Current guidelines for the management of aggressive non-Hodgkin's lymphoma

The prognosis of aggressive non-Hodgkin's lymphoma (NHL) has improved greatly during recent years with the use of combination chemotherapy. Planning the treatment must take into consideration the patient's age, performance status, histological subtype and disease extent and severity. Recently, a 4-part International Prognostic Index (IPI), based on 5 prognostic factors, has permitted the allocation of patients with NHL in 2 well defined prognostic groups: good prognosis (low and low-intermediate risk) and poor prognosis (intermediate-high and high risk). Conventional chemotherapy with CHOP (a chemotherapeutic regimen consisting of a combination of cyclophosphamide, doxorubicin, vincristine and prednisone) or other equivalent third-generation regimens may be considered the standard treatment for the good prognosis group. In the poor prognosis group the probability of long term survival is less than 40% with conventional chemotherapy. Therefore, an early intensification with high dose therapy following peripheral stem cell transplantation (PSCT) should be considered in the setting of randomised trials. Localised stage disease, defined as stages I-IE and II-IIE without adverse prognostic factors, has a very good prognosis with a long term survival exceeding 80% using brief conventional chemotherapy regimens plus involved field radiotherapy. Refractory or relapsing patients after the drugs of first choice are given who subsequently respond to salvage chemotherapy should be enrolled for a course of high dose consolidation chemotherapy followed by PSCT. Elderly patients without severe organ dysfunction can take advantage from specifically devised chemotherapy regimens, with a response rate similar to that of younger patients. However, despite major advances in the treatment of aggressive NHL, additional clinical trials are required to enable the clinician to define the best therapeutic programmes to treat patients with this disorder.     

Administration of rhG-CSF increases complete remission rates after CHOP and ProMACE/CytaBOM for non-Hodgkin's lymphoma: a pilot study. Hokkaido Study Group of Malignant Lymphoma and rhG-CSF

To evaluate the clinical effects of the administration of recombinant human granulocyte-stimulating factor (rhG-CSF) post chemotherapy for patients with advanced-staged intermediate-grade or high-grade non-Hodgkin's malignant lymphoma (NHL), we conducted this multicenter study and compared the responses between both the regimens, CHOP as a first-generation chemotherapy and ProMACE/CytaBOM as a third-generation chemotherapy, when combined with the rhG-CSF administration. In this multicenter study, where forty patients were registered, patients in both the CHOP and ProMACE/CytaBOM groups were treated with the original regimen designs without the necessity of reducing drug dosages when combined with the administration of rhG-CSF. The administration of rhG-CSF post both of the cytotoxic therapies brought about much higher rates of complete remission in both the groups (CHOP, 75 percent; ProMACE/CytaBOM, 75 percent), as compared with those of the previous study without the rhG-CSF administration. Regarding response rates according to the International prognostic factor index, the CHOP group showed a lower rate of complete remission in patients with risk factors, compared with ProMACE/CytaBOM group. This result suggested that the administration of rhG-CSF may offer one important approach for improving the first-line therapy for aggressive NHL with high risk factors.     

Hypercalciuria

BACKGROUND: Second- and third-generation chemotherapy protocols for the treatment of aggressive non-Hodgkin's lymphomas (NHL) have considerable, and age-related, toxic effects. In addition, they do not seem to prolong overall survival in comparison to standard CHOP chemotherapy. In this phase II study we investigated the feasibility and efficacy of the addition of etoposide to the conventional CHOP regimen. PATIENTS AND METHODS: Toxicity and clinical efficacy were determined in 132 patients with previously untreated high-grade NHL. There were 51 patients in clinical stage I and II and 81 patients in stage III and IV, with a median age of 54 years (range 17-85). Patients received standard-dose CHOP plus etoposide 100 mg/m2 i.v. on day 1 and 200 mg/m2 p.o. on days 2-3. RESULTS: The overall response rate was 84%, with 70% complete and 14% partial responses. The predicted three- and five-year survivals for the group as a whole were 60% and 53%, respectively, and the corresponding disease-free survivals for patients achieving complete remissions were 65% and 56%, respectively. Outcome was not different from that of CHOP-treated patients in a recently completed Nordic study performed during the same time period. Myelosuppression (WHO grade 3-4), observed in 87% of patients and infectious complications (WHO grade 3-4) in 33%, dominated the toxicity profile of this regimen. Fifty-seven of 92 complete responders (62%) received 6-8 CHOP-E cycles with no reductions in planned dose intensity. LDH level higher than normal, extranodal sites = 2, stage III-IV at diagnosis were all indicators of a poor survival. CONCLUSIONS: We conclude that CHOP-E treatment is effective in high-grade NHL. However, mainly due to severe myelosuppression frequent schedule modifications were required and the results are not obviously superior to those of conventional CHOP.     

