 Y-ibritumomab tiuxetan resulted in long-term response durations in approximately one third of the patients that received it.

In vitro compatibility and stability of admixtures containing etoposide, epirubicin hydrochloride and vindesine sulphate in a single infusion bag.

WHAT IS KNOWN AND OBJECTIVES: The etoposide, doxorubicin hydrochloride, vincristine sulphate, cyclophosphamide and prednisone (EPOCH) chemotherapy regimen is effective in patients with relapsed or refractory non-Hodgkin's lymphoma. However, vincristine and doxorubicin hydrochloride are relatively toxic, leading to neurovirulence and cardiotoxicity, respectively. In this study, we replaced these drugs with vindesine and epirubicin hydrochloride to reduce the cardiotoxicity and evaluated admixtures containing these drugs along with etoposide in a single infusion bag in vitro. METHODS: The appearance and pH of the admixtures were evaluated, and the number of particles was detected. High-performance liquid chromatography was used to measure the concentration and degradation rates of etoposide, epirubicin hydrochloride and vindesine sulphate in each admixture. RESULTS AND DISCUSSION: No precipitation occurred when mixing clinically relevant concentrations of etoposide, epirubicin hydrochloride and vindesine sulphate in a 0.9% NaCl injection solution. Furthermore, the delta pH of the admixtures was ≤0.12 throughout the experiment, and the number of particles (≥10 and ≥25 µm) in the solutions over the 24 hours post-preparation period met USP standards. Etoposide, epirubicin hydrochloride and vindesine sulphate were retained at >96% of their initial concentrations in the admixtures at 25°C over the course of the experiment. Etoposide, epirubicin hydrochloride and vindesine sulphate are compatible when mixed in a 0.9% NaCl injection solution, and the admixtures are stable for at least 24 hours when stored in infusion bags. WHAT IS NEW AND CONCLUSION: This in vitro analysis indicates the suitability of our novel admixtures containing less toxic drug equivalents in a single infusion bag for clinical application.

Neoadjuvant Intraarterial Chemotherapy for Treatment of Malignant Vaginal Tumors in Children: A Single-Center Experience.

Six patients (aged 3-36 mo) with vaginal tumors (rhabdomyosarcoma and endodermal sinus tumor [EST]; n = 3 each) received intraarterial chemotherapy (IAC) and intravenous chemotherapy. Patients underwent internal iliac artery infusion with cisplatin, pirarubicin, and vindesine. Intravenous chemotherapy with vindesine, ifosfamide, and etoposide was administered after 3 weeks. Vaginal tumors disappeared in all patients after 2 or 3 cycles of alternating therapy. Two patients underwent resection of pelvic metastases. Intravenous consolidation chemotherapy was applied. Four patients were disease-free at a median follow-up of 5.8 years. One patient had pelvic recurrence treated with "salvage" therapy with IAC and surgery and was disease-free for 2.5 years.

Prognostic implications of diffusion-weighted magnetic resonance imaging in patients with superior sulcus tumors receiving induction chemoradiation therapy.

OBJECTIVE: The aim of this study was to evaluate a diffusion-weighted magnetic resonance imaging to represent therapeutic response of induction chemoradiation and outcome in patients with non-small cell lung cancer of the superior sulcus. METHODS: Seventeen patients with non-small cell lung cancer of the superior sulcus (median age, 57 years; range, 44-70 years) received induction chemoradiation, followed by surgery. Diffusion-weighted magnetic resonance imaging of the lesion using b values of 0 and 800 s/mm(2) was acquired before treatment and after induction chemoradiation. Changes in tumoral apparent diffusion coefficient were compared with clinical and histopathological response. Cumulative disease-free survival and proportion of surviving were estimated by the Kaplan-Meier method. Survival of diffusion responders and non-responders were compared by log-rank test. RESULTS: A significant correlation was observed between changes of diffusion response after induction chemoradiation and overall survival. Using a defined threshold of percent increase in mean apparent diffusion coefficient, nine out of 17 patients (53%) were classified as diffusion responders and had a mean increase in mean apparent diffusion coefficient of 40.7 ± 11.2%, while eight diffusion non-responding patients (47%) had a mean increase of 11.0 ± 15.5% (P < 0.0001). Significant difference was found in overall survival between diffusion responders and diffusion non-responders (88.9 months versus 20.3 months, P = 0.002). CONCLUSIONS: Diffusion-weighted magnetic resonance imaging represented therapeutic effect and prognosis after induction chemoradiation in patients with non-small cell lung cancer of the superior sulcus.

