A new therapeutic approach in very refractory diffuse large B-cell lymphoma.

PURPOSE: Patients with diagnosis of diffuse large B-cell lymphoma, who relapse after stem cell transplant (SCT) or are no candidates to SCT, have a poor prognosis and no current treatment is available. Thus, we conduct a rotatory chemotherapy schedule that employed low doses of chemotherapy agents to assess efficacy and toxicity in this setting of patients; the end point was the improved outcome. METHODS: Retrospectively we revised an analysis of 461 patients who were treated with a low-doses regimen of cytotoxic agents, who were treated in a single institution, all patients has been treated with at least two salvage regimens, including SCT, > 18 years, performance status < 3, and that were informed about the possibility of severe toxicities,, were considered candidates to the study. They received a weekly rotatory scheme including low doses of cytotoxic agents during 2 years. RESULTS: Overall response rate was achieved in 314 patients (68%, 95% Confidence interval (CI) 59-76%) and complete response was achieved in 151 cases (32%, 95% CI 25-38%); actuarial curves at 10 years show that progression-free survival was 58% (95% CI 51-66%) and OS was 50% (95% CI 43-57%). Dose reduction was not necessary; toxicity was minimal and well controlled. No death related to acute or late toxicities has been observed. CONCLUSION: Low doses of cytotoxic agents for continuous, prolonged periods, with minimal drug-free intervals, represent a novel, active, and easily tolerated approach to management of patients with DLBCL in a terminal phase and improved outcome.

Genome Sequence of Serratia plymuthica V4.

Serratia spp. are gammaproteobacteria and members of the family Enterobacteriaceae. Here, we announce the genome sequence of Serratia plymuthica strain V4, which produces the siderophore serratiochelin and antimicrobial compounds.

Prevalence of primary drug resistance-associated mutations among HIV type 1 vertically Infected children in Belo Horizonte, Brazil.

In the past few years there has been increasing concern about the transmission of drug-resistant HIV. This study aimed to describe the frequency of primary mutations associated with HIV-1 drug resistance and the prevalence of genetic HIV subtypes in a population of vertically infected children before the initiation of HAART. At the time of genotypic testing, the median age was 6.0 years (IQR 25-75%: 3.8-9.2) and the median age at admission was 3.84 years (IQR 25-75%: 1.23-6.11). Antepartum maternal ARV exposure for PMTCT occurred for three (7.3%) mothers. According to the WHO criteria, primary ARV resistance mutations were detected in four out of 41 (9.8%) children. Subtype B was the most prevalent (63.4%). The relatively high prevalence of primary HIV-1 DRMs in this cohort of perinatally infected children in Brazil supports the local recommendation to perform resistance testing in all newly diagnosed children, regardless of age at diagnosis and antenatal ARV exposure.

Influence of biofilm composition on the resistance to detachment.

Bacillus cereus and Pseudomonas fluorescens were used to develop monoculture biofilms in a bioreactor rotating system using a stainless steel cylinder for biofilm formation. The biofilms were allowed to grow for 7 days, exposed continuously to a Reynolds number of agitation (ReA) of 2,400. Afterwards, the biofilms were characterised in terms of respiratory activity, amount of biomass, cellular density, cellular size and total and extracellular proteins and polysaccharides. The biofilm mechanical stability was assessed by sequential submission of the biofilms to increasing ReA, respectively, 4,000, 8,100, 12,100 and 16,100. The results showed that P. fluorescens biofilms were five times more active, had a higher amount of biomass, cellular density, a reduced cellular size and a four-fold higher amount of extracellular proteins and polysaccharides than B. cereus biofilms. The application of shear stress forces higher than the one under which the biofilm was formed (ReA = 2,400) caused biomass removal. The high percentage of removal occurred with the implementation of a ReA of 8,100 for both B. cereus and P. fluorescens biofilms. The total series of ReA did not give rise to total biofilm removal, as only about 76% of P. fluorescens biofilm mass and 53% of B. cereus biofilm mass were detached from the cylinders. This latter result evidences that B. cereus had a higher mechanical stability than P. fluorescens biofilms. The overall results demonstrate that P. fluorescens and B. cereus formed physiologically distinct biofilms, B. cereus biofilms mainly being constituted by cells and P. fluorescens biofilms largely constituted by extracellular proteins and polysaccharides. B. cereus biofilms had a substantially higher mechanical stability than P. fluorescens biofilms.