Adjuvant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy after radiation therapy in stage I low-grade and intermediate-grade non-Hodgkin lymphoma. Results of a prospective randomized study

BACKGROUND: In a prospective randomized manner, this study evaluated the effect of adjuvant chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone; CHOP) in patients with Stage I non-Hodgkin lymphoma (NHL) who have achieved a complete response (CR) after radiation therapy (RT). METHODS: Forty-four patients with clinical or pathologic Stage I intermediate-grade or low-grade NHL were randomized to receive regional RT alone (median dose, 40 Gy) or regional RT followed by six cycles of CHOP chemotherapy. There were no differences in clinical and pathologic characteristics between the two treatment groups. RESULTS: The median follow-up was 7 years (range, 2-10 years). The actuarial relapse-free survival (RFS) rate for the RT plus CHOP group at 7 years was 83% compared with 47% (P < 0.03) for the RT-alone group. The overall survival (OS) for the two groups was 88% and 66%, respectively (P = 0.2). In patients with intermediate-grade NHL, the 7-year actuarial RFS for RT and CHOP was 86% compared with 20% for RT alone (P = 0.004). The corresponding actuarial survival rates were 92% and 47%, respectively (P = 0.08). In patients with low-grade histologic findings, the addition of adjuvant CHOP did not improve RFS (P = 0.6) or OS. All relapses in this study were at sites remote from the initially involved areas, and in 5 of 11 patients (45%), there were recurrences 5 years or longer after initial treatment. CONCLUSIONS: This study showed that adjuvant CHOP chemotherapy significantly improves RFS in patients with Stage I intermediate-grade NHL who achieve a CR after regional-field RT. The chemotherapeutic regimen favorably affected their probability of survival.     

DNA unwinding in the CYC1 and DED1 yeast promoters

The superiority of intensive versus standard chemotherapy for aggressive (I: intermediate; H: high grade) NHL is still debated; increased antitumor activity may be counterbalanced by increased toxicity. We have designed a first-line five-drug regimen (vincristine, idarubicin, cyclophosphamide, etoposide and deflazacort), with the aim of potentiating the CHOP protocol without losing tolerability and ease of administration. Seventy-one patients (33% aged > or = 65) entered the study. CR was obtained in 66.7% of patients (I: 74%; H: 56%), PR in 19.7%: overall response rate was 86.4%. Six patients were resistant, two died during treatment. With a median follow up of two years, relapse has occurred in 14 patients (8 I, 6 H). At 3 years, overall survival was projected to be 62.5% (I 73.5%; H 31.4%), disease free survival 66% (I 71%, H 56.3%). No organ toxicity occurred. Myelosuppression was moderate, with a nadir on the 14th day. Febrile episodes occurred in 16% of courses, dose delay in 19% of courses; dose reduction in 3% of patients. No patient required hospitalization. G-CSF was only occasionally used. This regimen has shown a potent antitumor effect with an excellent tolerance, even in elderly patients.     

Chemotherapy for non-Hodgkin's lymphoma

This review highlights the role of chemotherapy for intermediate grade non-Hodgkin's lymphoma (NHL) including immunoblastic large cell lymphoma and low grade NHL. The combined modality treatment (CMT) consisting of chemotherapy including adriamycin (ADM) and involved-field irradiation (IFI) is considered standard therapy for localized intermediate grade NHL since a superior outcome (long-term disease-free survival rate is about 80%) can be obtained by CMT. However, developing dose-intensified regimens in initial chemotherapy will change the role of IFI. The phase II study using second and third generation regimens for advanced intermediate grade NHL showed a better outcome than first generation regimen CHOP. Unfortunately, the recent phase III intergroup trial concluded that none of the second or third generation treatment was superior to CHOP, and this regimen is now considered to be standard chemotherapy. However, the cure rate of the CHOP regimen (about 30%) is not satisfactory, and efforts should be underway to develop promising regimens with significantly increased dose intensity. While radiotherapy such as IFI, extended-field irradiation and total lymph node irradiation for localized low grade NHL obtained a more than 50% disease-free survival rate, the role of chemotherapy remains controversial. To date, many randomized trials of single agent chemotherapy regimen, combination chemotherapies with or without ADM, and CMT have shown no overall survival benefit for advanced low grade NHL, so there is no standard therapy for it.     