A phase 1 dose escalation study of idarubicin combined with methotrexate, vindesine, and prednisolone for untreated elderly patients with primary central nervous system lymphoma. The GOELAMS LCP 99 trial.

Treatment of primary central nervous system lymphoma (PCNSL) in elderly patients remains unsatisfactory. To develop a new high-dose methotrexate (HD-MTX)-based regimen including idarubicin, a phase 1 multicenter dose escalation study was conducted to determine the maximum-tolerated dose (MTD) of idarubicin. Thirty-five immunocompetent patients with PCNSL were enrolled. The median age was 65 years (range, 60-70 years). MTX and vindesine (VDS) were given at the fixed dose of 3 g/m(2) (6-hr intravenous [IV]) and 3 mg/m(2) IV on day 1, respectively. Prednisolone (PRED) was given at the fixed dose of 60 mg/m(2) (IV or orally) on days 1-5. Idarubicin was escalated in increments of 2 mg/m(2) with doses ranging from 12-18 mg/m(2) IV on day 1. Treatment was repeated three times every 3 weeks. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia for more than 7 days, thrombocytopenia grade 4 or nonhaematological toxicity more than grade 2. The MTD of idarubicin was reached at 16 mg/m(2) . At this level, the main haematological toxicities were thrombocytopenia grade 4: 5% and neutropenia grade 3 or 4 (52%); the main nonhaematological toxicities were grade 3 or 4 infectious disease (5%) and grade 2 renal failure (9%). For the study population, median overall and progression-free survival were 19 and 13 months, respectively. Our study suggests that the MTD of idarubicin in combination with HD-MTX, VDS, and PRED, should be 16 mg/m(2) . Further studies will be necessary to challenge a standard treatment in elderly patients with PCNSL.

Adjuvant chemotherapy versus surgery alone for esophageal squamous cell carcinoma: a meta-analysis of randomized controlled trials and nonrandomized studies.

The effect of adjuvant chemotherapy on survival of patients with thoracic esophageal squamous cell carcinomas is still controversial, and the subgroup of patients who will most likely benefit from the adjuvant chemotherapy on long-term survival has not yet been identified clearly. Studies published from 1995 to May 2012 were searched in Medline, Embase, PubMed, Cancerlit, the Cochrane Library, CNKI and major scientific meetings. Randomized controlled trials and nonrandomized studies comparing surgery plus adjuvant chemotherapy with surgery alone in patients with resectable thoracic esophageal squamous cell carcinomas were included. Eleven studies with a total of 2047 patients were identified, consisting of the adjuvant chemotherapy arm (n = 887) and surgery-alone arm (n = 1160). There was not statistically significant benefit on 3-year overall survival for adjuvant chemotherapy (risk ratio [RR] = 0.89, 95% confidence interval [CI], 0.72 to 1.09; P = 0.25). Adjuvant chemotherapy could significantly prolong the 1-year disease-free survival (DFS) (RR = 0.68, 95%CI, 0.51 to 0.89; P = 0.006), but not 3-year DFS (RR = 0.97, 95%CI, 0.73 to 1.29; P = 0.84). Further analysis showed that patients with stage III-IV diseases could benefit from adjuvant chemotherapy on 3-year overall survival (RR = 0.43, 95%CI, 0.31 to 0.61; P = 0.00001), but not in the case of patients with stageI-IIdiseases (RR = 1.12, 95%CI, 0.65 to 1.93; P = 0.68). Additionally, patients with positive lymph node could benefit on 5-year DFS from adjuvant chemotherapy (RR = 0.79, 95%CI, 0.64 to 0.99; P = 0.04). The modality treatment with adjuvant chemotherapy for patients with squamous cell carcinoma of thoracic esophagus might be determined according to pathological stage or the status of lymph node metastasis.