Biological modifiers as cytoreductive therapy before stem cell transplant in previously untreated patients with multiple myeloma.

BACKGROUND: High dose chemotherapy with supporting autologous stem cell transplantation is now considered the treatment of choice in patients with multiple myeloma <65 years old. The best regimen appears to be VAD (vincristine, doxorubicin and dexamethasone), but acute and late toxicity can limit the use of this combination. The use of biological modifiers has not been considered in this situation. We developed a new cytoreductive regimen, in an attempt to retain clinical efficacy but reduce toxicity. PATIENTS AND METHODS: Thirty-six patients, previously untreated with diagnosis of multiple myeloma were enrolled to received the DAI regimen (dexamethasone 30 mg/m(2), i.v., days 1-4, all-trans-retinoic acid 45 mg/m(2), p.o., days 5-14 and interferon alpha 2a, 4.5 MU s.c., days 5-14) administered every 28 days for six cycles before high-dose chemotherapy (melphalan 200 g/m(2)) and autologous stem cell transplantation. RESULTS: Overall response was observed in 29 cases (80%), complete response in 19 and partial response in 10 patients. Five patients were >65 years old and were treated with dexamethasone/thalidomide. Twenty-four patients underwent transplants. At a median follow-up of 31.6 months, no relapse or disease progression was observed, thus actuarial curves at 3-years showed that event-free survival was 86% and overall survival was 94%. Toxicity was mild. CONCLUSIONS: This regimen appears to be an excellent alternative as cytoreductive treatment before high-dose chemotherapy and autologous stem cell transplantation with excellent overall response and minimal toxicity. Controlled clinical trials are warranted to define the role of this new therapeutic approach.

Chemotherapy plus interferon-alpha2b versus chemotherapy in the treatment of follicular lymphoma.

The best treatment of follicular lymphoma remains to be determined because the long natural history of follicular lymphoma requires mature data for accurate analysis. Although the goal of primary treatment remains durable remission, the sequential application of effective treatments may also result in a prolongation of median survival time. The use of interferon (IFN) with doxorubicin-based chemotherapy has demonstrated an increase of event-free survival but not in overall survival; however, its acute and late cardiac toxicity limits its use. For this reason, we began a controlled clinical trial to assess the efficacy and toxicity of chemotherapy: COPP (cyclophosphamide, vincristine, prednisone, and procarbazine) + IFN alternating every month for six cycles compared to six cycles of chemotherapy. In an intent-to treat analysis, 55 patients were enrolled (median age 61 years). Most cases (91%) with advanced disease were randomly assigned to chemotherapy + IFN (28 cases) or chemotherapy (27 cases). Complete remission was observed in 16 patients: 59% (95% CI, 53-70%) in the chemotherapy arm compared to 20 patients 71% (95% CI, 58-79%) in the chemotherapy + IFN arm; total responses were 74% and 86%, respectively. At a median follow-up of 60 months, event-free survival was 100% for patients treated with chemotherapy + IFN, which was statistically different from patients treated with chemotherapy 70%. At 7 years, median survival has not yet been reached; 72% of patients chemotherapy + IFN remain alive without disease (95% CI, 59-81%), which is not statistically different from 72% (95%CI, 50-73%) in the chemotherapy arm. Non-hematological toxicity was most frequent and severe in the chemotherapy arm; hematological toxicity was similar in both groups. Thus, it appears that chemotherapy + IFN, as described herein, improves event-free survival but the overall survival rates remain unchanged. The use of COPP appears to be better that anthracycline-based chemotherapy because it avoids the presence of acute and late cardiac toxicity.

Evaluation on a six-dose treatment of anti CD 20 monoclonal antibody in patients with refractory follicular lymphoma.