Alternating triple therapy for the treatment of intermediate grade and immunoblastic lymphoma

BACKGROUND: CHOP is currently considered the gold standard of treatment for intermediate grade lymphomas. We designed a new regimen known as 'ATT' (alternating triple therapy) which uses three non-cross resistant combinations in alternating sequence for nine cycles. MATERIALS AND METHODS: This is a phase II clinical trial with comparison to CHOP/CMED historical controls using prognostic factors. The tumor score system was used to evaluate the results of this trial. Two hundred sixty-eight eligible patients who had one or more of the following adverse features: bulky disease, elevated LDH or > 1 extranodal site were analyzed. Outcome measures consist of survival and failure free survival. RESULTS: At a median follow-up of 32 months, there was no statistically significant difference in survival for those with favorable prognostic factors (tumor score < or = 2). However, there was a statistically significant difference in favor of ATT for those with unfavorable tumor scores. When we examined the failure-free survival of those with unfavorable tumor scores, we again observed a superiority for the ATT regimen over CHOP/CMED but the opposite was true for those with favorable tumor scores. We also found a statistically significant difference in favor of the ATT regimen when compared with CHOP/CMED for patients < or = 60 years old with a tumor score > or = 3, while no advantage was found for those > 60 years. CONCLUSIONS: ATT appears more effective but only for patients < 60 years old with unfavorable tumor scores. In those older than 60 years with favorable tumor score, CHOP/CMED appears superior. ATT might be an adequate regimen for young patients with poor prognostic features while CHOP/CMED might be a better choice for those with good prognosis irrespective of age. For those > 60 years with unfavorable tumor scores neither ATT or CHOP/CMED were adequate treatment. Because of the phase II nature of this study, these conclusions should be considered as hypotheses which require prospective testing.     

Phase III comparative trial using CHOP vs CIOP in the treatment of advanced intermediate-grade non-Hodgkin's lymphoma

Until now, literature data support the fact that the CHOP regimen represents the standard first line treatment for patients with advanced intermediate-grade non-Hodgkin's lymphoma. Recently, idarubicin has been introduced in clinical trials because of its favourable preclinical profile: it is more active than daunorubicin and doxorubicin against a number of experimental tumour systems and is significantly less cardiotoxic in animal models. From March 1991 to June 1993, 115 previously untreated patients with stage II to IV intermediate-grade non-Hodgkin's lymphoma, according to the Kiel classification, were enrolled in a phase III comparative trial. The objectives of the study were to compare the efficacy and safety of using idarubicin instead of doxorubicin in the polychemotherapeutic regimen CHOP (cyclophosphamide, doxorubicin, vincristine, and dexamethasone). Of the 115 patients registered for the trial, 103 were evaluable: 52 received CH (doxorubicin)OP and 51 received CI(Idarubicin)OP. Known prognostic factors were equally distributed among the two groups. There were no significant differences between the 2 groups in the rates of partial and complete response. The overall response rate was 87%, with complete response in 62%: 63% in the CHOP group, and 59% in the CIOP group. At 30 months (median 20 months), 86% of all CR patients were alive without disease in the CHOP group and 85% in the CIOP group. Patients treated with CHOP experienced severe alopecia more frequently (P = .004). Only three patients in the CIOP group showed cardiac adverse events (1 moderate and 2 mild), while in the CHOP group 4 mild, 2 moderate and 1 severe were recorded. LVEF monitoring was carried out in 31 patients of the CHOP group and in 27 of the CIOP group. A median drop of 8.3% of the LVEF was observed in patients treated with CHOP regimen as compared to 4.8% in patients with CIOP regimen (P = .0001). In this trial, the "idarubicin arm" (CIOP regimen) was found to have an equivalent therapeutic efficacy and, slightly, reduced clinical toxicity in comparison to the standard doxorubicin-containing CHOP regimen in patients with intermediate-grade non-Hodgkin's lymphoma.     

