Survival of multiple myeloma patients who are potential candidates for early high-dose therapy intensification/ autotransplantation and who were conventionally treated

PURPOSE: To analyze the outcome of patients with multiple myeloma (MM) who were potential candidates for early high-dose therapy (HDT) intensification followed by autotransplantation from a series treated with conventional chemotherapy. PATIENTS AND METHODS: From January 1985 through December 1989, 487 patients with symptomatic MM were entered onto a randomized study to compare melphalan and prednisone (MP) versus vincristine, cyclophosphamide, melphalan, and prednisone (VCMP) /vincristine, carmustine (BCNU), doxorubicin, and prednisone (VBAP). The sub-group of 77 patients who could have been candidates for early intensification with HDT followed by stem-cell support (ie, < 65 years of age, stage II or III disease, performance status < 3, and objective or partial response to initial chemotherapy) are the subjects of this report. RESULTS: Seventy-seven of 487 patients could have been candidates for early intensification. The median age was 56 years (range, 27 to 64). At diagnosis, 12% had abnormal renal function, 16% hypercalcemia, and 42% serum beta 2-microglobulin level > or = 6 mg/L; 62% had stage III disease at diagnosis. Thirty-six patients were initially treated with MP and 41 with VCMP/VBAP. The median response duration to initial chemotherapy was 22 months, and the actuarial probability of being in continued first response at 5 years was 14%. After a median follow-up time of 58 months, 59 patients have died, one was lost to follow-up evaluation, and 17 are still alive 69 to 119 months after initial chemotherapy. The median survival time from initiation of treatment was 60 months and from the time when autotransplantation would be considered, 52 months. The only independent prognostic parameter for survival was renal function at diagnosis. CONCLUSION: The median survival time of patients with MM who are less than 65 years of age and who respond to initial chemotherapy is 5 years. This survival duration is similar to that reported in selected series of patients given early HDT and stresses the importance of ongoing randomized trials to determine the role of HDT in the treatment of younger myeloma patients.     

Effect of peroral anti-bacterial antiserum treatment on intestinal immune parameters of germ-free piglets intragastrically infected with virulent Salmonella typhimurium or enteropathogenic E. coli

Between August 1990 and August 1995, 231 patients (median age 51, 53% Durie-Salmon stage III, median serum beta-2-microglobulin 3.1 g/L, median C-reactive protein 4 g/L) with symptomatic multiple myeloma were enrolled in a program that used a series of induction regimens and two cycles of high-dose therapy ("Total Therapy"). Remission induction utilized non-cross-resistant regimens (vincristine-doxorubicin-dexamethasone [VAD], high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor with peripheral blood stem cell collection, and etoposide-dexamethasone-cytarabine-cisplatin). The first high-dose treatment comprised melphalan 200 mg/m2 and was repeated if complete (CR) or partial (PR) remission was maintained after the first transplant; in case of less than PR, total body irradiation or cyclophosphamide was added. Interferon--2b maintenance was used after the second autotransplant. Fourteen patients with HLA-compatible donors underwent an allograft as their second high-dose therapy cycle. Eighty-eight percent completed induction therapy whereas first and second transplants were performed in 84% and 71% (the majority within 8 and 15 months, respectively). Eight patients (3%) died of toxicity during induction, and 2 (1%) and 6 (4%) during the two transplants. True CR and at least a PR (PR plus CR) were obtained in 5% (34%) after VAD, 15% (65%) at the end of induction, and 26% (75%) after the first and 41% (83%) after the second transplants (intent-to-treat). Median overall (OS) and event-free (EFS) survival durations were 68 and 43 months, respectively. Actuarial 5-year OS and EFS rates were 58% and 42%, respectively. The median time to disease progression or relapse was 52 months. Among the 94 patients achieving CR, the median CR duration was 50 months. On multivariate analysis, superior EFS and OS were observed in the absence of unfavorable karyotypes (11q breakpoint abnormalities, -13 or 13-q) and with low beta-2-microglobulin at diagnosis. CR duration was significantly longer with early onset of CR and favorable karyotypes. Time-dependent covariate analysis suggested that timely application of a second transplant extended both EFS and OS significantly, independent of cytogenetics and beta-2-microglobulin. Total Therapy represents a comprehensive treatment approach for newly diagnosed myeloma patients, using multi-regimen induction and tandem transplantation followed by interferon maintenance. As a result, the proportion of patients attaining CR increased progressively with continuing therapy. This observation is particularly important because CR is a sine qua non for long-term disease control and, eventually, cure.     