Treatment of refractory follicular lymphoma with monoclonal antibody CD 20 has been proven to be a good therapeutic option. However, most studies used four weekly doses and time to treatment failure (TTF) and overall survival (OS) could be considered very short: 11.0 and 13.6 months respectively. We started a pilot study to evaluate if six infusions at the same doses and schedule could improve the outcome in these patients. Seventeen patients with refractory follicular lymphoma heavily treated with chemotherapy (> 2 regimens), radiotherapy and biological modifiers were enrolled in a pilot study. They received 6 weekly doses, at 375 mg/m2, of monoclonal anti CD 20. In an intent to treat analysis, overall response was 76%, of which 47% (8 patients) were complete response and 5 patients were partial response. With a median follow-up of 28.6 months, 7 complete responders remain alive, free of disease, and 2 partial responses remain stable without additional treatment. Median to TTF has not been reached; yet, actuarial curves showed that at 3 years, 53% of patients are alive. The four patients who were failure died secondary to tumor progression. Overall survival (OS) at 3-year was 76%. Toxicity was mild, all patients completed the schedule on time and doses. The addition of two doses of anti CD 20 clearly improved OS and TTF in a group of patients with refractory follicular lymphoma heavily treated and with poor prognostic factors. However, the number is too short to draw definitive conclusions; more clinical trials are necessary to determine if 4 or 6 doses of anti CD 20 therapy are better in this setting of patients.

Rituximab in the treatment of refractory follicular lymphoma -- six doses are better than four.

Seventeen patients with refractory follicular lymphoma heavily treated with chemotherapy (>2 regimens), radiotherapy, and biological modifiers were enrolled in a pilot study to receive six weekly doses, instead of the more frequent four doses, of monoclonal anti CD20, at a standard dose of 375 mg/m(2). In an intent-to-treat analysis, overall response was 76%, of which 47% (8 patients) were a complete response. With a median follow-up of 33.6 months, 7 complete responders remained alive and free of disease, and 2 partial-response patients remained stable without additional treatment. Actuarial curves showed that at 3 years, 53% of patients should be alive and free of disease. The 4 patients who were failures died secondary to tumor progression. Overall survival at 3 years was 76%. Toxicity was mild; all patients completed the schedule on time and doses. The addition of two doses of anti-CD 20 clearly improved the outcome in a group of patients with refractory follicular lymphoma heavily treated and poor prognostic factors. However, the number is too small to drawn definitive conclusions, and more clinical trials are necessary to determine if four of six doses of anti-CD20 therapy are better in this setting of patients.

Interferon alfa 2b as maintenance therapy in poor risk diffuse large B-cell lymphoma in complete remission after intensive CHOP-BLEO regimens.

OBJECTIVES: We conducted a randomized clinical trial to evaluate the role of interferon alfa 2b (IFN) as maintenance therapy in patients with diffuse large B-cell lymphoma with high or high-intermediate clinical risk on complete remission (CR) after CHOP-BLEO regimens. METHODS: Patients were initially treated with CHOP-BLEO regimens (which include increased doses of cyclophosphamide and epirubicine, instead of doxorubicin). If the patients achieved CR they were randomly assigned to receive either maintenance therapy with IFN 5.0 MU, three times at week by 1 yr, or no treatment (control group). RESULTS: Two hundred and twenty-three patients were considered as candidates for the study. They were of high (80%) or high-intermediate (20%) clinical risk; additionaly most patients had poor prognostic factors such as high levels of beta 2 microglobulin, lactic dehydrogenase levels, bulky disease (defined as a tumor mass >10 cm) or multiple extranodal involvement. In an intent-to-treat analysis all patients were evaluable to efficacy and toxicity. Median follow-up was 45 months, the estimated 5-yr overall survival and event-free survival (EFS) for patients who received IFN were 71% (95% confidence interval (CI): 61-83%) and 57% (95% CI: 39-69%), respectively, values which were not statistically different from the control group: 69% (95% CI: 63-79%) and 54% (95% CI: 37-63%), respectively (p=0.2). Toxicity was mild. CONCLUSIONS: These results suggest that IFN used as maintenance therapy at these doses and schedules is not useful in aggressive malignant lymphoma when more intensive chemotherapy has been employed during induction treatment. Nevertheless, follow-up is too short, and long-term follow-up would be necessary in order to draw definitive conclusions. Probably, an multicenter study is necessary to define the role of IFN as maintenance therapy in this patient setting.

Angiocentric nasal T/natural killer cell lymphoma: a single centre study of prognostic factors in 108 patients.