MIB-1 labeling indices in benign, aggressive, and malignant meningiomas: a study of 90 tumors

Predicting tumor behavior in meningiomas based on histology alone has been problematic. This study retrospectively compares histology and MIB-1 (cell proliferation marker) labeling indices (LI) in benign, aggressive, and malignant meningiomas. Six histological features, including mitoses, necrosis, loss of pattern, hypervascularity/hemosiderin deposition, prominent nucleoli, and nuclear pleomorphism, were compared in 90 meningiomas (Fisher's exact test). Tumors with two or more of the above features were designated as aggressive meningiomas. Malignant meningiomas were characterized by brain invasion or metastasis. The MIB-1 LIs (% positive tumor cell nuclei) were compared between the three groups (Kruskal-Wallis test, Wilcoxon two-sample test). Of the benign meningiomas (n=37; mean age, 54 years), 41% had one of the six histological features, with nuclear pleomorphism (n=10) being the most frequent. The aggressive tumors (n=29; mean age, 61 years) were characterized by nuclear pleomorphism (n=28), mitoses (n=20), necrosis (n=16), loss of pattern (n=16), prominent nucleoli (n=6), and hypervascularity/hemosiderin deposition (n=5). Malignant tumors (n=24; mean age, 59 years) were characterized by nuclear pleomorphism (n=22), mitoses (n=21), loss of pattern (n=21), necrosis (n=21), nucleoli (n=17), and hypervascularity/hemosiderin deposition (n=3). Significant differences were found between the aggressive and malignant groups with regard to loss of pattern, necrosis, and nucleoli (P=.0043, .011, and .00029, respectively). Mean MIB-1 LIs for the benign, aggressive, and malignant groups were 1.0% (range, 0 to 5.5%),5.5% (range, 0.1 to 32.5%), and 12.0% (range, 0.3 to 32.5%), respectively. Differences in the mean MIB-1 LI between groups were statistically significant, with P values of <.0001 (benign v aggressive) and .0012 (aggressive v malignant). Mean MIB-1 LIs for recurrent versus nonrecurrent tumors were 7.1% (range, 0 to 32.5%) versus 3.8% (range, 0 to 20.9%) (P=.32). The mean MIB-1 LI for patients who were alive with or without tumor was 6.2% (range, 0 to 32.5%) versus a mean MIB-1 LI of 14.2% (range, 2.8% to 32.5%) for patients who died of or with tumor (P=.0013). In conclusion, (1) There is a statistically significant difference in the increasing MIB-1 LI means between benign, aggressive, and malignant meningiomas and between patients who were alive versus those who died; (2) there is some overlap in MIB-1 LI ranges between groups, which warrants caution in interpreting an individual MIB-1 LI in a given tumor.     

Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin's lymphoma. Groupe d'Etude des Lymphomes de l'Adulte (GELA)

Little is known about the expression of bcl-2 protein in intermediate and high grade non-Hodgkin's lymphoma (NHL) and its clinical and prognostic significance. We performed immunohistochemical analysis of bcl-2 expression in tumoral tissue sections of 348 patients with high or intermediate grade NHL. These patients were uniformly treated with adriamycin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) in the induction phase of the LNH87 protocol. Fifty eight cases were excluded due to inadequate staining. Of the 290 remaining patients, 131 (45%) disclosed homogeneous positivity (high bcl-2 expression) in virtually all tumor cells, whereas 65 (23%) were negative and 94 (32%) exhibited intermediate staining. High bcl-2 expression was more frequent in B-cell NHL (109 of 214, 51%) than in T-cell NHL (6 of 35, 17%) (P = .0004), and was heterogeneously distributed among the different histological subtypes. Further analysis was performed on the 151 patients with diffuse large B-cell lymphoma (centroblastic and immunoblastic) to assess the clinical significance and potential prognostic value of bcl-2 expression in the most frequent and homogeneous immunohistological subgroup. High bcl-2 expression, found in 44% of these patients (67 of 151), was more frequently associated with III-IV stage disease (P = .002). Reduced disease-free survival (DFS) (P < .01) and overall survival (P < .05) were demonstrated in the patients with high bcl-2 expression. Indeed, the 3-year estimates of DFS and overall survival were 60% and 61%, respectively (high bcl-2 expression) versus 82% and 78%, respectively (negative/intermediate bcl-2 expression). A multivariate regression analysis confirmed the independent effect of bcl-2 protein expression on DFS. Thus bcl-2 protein expression, as demonstrated in routinely paraffin-embedded tissue, appears to be predictive of poor DFS, in agreement with the role of bcl-2 in chemotherapy-induced apoptosis. It might be considered as a new independent biologic prognostic parameter, which, especially in diffuse large B-cell NHL, could aid in the identification of patient risk groups.     