[Clinical and capillaroscopic regression of CD30 anaplastic lymphoma associated with limited cutaneous systemic sclerosis following autologous bone marrow transplantation]. / Régression clinique et capillaroscopique après autogreffe de moelle d'une sclérodermie systémique cutanée limitée associée à un lymphome anaplasique CD30.

BACKGROUND: In rare cases, tumors are associated with secondary Raynaud's phenomenon in systemic sclerosis (SSc). We report the case of a patient presenting cutaneous limited SSc associated with CD30 anaplastic lymphoma with cutaneous and lymph node involvement in whom the capillaroscopic scleroderma pattern regressed completely after autologous bone marrow transplantation, with complete remission of the lymphoma. CASE REPORT: A 37-year-old man presented bilateral Raynaud's phenomenon associated with digital ulcers contracted one year earlier but subsequently neglected. Right axillary lymph nodes and regional cutaneous tumors were present, leading to the diagnosis of CD30+ anaplastic lymphoma with cutaneous and lymph node involvement. Chemotherapy containing cyclophosphamide achieved only partial remission of the lymphoma. Clinical examination showed bilateral Raynaud's phenomenon, sclerodactyly, a right axillary subcutaneous nodule and a pathological Allen's test for the right hand. Antinuclear antibodies were positive without any other immunological abnormalities, and capillaroscopy showed an SSc pattern with numerous megacapillaries. Digital blood pressure was reduced in the right index and the left middle fingers, in which ulcers of the pulp were observed. Bone marrow transplantation was performed, resulting in complete remission of the lymphoma and disappearance of the sclerodactyly, with no recurrence of the pulp ulcers and complete normalization of capillaroscopic appearance and digital pressure. DISCUSSION: This case raises the question of authentic SSc and neoplasia and highlights the importance of capillaroscopy in the follow-up of SSc. The complete regression of SSc and of capillaroscopic abnormalities could be explained by the paraneoplastic nature of SSc or by the direct action of the chemotherapy and bone marrow transplantation.

Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B).

BACKGROUND: The superiority of a chemotherapy with doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (ACVBP) in comparison with cyclophosphamide, doxorubicin, vincristin and prednisone plus radiotherapy for young patients with localized diffuse large B-cell lymphoma (DLBCL) was previously demonstrated. We report the results of a trial which evaluates the role of rituximab combined with ACVBP (R-ACVBP) in these patients. PATIENTS AND METHODS: Untreated patients younger than 66 years with stage I or II DLBCL and no adverse prognostic factors of the age-adjusted International Prognostic Index were randomly assigned to receive three cycles of ACVBP plus sequential consolidation with or without the addition of four infusions of rituximab. RESULTS: A total of 223 patients were randomly allocated to the study, 110 in the R-ACVBP group and 113 in the ACVBP group. After a median follow-up of 43 months, our 3-year estimate of event-free survival was 93% in the R-ACVBP group and 82% in the ACVBP group (P = 0.0487). Three-year estimate of progression-free survival was increased in the R-ACVBP group (95% versus 83%, P = 0.0205). Overall survival did not differ between the two groups with a 3-year estimates of 98% and 97%, respectively (P = 0.686). CONCLUSION: In young patients with low-risk localized DLBCL, rituximab combined with three cycles of ACVBP plus consolidation is significantly superior to ACVBP plus consolidation alone.

Receipt of maintenance therapy is most predictive of survival in older acute lymphoblastic leukemia patients treated with intensive induction chemotherapy regimens.