Multiple myeloma in young patients: clinical presentation and treatment approach

Multiple myeloma (MM) in patients younger than 40 or 30 years accounts for only 2% and 0.3% of all myelomas, respectively. The presenting clinical and laboratory features are similar to those observed in patients of all ages who have myeloma, except a higher proportion of young patients have only light-chain myeloma. Some very young patients, particularly those younger than 30 years, have multiple skeletal lesions with extramedullary spread and a small M-component with few bone marrow plasma cells. In young patients with MM, particularly in those with good prognostic features (that is, normal renal function or low beta2-microglobulin level) and also in those younger than 30 years, the survival is longer than that in series of patients of all ages with MM. Young patients with MM might benefit from early high-dose therapy followed by autologous or allogeneic stem cell rescue. The current status of autologous and allogeneic transplantation in MM is reviewed.     

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 evaluation of dissolution properties and degradation products of omeprazole in enteric-coated pellets

Between 1985 and 1990, 133 patients with advanced multiple myeloma (MM) (74% resistance; 41% resistant relapse, RR) were treated with five high-dose therapy (HDT) regimens including: melphalan < or =100 mg/m2 (MEL 100) (46 patients); MEL 100 plus GM-CSF (24 patients); MEL 140 plus autologous bone marrow transplantation (ABMT) (eight patients); MEL 140 plus TBI 850 cGy plus ABMT (37 patients); and thiotepa 750 mg/m2 (THIO 750) + TBI 850 cGy plus ABMT (18 patients). The median follow-up of alive patients as of December 1997 was 9 years. Overall, 17% experienced treatment-related mortality within 60 days (TRM) and 12% achieved stringently defined complete remission (CR) with a median duration of 16 months; four of 16 patients (25%) remain in CR at 10 years. The median durations of event-free survival (EFS)/overall survival (OS) were 6/15 months. Superior EFS/OS were noted with MEL 100 plus GM-CSF and the two TBI-containing regimens (9/24 months among 79 patients) compared to the remaining 54 patients receiving MEL < or =100 or MEL 140 plus ABMT (3/5 months) (P = 0.0001/0.0001, respectively). Multivariate regression analyses (MVA) were performed so that, despite patient heterogeneity among the five treatment groups, potentially relevant disease, host, treatment, and supportive care variables could be identified that were associated with TRM, CR, EFS and OS. TRM was higher with creatinine >2.0 mg/dl, absence of ABMT/GM-CSF support and age >50 years; CR was superior with TBI-containing regimens and < or =12 months of prior therapy; EFS and OS both were longer with B2M < or =2.5 mg/l, age < or =50 years, absence of RR and with ABMT/GM-CSF support. In the presence of >2 favorable variables (32 % of patients), median EFS/OS durations of 18/48 months were observed which progressively declined with 2 and <2 favorable parameters to 6/11 months (28% of patients) to 3/5 months (40% of patients) (P = 0.0001/0.0001). At 10 years, 10 and 20% of patients with >2 favorable variables were event-free and alive, which was also true for the 37 patients receiving MEL 140 plus TBI. To appreciate possible long-term contributions of supportive care or treatment intensity, landmark analyses performed at 1, 2, 4 and 6 months revealed virtually identical ranking orders of prognostically favorable variables to those seen pre-HDT; once supportive care was accounted for, regimen intensity with added TBI did not emerge as an independent favorable feature.     