Autologous stem-cell transplantation for non-Hodgkin's lymphomas: the role of graft purging and radiotherapy posttransplantation--results of a retrospective analysis on 120 patients autografted in a single institution

PURPOSE: To analyze retrospectively survival and prognostic factors of patients with non-Hodgkin's lymphoma (NHL) autografted from 1979 to 1995 in a single institution. PATIENTS AND METHODS: A total of 120 patients, 64 with aggressive and 56 with low-grade NHL, were autografted. The carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) regimen was used in 104. The autograft was marrow in 101 patients. Marrow was purged in vitro by mafosfamide for 63 patients (adjusted dose [AD] in 32; unique dose [UD] in 31); 27 patients received a CD34+-selected graft. Following intensification, 45 patients received additional radiotherapy on previous sites of involvement. RESULTS: Outcome at 5 years for patients transplanted with low-grade NHL in first complete remission (CR1), in first partial remission (PR1), and in second complete remission (CR2) or beyond showed an event-free survival (EFS) of 75% +/- 12%, 46% +/- 18%, and 57% +/- 24%, a relapse incidence (RI) of 21% +/- 12%, 49% +/- 19%, and 43% +/- 25%, and a transplant-related mortality (TRM) of 5% +/- 5%, 10% +/- 7%, and 0%, respectively. For patients with aggressive NHL transplanted in CR1, in PR1, in CR2 or beyond, and in resistant relapse or in primary refractory disease, the EFS was of 73% +/- 9%, 58% +/- 19%, 29% +/- 16%, and 10% +/- 9%, the RI 22% +/- 9%, 14% +/- 9%, 77% +/- 18%, and 66% +/- 20%, and the TRM 6% +/- 6%, 32% +/- 21%, 11% +/- 10%, and 71% +/- 22%, respectively. In patients autografted upfront in first remission, additional radiotherapy was associated with a higher EFS, in univariate (P = .03) and multivariate analysis (P = .02, relative risk [RR] = .021). The role of graft purging with mafosfamide on the outcome reflected by the dose of colony-forming unit-granulocyte-macrophage (CFU-GM) per kilogram infused postpurging was assessed by univariate analysis: patients in first remission who received lower doses of CFU-GM had a lower RI and a higher EFS. CONCLUSION: This retrospective analysis suggests that marrow purging and posttransplant radiotherapy improve the outcome of patients with NHL autografted in first remission.     

CHOP vs. ProMACE-CytaBOM in the treatment of aggressive non-Hodgkin's lymphomas: long-term results of a multicenter randomized trial.(PETHEMA: Spanish Cooperative Group for the Study of Hematological Malignancies Treatment, Spanish Society of Hematology)

From May 1985 to May 1989, 175 patients with previously untreated aggressive non-Hodgkin's lymphoma were randomized to receive CHOP or ProMACE-CytaBOM. Eligibility criteria included follicular large-cell diffuse small cleaved-cell, diffuse mixed, diffuse large-cell and immunoblastic lymphoma with an Ann Arbor stage II, III or IV. One hundred and forty-eight patients were evaluable. There were no significant differences between the 2 treatments in response rate (83.5% [57.5% CR] for CHOP vs. 88% [62% CR] for ProMACE-CytaBOM), time to treatment failure (29% vs. 31% at 5 yr), or overall survival (42% in both groups at 5 yr). Furthermore, there were no significant differences between the 2 regimens when response rates and outcome were analyzed for different prognostic subgroups. Toxicity was not significantly different between the 2 regimens, although only 1 patient died as result of treatment-related toxicity in the CHOP arm compared to 6 patient in the ProMACE-CytaBOM group (p = 0.126). In conclusion, in this study ProMACE-CytaBOM has not proved to be superior to CHOP in aggressive lymphomas. This trial gives support to the notion that CHOP still is the standard chemotherapy for aggressive lymphomas, and that new treatment approaches for these lymphomas should be compared to CHOP.     