While the prognosis for older adults diagnosed with acute lymphoblastic leukemia (ALL) is frequently poor, long-term survival can be achieved in patients treated with curative intent. We reviewed the outcomes of 37 patients age ≥60 treated at our institution with either DVP- or hyperCVAD-based chemotherapy regimens from 2003-2011. In this patient population, a complete response rate of 92%, relapse rate of 56% and median overall survival of 18.1 months was experienced. Univariate analysis revealed that receipt of maintenance therapy vs. no maintenance therapy was associated with a statistically-significant impact on overall survival (p = 0.001, HR 0.15 for death), while disease-related characteristics including high-risk white blood cell count at diagnosis and Philadelphia chromosome status as well as treatment-related factors including chemotherapy regimen or completion of intensive therapy were not. Many patients were unable to initiate or remain on maintenance therapy due to toxicities including infections and cytopenias. Our analysis reveals the benefit of prolonged therapy in the treatment of older adults with ALL as well as the high incidence of treatment-related toxicity experienced by these patients.

[Clinical characteristics and efficacy analysis for patients over 55 years of age with acute lymphoblastic leukemia].

OBJECTIVE: We investigated the clinical characteristics and therapeutic of elderly patients (≥55) with acute lymphoblastic leukemia (ALL). METHODS: From Jenuary 2000 to July 2012, 45 elderly patients (≥55) were enrolled in the study. Patients assighed into CVDP VDP/VP induction chemotherapy based on organ function. Patients in complete remission (CR) undertake consolidation therapy, maintenance therapy or follow up. The patient who had appropriate donor received allogeneic hematopoietic stem cell transplantation (allo-HSCT). CR, Overall survival (OS), disease free survival (DFS), relapse rate and prognosis factors were analyzed. RESULTS: 45 elderly patients (≥55) about 9.6% in all 470 cases ALL simultaneity, and B-ALL about 88.9%. 27 patients (60%) obtained CR after 1 cycle of induction chemotherapy. 33 patients (73.3%) obtained overall CR. The CR rate significantly decreased in the elderly patients more than 60 years old vs. 55-60 years old patients (86.2% vs. 50%;P=0.009). All 45 patients 2 years OS rate was 33.7%, The median OS was 12 months (95%CI,6.68-17.32). 55-60 years (P=0.014), CR (P=0.002) and consolidation therapy (P=0.001) were independent favorite prognostic factors for OS. CVDP induction chemotherapy (P=0.013) and consolidation (P=0.049) were independent favorite prognostic factors for DFS. CONCLUSION: The outcomes of elderly patients with ALL were poor, 55-60 years, CVDP induction chemotherapy, CR and consolidation therapy were independent favorite prognostic factors.

Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial.

BACKGROUND: The outcome of diffuse large B-cell lymphoma has been substantially improved by the addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy regimens. We aimed to assess, in patients aged 18-59 years, the potential survival benefit provided by a dose-intensive immunochemotherapy regimen plus rituximab compared with standard treatment plus rituximab. METHODS: We did an open-label randomised trial comparing dose-intensive rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) with subsequent consolidation versus standard rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP). Random assignment was done with a computer-assisted randomisation-allocation sequence with a block size of four. Patients were aged 18-59 years with untreated diffuse large B-cell lymphoma and an age-adjusted international prognostic index equal to 1. Our primary endpoint was event-free survival. Our analyses of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00140595. FINDINGS: One patient withdrew consent before treatment and 54 did not complete treatment. After a median follow-up of 44 months, our 3-year estimate of event-free survival was 81% (95% CI 75-86) in the R-ACVBP group and 67% (59-73) in the R-CHOP group (hazard ratio [HR] 0·56, 95% CI 0·38-0·83; p=0·0035). 3-year estimates of progression-free survival (87% [95% CI, 81-91] vs 73% [66-79]; HR 0·48 [0·30-0·76]; p=0·0015) and overall survival (92% [87-95] vs 84% [77-89]; HR 0·44 [0·28-0·81]; p=0·0071) were also increased in the R-ACVBP group. 82 (42%) of 196 patients in the R-ACVBP group experienced a serious adverse event compared with 28 (15%) of 183 in the R-CHOP group. Grade 3-4 haematological toxic effects were more common in the R-ACVBP group, with a higher proportion of patients experiencing a febrile neutropenic episode (38% [75 of 196] vs 9% [16 of 183]). INTERPRETATION: Compared with standard R-CHOP, intensified immunochemotherapy with R-ACVBP significantly improves survival of patients aged 18-59 years with diffuse large B-cell lymphoma with low-intermediate risk according to the International Prognostic Index. Haematological toxic effects of the intensive regimen were raised but manageable. FUNDING: Groupe d'Etudes des Lymphomes de l'Adulte and Amgen.