High-dose cladribine therapy for chronic myelogenous leukemia in the accelerated or blast phase

PURPOSE: A phase II clinical trial was performed to evaluate the effectiveness of high-dose cladribine (2CDA) for treatment of chronic myelogenous leukemia (CML) in the accelerated or blast phase. PATIENTS AND METHODS: Nineteen patients were treated. The median age was 55 years (range, 30 to 73). Six were older than 60 years. Eight had progressed after intensive combination chemotherapy and three after allogeneic or autologous transplantation. For the first course, 16 patients received 2CDA at 15 mg/m2/d intravenously (i.v.) over 1 hour for 5 days. Two received 18 mg/m2 and one received 21.5 mg/m2 daily. The second course was escalated to 20 mg/m2/d in five patients. RESULTS: Rapid cytoreduction of leukemia occurred in the blood, with the nadir at 10 to 12 days. The median WBC count decreased from 36,900/microL before treatment to 500/microL at the nadir and recovered to 5,200/microL at day 30. The median platelet count changed from 113,000/microL to 24,000/microL at the nadir and 71,000/microL at day 30. The complete remission (CR) plus partial remission (PR) rate was 47% (95% confidence interval [CI], 23% to 72%). One 64-year-old man with lymphoid blast phase of CML had a morphologic and cytogenetic CR that lasted 9 months. The median survival for all patients was 34 weeks, and the median survival for the eight responders was 56 weeks (range, 11 to 167). The median number of days spent in hospital over the entire treatment period was 19 (range, 4 to 60). CONCLUSION: High-dose 2CDA therapy provides effective palliation for CML in accelerated or blast phases, even for heavily pretreated patients.     

Primary plasma cell leukemia: clinical, immunophenotypic, DNA ploidy, and cytogenetic characteristics

We report on a series of 26 patients diagnosed with primary (de novo) plasma cell (PC) leukemia (PCL) in whom we analyzed the clinicobiologic characteristics of the disease together with the immunophenotype, DNA cell content, proliferative index, and numeric chromosomal aberrations of the neoplastic PC, and compared them with 664 multiple myeloma (MM) patients at diagnosis. The median age, sex ratio, and bone lesion extension were similar, but PCL cases displayed a higher prevalence of clinical stage III, extramedullary involvement, and Bence Jones cases, with fewer IgA cases than for MM patients. In addition, according to several prognostic indicators (beta2-microglobulin serum level, proportion of S-phase PCs, proteinuria, calcium serum level, lactate dehydrogenase [LDH] and renal function), the incidence of adverse prognostic factors was significantly higher in PCL versus MM. Immunophenotypic expression was similar for CD38, CD138, CD2, CD3, CD16, CD10, CD13, and CD15, but PCL differed from MM in the expression of CD56, CD9 HLA-DR, CD117, and CD20 antigens. Twenty-two PCL cases were diploid and one was hypodiploid, while most MM cases (57%) showed DNA hyperdiploidy. With the fluorescent in situ hydridization (FISH) technique, 12 of 13 PCL cases displayed the numeric aberrations, -13 (86%), +/-1 (57%), +18 (43%), and -X in women (25%), but they lacked several numeric aberrations usually found in MM such as +3, +6, +9, +11, and +15. PCL cases had a lower overall response to therapy than MM cases (38% v 63%, P =.01332). Among PCL patients, a trend for a worse response was observed in cases treated with melphalan and prednisone (MP) versus polychemotherapy. Overall survival was significantly worse in PCL versus MM patients (8 v 36 months, P <.0001), but it was significantly better in PCL patients treated with polychemotherapy versus MP (18 v 3 months, P =.0137). By contrast, MM patients did not show significant differences in overall survival according to the treatment used, MP or polychemotherapy. Ten variables seemed to predict survival in PCL patients, but only the beta2-microglobulin level and S-phase PCs retained an independent value in multivariate analysis. In summary, our study illustrates that PCs from PCL display singular phenotypic, DNA cell content, and cytogenetic characteristics that lead to a different disease evolution versus MM.     

Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients

OBJECTIVES: Our aim was to identify prognostic variables for long-term postoperative survival in trimodality management of malignant pleural mesothelioma. METHODS: From 1980 to 1997, 183 patients underwent extrapleural pneumonectomy followed by adjuvant chemotherapy and radiotherapy. RESULTS: Forty-three women and 140 men (age range 31-76 years) had a median follow-up of 13 months. The perioperative mortality rate was 3.8% (7 deaths) and the morbidity, 50%. Survival in the 176 remaining patients was 38% at 2 years and 15% at 5 years (median 19 months). Univariate analysis identified 3 prognostic variables associated with improved survival: epithelial cell type (52% 2-year survival, 21% 5-year survival, 26-month median survival; P =.0001), negative resection margins (44% at 2 years, 25% at 5 years, median 23 months; P =.02), and extrapleural nodes without metastases (42% at 2 years, 17% at 5 years, median 21 months; P =.004). Using the Cox proportional hazards, the relative risk of death was calculated for nonepithelial cell type (OR 3.0, CI 2.0-4.5; P <.0001), positive resection margins (OR 1.7, CI 1.2-2.6; P =.0082), and metastatic extrapleural nodes (OR 2.0, CI 1.3-3.2; P =.0026). Thirty-one patients with 3 positive variables had the best survival (68% 2-year survival, 46% 5-year survival, median 51 months; P =.013). A previously published staging system using these variables stratified survival (P <.05). CONCLUSIONS: (1) Multimodality therapy including extrapleural pneumonectomy is feasible in selected patients with malignant pleural mesotheliomas, (2) pre-resectional evaluation of extrapleural nodes may select patients for radical therapy, (3) microscopic resection margins affect long-term survival, highlighting the need for further investigation of locoregional control, and (4) patients with epithelial, margin-negative, extrapleural node-negative resection had extended survival.     

2-chlorodeoxyadenosine induces durable remissions and prolonged suppression of CD4+ lymphocyte counts in patients with hairy cell leukemia

A number of effective treatments are available for patients with hairy cell leukemia (HCL). 2-Chlorodeoxyadenosine (2-CdA) induces more than 80% complete responses, but is associated with profound suppression of CD4+ lymphocyte counts. However, the duration of each is uncertain. We have analyzed a previously reported cohort of 40 patients who had responded to 2-CdA. Eight patients (20%) have relapsed at a median of 16 months (range, 3 to 23 months). The remaining 32 patients were observed for a median of 30 months (range, 7 to 43 months). No patients have died. At 3 years, the actuarial disease-free survival rate is 77% (95% confidence interval, 70% to 84%). The median CD4+ lymphocyte count before therapy was 743/microL (range, 58 to 2,201/microL). The median CD4+ nadir after treatment was 139/microL (range, 25 to 580/microL). There was a single opportunistic infection and no second malignancies observed. Although there was evidence of some improvement in CD4+ lymphocyte counts on sequential testing, CD4+ counts remained significantly lower than baseline (P < .0001) at a median of 23 months after therapy (median, 237/microL; range, 25 to 514/microL), and were also lower than baseline (P < .002) in those patients with more than 1 year of follow-up (median, 27 months; range, 13 to 42 months). The median time to reach an absolute CD4+ lymphocyte count of 365/microL, the lower limit of the normal range, was 40 months. Although responses to 2-CdA are durable in the majority of patients with HCL, the uncertain long-term consequences of the observed CD4+ lymphocytopenia suggest caution in the broad application of this therapy.     