MT方案治疗急性单核细胞白血病的疗效及其与染色体核型的关系

目的 研究米托蒽醌联合替尼泊苷(MT)方案在急性单核细胞白血病(M5)诱导缓解中的疗效及患者不良反应,并观察疗效与白血病染色体核型的关系.方法 将33例M5患者按治疗史分两组:初治组23例(A组)、DA(柔红霉素联合阿糖胞苷)或HDA(三尖杉酯碱、柔红霉素和阿糖胞苷)1个疗程无效组10例(B组).按核型预后分两组:预后中等组29例(C组),预后不良组4例(D组),均采用MT方案2个疗程诱导缓解,分别统计4组的临床疗效及患者不良反应.结果 MT方案对A、B组的M5诱导完全缓解(CR)率分别为83%(19/23)及60%(6/10),有效率达91%(21/23)及70%(7/10).C、D组CR率分别为83%(24/29)及25%(1/4),有效率为88%(26/29)及50%(2/4),其中复杂核型CR率为0(0/3),非复杂核型的11q23染色体异常患者一次化疗达CR率100%(4/4).MT方案对M5化疗后白细胞最低点在第(7±3)天出现,为(0.4±0.2)×109/L,白细胞<1×109/L时间达(8±5)d,未见化疗相关死亡病例.结论 MT方案简单有效、较安全,是治疗M5的较佳化疗方案,对1个疗程DA、HDA方案无效者亦可试用.MT方案化疗疗效与核型预后分组有关,对11q23染色体异常的M5患者疗效较好,对复杂核型患者疗效欠佳.     

Cell death and oxidative damage in inflammatory myopathies

AIMS: To evaluate the independent prognostic value of apoptotic versus proliferative fractions in a series of 92 patients with non-Hodgkin's lymphomas (NHL). METHODS AND RESULTS: Apoptotic fractions were quantified by use of the TdT (terminal deoxynucleotidyl-transferase)-mediated in-situ end-labelling technique (TUNEL), the percentage of positive cells constituting the apoptotic index (AI). Proliferative rate was expressed as percentage of Ki67 positive cells (Ki67 LI). Tissues were also stained for p53 protein with the DO-1 antibody. Patients were followed up until death (n = 33) or for an average of 63 months (n = 56). AI increased with malignancy grade and proliferative activity but was not related to location, cell of origin, clinical stage, bone marrow involvement and p53 expression. In multivariate analysis, overall survival was independently influenced by grade, stage, p53 LI and chemotherapy. The independent predictors of disease-free survival were Ki67 LI location and chemotherapy. AI turned out to be the only independent (negative) predictor of post-relapse survival. On the other hand, a low Ki67 LI increased the risk of relapse (logistic regression analysis) whereas a low p53 LI increased the probability of complete response. CONCLUSIONS: Our results suggest that the combined assessment of apoptotic fraction, proliferative rate and p53 expression may provide important prognostic information independent of other clinicopathological parameters in NHL.     

The meeting of pain and depression: comorbidity in women

The use of allogeneic BMT in patients with relapsed non-Hodgkin lymphoma (NHL) offers the advantage of tumor-free bone marrow and possibly a 'graft-versus-lymphoma effect' which may decrease the risk of recurrence. However, allogeneic BMT also poses an increased risk of death due to graft-versus-host disease (GVHD) which can be ameliorated by T cell depletion. We performed a retrospective review of 37 patients who underwent T cell-depleted allogeneic BMT for aggressive and indolent NHL between 1988 and 1996. Polymerase chain reaction (PCR) was used to identify indolent NHL patients with the BCL2/IgH translocation which served as a marker of residual disease. Sixteen of 37 patients (44%) are alive and progression-free with a median follow-up of 4.4 years (range 1-10.3). The incidence of grade 2-4 acute GVHD was 36% and extensive chronic GVHD developed in 12%. Patients with aggressive NHL have an overall PFS of 33% (12-54%); those with chemotherapy-resistant and sensitive disease have PFS of 17% (0-47%), and 40% (15-65%) respectively at 5 years. Patients with indolent histologies have overall PFS of 62% (37-86%); those with chemotherapy-resistant and sensitive disease have PFS of 55% (25-85%) and 80% (45-100%) respectively at 5 years. Eight patients with indolent disease had a BCL2/IgH translocation detectable by PCR. Five of these eight patients remain alive and progression free at a median of 6.5 years after BMT (range 2.1-7.4 years), four of whom remain PCR positive from 1.7 to 2.9 years after transplantation. We conclude that T cell-depleted allogeneic BMT poses a low risk for death due to GVHD, and should be considered for patients with relapsed and refractory indolent NHL.     