A retrospective study of the preoperative treatment of advanced Wilms tumor in children with chemotherapy versus transcatheter arterial chemoembolization alone or combined with short-term systemic chemotherapy.

PURPOSE: To evaluate the therapeutic effect of preoperative transcatheter arterial chemoembolization (TACE) combined with short-term systematic chemotherapy in the treatment of advanced Wilms tumor. MATERIALS AND METHODS: This was a retrospective study on 66 patients with unilateral advanced Wilms tumor, age 5 months to 11 years (median, 2.9 years; 30 boys and 36 girls), treated at our institution between 1995 and 2007. Characteristics of the patient population were maximal tumor diameter > 10 cm, or involvement of periaortic lymph nodes, or inferior vena cava invasion, or distal metastasis, or tumor with anaplastic histology. Patients were divided into three groups. Twenty patients were treated with conventional preoperative chemotherapy (PC group) using vindesine, actinomycin D, and pirarubicin for 4 weeks; 21 patients were treated in the TACE group with preoperative renal arterial chemoembolization using Lipiodol-pirarubicin-vindesine emulsion; and 25 patients were treated with preoperative chemoembolization combined with short-term systematic chemotherapy (T+S) for 2 weeks. RESULTS: No drug-induced cardiotoxicity, nephrotoxicity, or hepatic dysfunction was observed. Complete surgical removal of the tumor was achieved in 12 (65.0%), 17 (80.9%), and 22 (88.0%) patients in the PC, TACE, and T+S groups, respectively (T+S group vs PC group, P = .030). The 2-year relapse-free survival rates were 65.0%, 80.9%, and 100.0% in the PC, TACE, and T+S groups, respectively (T+S vs PC, P = .001). CONCLUSIONS: From our experience, preoperative chemoembolization combined with short-term systematic chemotherapy is able to achieve higher rates of complete tumor resection and relapse-free survival in the treatment of advanced Wilms tumor.

Beclin1­armed oncolytic Vaccinia virus enhances the therapeutic efficacy of R­CHOP against lymphoma in vitro and in vivo.

Non­Hodgkin lymphoma (NHL) is a form of lymphoid malignancy, with diffuse large B cell lymphoma (DLBCL) being the most common NHL isoform. Approximately half of patients with DLBCL are successfully cured via first­line Rituximab, Cyclophosphamide, Epirubicin, Vindesine, Prednisolone (R­CHOP) treatment. However, 30­40% of patients with DLBCL ultimately suffer from treatment­refractory or relapsed disease. These patients often suffer from high mortality rates owing to a lack of suitable therapeutic options, and all patients are at a high risk of serious treatment­associated dose­dependent toxicity. As such, it is essential to develop novel treatments for NHL that are less toxic and more efficacious. Oncolytic Vaccinia virus (OVV) has shown promise as a means of treating numerous types of cancer. Gene therapy strategies further enhance OVV­based therapy by improving tumor cell recognition and immune evasion. Beclin1 is an autophagy­associated gene that, when upregulated, induces excess autophagy and cell death. The present study aimed to develop an OVV­Beclin1 therapy capable of inducing autophagic tumor cell death. OVV­Beclin1 was able to efficiently kill NHL cells and to increase the sensitivity of these cells to R­CHOP, thereby decreasing the dose­dependent toxic side effects associated with this chemotherapeutic regimen. The combination of OVV­Beclin1 and R­CHOP also significantly improved tumor growth inhibition and survival in a BALB/c murine model system owing to the synergistic induction of autophagic cell death. Together, these findings suggest that OVV­Beclin1 infection can induce significant autophagic cell death in NHL, highlighting this as a novel means of inducing tumor cell death via a mechanism that is distinct from apoptosis and necrosis.