Angiocentric T cell/natural killer (NK) nasal lymphoma remains a rare clinical presentation in North America and Europe but is more common in Asia and Latin America. We have reviewed 108 cases of angiocentric T/NK cell lymphoma of the nasal cavity with a view to establishing prognostic factors. Most patients were high or high intermediate clinical risk and had additional poor prognostic factors such as bulky disease, high levels of beta 2 microglobulin, advanced stage and multiple extranodal involvement. At 8 years, overall survival was 82%, 90% and 84% for low-intermediate, high-intermediate and high clinical, respectively. Disease free survival was very similar: 79%, 83% and 80%, respectively. Multivariate analysis did not identify any factor influencing overall survival and disease-free survival. There was no evidence that the international prognostic index (IPI) was applicable in these patients and it appears that angiocentric T/NK cell lymphoma is an independent prognostic factor itself.

Second lethal events associated with treatment for Hodgkin's disease: a review of 2980 patients treated in a single Mexican institute.

Presence of second neoplasms and cardiac toxicity has been recognized as potential late lethal second events in patients treated for Hodgkin's disease. However, most reports analyze these association independently. We reviewed 2980 cases of patients treated during 1970-1995 with long-term follow-up (> 4 years) in an attempt to identify all late events in Hodgkin's disease secondary to the treatment or those which are unrelated. Three hundred and ten patients died, and of these 156 were secondary to relapse and tumor progression. Death associated second tumors and cardiac events were increased 37 fold and 29 fold respectively compared to the general population. The risk factors for this complications did not differ to previous reports and included alkylating agents and/or radiotherapy for second neoplasms and anthracycline therapy and radiotherapy for cardiac toxicity. Moreover, 61 patients died secondary to non-related events. Nevertheless, at 20-years overall survival was 90 % (95 % confidence interval (CI): 78 % to 97 %) and event free survival was 88 % (95 % CI: 76 % to 96 %) for these patients. Thus, second events, fatal in most cases, should be considered as an expected risk to the treatment in patients with Hodgkin's disease; the proposed modifications of therapy may indeed be useful to avoid or diminish these complications in the future.

Dexamethasone, all trans retinoic acid and interferon alpha 2a in patients with refractory multiple myeloma.

Few effective regimen are available for patients with refractory multiple myeloma (RMM). Generally, responses are scarce and disease free survival is very short. We developed a new therapeutic option in these patients using dexamethasone (40 mg/m2, i.v., daily, days 1 to 4), all-trans retinoic acid (45 mg/m2, po, daily, days 5 to 14) and interferon alpha 2a (9.0 MU, daily, subcutaneously, days 5 to 14). The treatment was administered every 21 days for 6 cycles. In a pilot study, 12 patients, heavily treated with chemotherapy and radiotherapy and in some cases with interferon, were allocated to receive the afore mentioned treatment. Response was observed in 10 patients (83%). With a median follow-up of 36.1 months (range 27 to 41), seven patients remain alive and disease-free without any treatment. Two patients were failures and have died due to tumor progression. Toxicity was mild and all patients received treatment according to the planned doses of drugs. The use of biological modifiers in combination with dexamethasone offer a safe and effective therapeutic option in patients with refractory multiple myeloma. More studies are warranted to define the role of this type of treatment.

High Dose Chemotherapy in the Treatment of Poor Prognosis Malignant Lymphoma.

UNLABELLED: The aim of the present study was to evaluate an intensive chemotherapy regimen in patients with poor prognosis malignant lymphoma. Sixty previously untreated patients with malignant lymphoma of high- or high-intermediate risk were treated with an intensive regimen. Patients received increasing doses of cyclophosphamide 1000 mg/m(2), and epirubicin 120 mg/m(2), in an CEOP-Bleo regimen with granulocyte-macrophage colony stimulating factor as hematological support. Moreover the high clinical risk patients had more adverse prognostic factors such as bulky disease, elevated levels of beta 2 microglobulin and multiple extranodal sites of involvement at diagnosis. Complete response was achieved in 49 out of 60 patients (81%) (95% confidence interval 63% to 89%). With a median follow-up of 43.6 months (ranged 31 to 61 months), only five patients have relapsed. Thus, at 5-years 72% of the patients remain in first complete response and 74% of the patients are alive free of disease. TOXICITY: severe granulocytopenia was observed in the 46% of the chemotherapy cycles; infection-related granulocytopenia was observed in 17%, but no fatality due therapy was observed. Granulocyte recovery was faster and delay on treatment was minimal (3.4 days). No thrombocytopenia, severe mucositis or cardiac abnormalities were observed. The CEOP-Bleo regimen with increasing doses of cyclophosphamide and epirubicin is an useful and well tolerated regimen for the treatment of poor prognosis malignant lymphoma.