Presenting features and prognosis in 72 patients with multiple myeloma who were younger than 40 years

The purpose of this study was to analyse the presenting clinical and laboratory features and the outcome of 72 patients with multiple myeloma (MM) who were younger than 40 years. The records of all Mayo Clinic patients with MM younger than 40 years who were seen between 1 January 1956 and 31 December 1992 were reviewed. Survival was measured from the date when treatment was required to the date of last follow-up or death. The frequency of MM in patients younger than 40 and 30 years in 3278 Mayo Clinic patients was 2.2% and 0.3%, respectively. The main presenting clinical features were bone pain (66%), fatigue (26%), extramedullary plasmacytomas (19%) and bacterial infection (11%). Renal function impairment (creatinine level > or = 177 micromol/l) and hypercalcaemia (serum calcium value > or = 2.75 mmol/l) occurred in 29% and 30% of patients, respectively. Among the 57 patients evaluable for response the objective response rate was 54%. 14/35 patients treated with a single alkylating agent achieved an objective response, whereas 17/22 patients given combination chemotherapy had an objective response (P=0.013). However, this higher response rate did not result in a significantly longer survival. The median survival for the 72 patients was 54 months. Patients with good prognostic features (normal renal function or low beta 2-microglobulin level) had a median survival of 8 years. The actuarial survival at 5 and 10 years after initiation of therapy was 43% and 13%, respectively. In summary, survival in very young patients with myeloma is longer than that observed in series of patients of all ages, especially in those with good prognostic factors.     

Antiphospholipid antibodies syndrome

OBJECTIVE: To measure the prognostic utility of helper T-cell (CD4) counts in human immunodeficiency virus (HIV)-infected patients undergoing major abdominal surgery. DESIGN: Retrospective case series. SETTING: Three university-affiliated hospitals. PATIENTS: Forty-three HIV-infected patients undergoing major abdominal surgery. MAIN OUTCOME MEASURES: Morbidity and mortality rates with respect to CD4 cell counts. RESULTS: Nineteen of 32 patients who had CD4 cell counts less than 0.20 X 10(9)/L (200 cells/microL) suffered major complications compared with 2 of 11 patients who had CD4 cell counts greater than 0.20 x 10(9)/L (200 cells/microL) (P=.03). Perioperative mortality was 38% for patients with CD4 cell counts less than 0.20 x 10(9)/L, and was 9% for those with CD4 cell counts greater than 0.20 x 10(9)/L (P=.13). Six months postoperatively, mortality rates were 47% and 9%, respectively (P=.03). Of patients with septic processes perioperatively (n=12), mortality was 75%, and was 19% (P=.009) for those with nonseptic processes (n=31). Nine patients had HIV-related intra-abdominal pathologic conditions at laparotomy. Mortality was 56% perioperatively (P=.13) and 88% after 6 months (P=.001). Sixty-eight percent of patients who received blood product transfusions developed complications, whereas only 7% of those who did not receive transfusions developed complications (P<.001). Overall mortality and morbidity rates were 37% and 49%, respectively. Patients with morbidity had lower CD4 cell counts (median, 0.034 x 10(9)/L) than those without complications (median, 0.102 x 10(9)/L) (P=.02). Similarly, patients who died had lower CD4 cell counts (median, 0.031 x 10(9)/L vs 0.088 x 10(9)/L) (P=.05). CONCLUSIONS: Patients with acquired immunodeficiency syndrome-defining CD4 cell counts undergoing major abdominal surgery developed more complications and had poorer outcomes at 6-month follow-up compared with HIV-infected patients whose CD4 cell counts were greater than 0.20 x 10(9)/L (200 cells/microL). A perioperative septic process and HIV-related pathologic conditions seen at laparotomy are also associated with worse outcomes.     