Dose-intensified treatment of Burkitt lymphoma and B-cell lymphoma unclassifiable, (with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma) in young adults (<50 years): a comparison of two adapted BFM protocols.

The chemotherapy dose-intensity in two adapted German BFM paediatric protocols (BFM 90 and NHL 86) was compared in contemporaneously treated adults <50 years with Burkitt lymphoma and B-cell lymphoma unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (collectively referred to as BL). In BFM 90, primary prophylaxis with Granulocyte-colony-stimulating factor was used, postinduction treatment was started at granulocytes > or =0.5 x 10(9)/L (> or =1.0 x 10(9)/L in NHL 86) with a higher mean methotrexate dose (2.9 g/m(2)/cycle, n = 23; 1.6 g/m(2)/cycle in NHL 86, n = 22, P < 0.001). Intervals between consecutive treatment-cycles were shorter in BFM 90 (P < 0.001) with no additional toxicity. However, the two-year failure-free survival with BFM 90 (82%) was similar to that achieved with NHL 86 (72%, P = 0.33). We conclude that BFM 90 enables safe intensification of therapy in young adults with BL compared to NHL 86, but registry-based studies are required to further evaluate the antineoplastic effects and cost-effectiveness of the two therapeutic approaches.

Coadministration of vindesine with high-dose methotrexate therapy increases acute kidney injury via BCRP, MRP2, and OAT1/OAT3.

PURPOSE: To investigate whether coadministration of vindesine is a risk factor for acute kidney injury caused by high-dose methotrexate in patients with hematologic malignancies and identify its mechanism. METHODS: A retrospective analysis was conducted on 211 cycles of HD-MTX therapy in 178 patients with hematological malignancies. Multivariate logistic regression analysis was performed to evaluate whether VDS coadministration was a risk factor for AKI and the inhibitory effect of VDS on MTX was studied in cell models in vitro. RESULTS: The occurrence of AKI was significantly higher in the MTX + VDS group than in the MTX group. Multivariate logistic regression analysis showed that VDS coadministration was an important risk factor for the occurrence of AKI [odds ratio (OR) = 2.62, 95% confidence interval (CI) 1.03-6.66]. After coadministration of VDS, serum MTX concentrations at 24 h, 48 h, and 72 h increased from 0.42 ± 0.46 µmol/L, 0.07 ± 0.01 µmol/L, and 0.03 ± 0.01 µmol/L to 0.98 ± 2.73 µmol/L, 0.18 ± 0.42 µmol/L, and 0.09 ± 0.21 µmol/L (p < 0.05, p < 0.01, and p < 0.01), respectively. Delayed elimination was closely related to AKI (p < 0.001). The transfected cell model results showed that VDS is an inhibitor of the transporters BCRP, MRP2, and OAT1/OAT3. VDS inhibited BCRP and MRP2-mediated transport of MTX with IC50 values of 17.91 µM and 34.73 µM, respectively. CONCLUSIONS: Coadministration of VDS increases HD-MTX-induced AKI in patients with hematologic malignancies, which may be explained by the fact that VDS increases the exposure to and decreases the excretion of MTX by inhibiting OAT1/OAT3, BCRP, and MRP2.