Short- and long-term smoking cessation for three levels of intensity of behavioral treatment.

Efficacy and costs of 3 levels of medical–behavioral treatment intensity in conjunction with nicotine replacement therapy (NRT) were compared in 240 one-pack-a-day smokers: (a) a low-intensity (LI) group that received 8 weeks of NRT (n?=?80) and 1 advice and education (A&E) session with a nurse practitioner (NP); (b) a moderate-intensity (MI) group that was provided NRT and 4 A&E sessions with an NP (n?=?80), and (c) a high-intensity (HI) group that received treatment combining NRT, 4 A&E sessions, and 12 weeks of individualized cognitive–behavioral therapy (n?=?80). Biochemically confirmed abstinence rates at 9, 26, and 52 weeks posttreatment initiation were highest for the HI (45%, 37%, 35%) group, followed by the LI (35%, 30%, and 27%) and MI (27%, 12%, 12%) groups. Group differences approached statistical significance at 9 weeks and were statistically significant at both 26 and 52 weeks. The cost of LI treatment was $308, that of MI was $338, and the HI treatment cost was $582. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of a one-year high-intensity versus low-intensity resistance training program on bone mineral density in older women

The purpose of this study was to determine the effects of a 12-month resistance training program, of two different intensities, on bone mineral density (BMD) in healthy, older women. Twenty-six Caucasian women (aged 65-79 years) completed the study. Subjects were randomly assigned to one of three groups: high-intensity (HI; n = 8), low-intensity (LI; n = 7), and control (CON; n = 11). The active groups performed 10 exercises, 3 days/week under supervision. Exercise intensity was maintained at 80% of one-repetition maximum (1-RM) for the HI groups, and at 40% 1-RM for the LI group. The volume of work was maintained constant between the two groups by assigning the LI group twice as many repetitions for each exercise. Maximal muscular strength and BMD of the lumbar spine and total hip were measured at baseline and at 12 months. Strength was evaluated using the 1-RM method, and BMD was determined by dual-energy X-ray absorptiometry. Exercise session attendance was similar for the two groups (81.0% HI; 76.8% LI). Muscular strength improved in the exercisers compared with the CON group (p < or = 0.05). Percentage change in lumbar spine BMD was 0.7 +/- 1.9%, 0.5 +/- 2.4%, and -0.1 +/- 2.3% for the HI, LI, and CON groups, respectively. Percentage change in total hip BMD was 0.8 +/- 2.3% (HI), 1.0 +/- 1.7% (LI), and 0.9 +/- 1.3% (CON). Group differences in BMD change were not significant (p > 0.05). These findings suggest that high-intensity and low-intensity resistance training regimens effectively increase muscular strength, but not lumbar spine or total hip BMD, in healthy, older women.     

The involvement of the Golgi apparatus in the pathogenesis of amyotrophic lateral sclerosis, Alzheimer''s disease, and ricin intoxication

The purpose of this study was to assess the safety and feasibility of using standard and escalated doses of cyclophosphamide with doxorubicin, vincristine and prednisone (CHOP) plus granulocyte colony stimulating factor (G-CSF) to treat elderly patients who have advanced stage intermediate grade lymphoma. Consenting patients age > or = 65 years who had an acceptable performance status and adequate cardiac, renal and liver function were eligible for this Phase I study. G-CSF, 5 ug per kg, was given daily with each cycle from day 2 until neutrophil recovery of > or = 10 x 10(9)/L. Ten patients received standard CHOP; sequential cohorts of 5 patients were then to be given CHOP with cyclophosphamide doses of 900, 1050, 1200, and 1350 mg/m2. If 2 patients had dose limiting toxicity, cohorts were expanded to 10 patients; if 3 patients within a cohort had dose limiting toxicity, the previous dose level was considered the maximum tolerated dose of cyclophosphamide. Secondary outcomes were average relative received dose intensity, response, progression-free and overall survival, toxicity, hospitalizations and transfusions. Eight patients (80%) completed 6 cycles of standard CHOP plus G-CSF. Therapy was stopped prematurely in 2 patients due to pneumonia (1) and disease progression (1). Six of 11 patients (55%) given CHOP with cyclophosphamide 900 mg/m2 (CHOP-900) completed treatment. Therapy was stopped in 5 patients due to a toxic death from infection (1), cumulative fatigue (3), and pneumonitis (1). Further dose escalations were not attempted due to the inability to complete 6 treatment cycles in 45% of CHOP-900 cases. The received dose intensities of cyclophosphamide relative to standard CHOP measured over the actual time on therapy were 96% with standard CHOP and 115% with CHOP-900. At 3 years, progression free survival is 40% with standard CHOP and 82% with CHOP-900; overall survivals are 40% and 91% respectively. Neutropenia of < 1.0 x 10(9)/L occurred in 47% of treatment cycles with standard CHOP and in 77% with CHOP-900. In both groups, the mean duration of neutropenia was < 2 days. From these studies we conclude that, standard CHOP with G-CSF can be safely given to elderly patients. Escalating the dose of cyclophos     

VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group

PURPOSE: The aim of this multicenter randomized study was to compare conventional therapy with conventional plus high-dose therapy (HDT) and autologous bone marrow transplantation (ABMT) as front-line treatment for poor-prognosis non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Between October 1991 and June 1995, 124 patients, aged 15 to 60 years, with diffuse intermediate- to high-grade NHL (Working Formulation criteria), stages II bulky (> or = 10 cm), III, or IV were enrolled. Sixty-one patients were randomized to receive etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (VACOP-B) for 12 weeks and cisplatin, cytarabine, and dexamethasone (DHAP) as a salvage regimen (arm A), and 63 to receive VACOP-B for 12 weeks plus HDT and ABMT (Arm B). RESULTS: There was no significant difference in terms of complete remissions (CRS) in the two groups: 75% in arm A, and 73% in arm B. The median follow-up observation time was 42 months. The 6-year survival probability was 65% in both arms. There was no difference in disease-free survival (DFS) or progression-free survival (PFS) between the two groups. DFS was 60% and 80% (P = .1) and PFS was 48% and 60% (P = .4) for arms A and B, respectively. Procedure feasibility was the major problem. In arm B, 29% of enrolled patients did not undergo HDT and ABMT. A statistical improvement in terms of DFS (P = .008) and a favorable trend in terms of PFS (P = .08) for intermediate-/high- plus high-risk group patients assigned to HDT and ABMT was observed. CONCLUSION: In this study, conventional chemotherapy followed by HDT and ABMT as front-line therapy seems no more successful than conventional treatment in terms of overall results. However, our results suggest that controlled studies of HDT plus ABMT should be proposed for higher risk patients.     

In vitro expansion of CD34+ cells from peripheral blood of myeloma and lymphoma patients

We studied the feasibility of in vitro expansion of CD34+ cells from patients with multiple myeloma (MM) or follicular non Hodgkin lymphoma (NHL). CD34+ cells were selected from peripheral blood (PB) using avidinbiotin immunoadsorption columns: purified CD34+ cells from three MM and five NHL patients were expanded. First, CD34+ cells (2 MM, 4 NHL) were grown for 14 days in 5 ml of IMDM plus 12.5% horse serum (HS), 12.5% fetal calf serum (FCS) and a commonly used combination of cytokines: IL1alpha, IL3, IL6, SCF, GM-CSF, G-CSF (10 ng/ml each) and EP (4 UI/ml). In these conditions, at day 14, average increase in CD34+, CFU-GM and total cell numbers were, respectively: x 6.0 x 23 and x 2,113 fold with 20 to 35% of granulocytic cells. In terms of CD34+ cell, CFU-GM and total cell outputs, MM cultures were comparable to NHL cultures, but MM cultures seemed to produce less granulocytic cells than NHL cultures. Next, in vitro expansion of PB CD34+ cells was tested in culture media suitable for clinical use. Two cultures (1 MM, 1 NHL) were carried out for 14 days in 20 ml of X-Vivo 10 medium, 2% human serum, IL1alpha, IL3, IL6, SCF, GM-CSF, G-CSF (6 ng/ml each) and EP (2 UI/ml). Increase in CD34+, CFU-GM and total cell numbers in these conditions were, respectively: x 5.7 and x 19.7, x 11.9 and x 40.9, x 424 and x 408 fold, with at least 75% of granulocytic cells in both cultures. We conclude that, although further improvements are necessary, in vitro expansion of PB CD34+ cells can presumably be carried out successfully for MM patients as well as for NHL patients, including in conditions suitable for clinical use.