Bloodstream infections in HIV-positive patients: a review of sixty-eight episodes

Despite adjuvant chemotherapy the prognosis of patients with breast cancer and a high number of involved axillary lymph nodes is very poor. The aim of the present study was to evaluate the efficacy of high-dose chemotherapy with autologous bone marrow support in patients with seven or more involved axillary lymph nodes. Nineteen patients underwent four courses of standard adjuvant chemotherapy, followed by high-dose busulphan/cyclophosphamide chemotherapy with autologous bone marrow support. The median age was 41.4 years and the median number of involved lymph nodes 11. Mucositis WHO grade > or = 3 was observed in 15 patients and 18 patients suffered febrile neutropenia. Transplant-related mortality was encountered in two patients, due to hepatic veno-occlusive disease and sepsis complicated by multi-organ failure, respectively. After a median follow-up period of 1490 days (range 582-2024 days) from diagnosis, nine patients have relapsed and the overall event-free survival (EFS) is 42% (95% CI 19-65%). The median EFS is 487 days. High-dose treatment with BuCy2 in high-risk breast cancer patients is a toxic regimen and does not seem to improve disease-free survival.     

Work time estimates for ophthalmic diagnoses and procedures. Results from the Eye Care Workforce Study

OBJECTIVE: To compare the clinical presentation, time elapsed to diagnosis, and survival of elderly patients (> or = 65 years) with that in younger patients with malignant primary brain tumors. DESIGN: Retrospective cohort study. SETTING: Four hospitals in Minneapolis, Minn. PATIENTS: Seven hundred fourteen patients diagnosed as having and treated for primary malignant brain tumors between 1980 and 1995; 230 (32%) were 65 years or older. MAIN OUTCOME MEASURES: The type and duration of the chief presenting symptom, the time elapsed to diagnosis, the treatment modalities used, and patient survival were analyzed. RESULTS: Time elapsed from onset of symptom to diagnosis was not longer for elderly patients than younger ones, with the exception of patients aged 18 to 24 years, who had a significantly longer delay in diagnosis (P = .004). Elderly patients were significantly less likely to present with headache or seizure (P<.001), and more likely to present with confusion, aphasia, or memory loss (for each, P<.001). With the single exception of confusion, the duration of all other presenting symptoms was not significantly longer for patients 65 years and older compared with younger patients. Survival is significantly reduced in older patients, and appears to worsen significantly in patients 45 years and older (P<.001). A significantly higher proportion of patients 65 years and older with glioblastoma multiforme received no treatment (P = .004) if diagnosed after 1990. CONCLUSIONS: Elderly patients (> or = 65 years) with malignant brain tumors are diagnosed as promptly as younger patients, although they have a markedly different constellation of symptoms. Since diagnosis of brain tumors continues to improve in the elderly, it may be more difficult to ascribe the steady increase in incidence to artifactual factors.     

Doxorubicin-based chemotherapy in elderly patients with metastatic breast cancer. Tolerance and outcome

BACKGROUND: Metastatic breast cancer in elderly patients is less often treated with chemotherapy than in younger patients because of concerns related to toxic effects and tolerance. This is especially the case with doxorubicin-containing regimens. METHODS: We conducted a retrospective study of 1011 consecutive patients with metastatic breast cancer treated with doxorubicin-based chemotherapy protocols between July 1973 and July 1984. Age was not an exclusion criterion. Patient characteristics, dose intensity, hematologic-related toxic effects, and the cause of death were analyzed. The Kaplan-Meier survival curves were plotted and tested by the generalized Wilcoxon test. RESULTS: Seven hundred sixty-seven patients aged between 50 and 64 years were identified. While the response rate was higher in the younger group, the overall survival curves were similar for the two groups (P = .06), as well as the time to progression of the disease (P = .15). The dose intensity was comparable between the groups (P = .49), as was the median platelet and white blood cell nadirs. Neutropenic fever occurred in 16% of each group (P = 83), and fever in 12% and 17% of each group, respectively (P = .05). Death from infections occurred in 3.1% and 3.2% of patients in the two groups, respectively (P = .82). CONCLUSION: Patients with metastatic breast carcinoma who are older than 65 years tolerate the acute side effects of doxorubicin-based combination chemotherapy as well as the younger age group. Time to progression of disease and the overall survival are similar for both groups. Doxorubicin-based regimens are safe and effective for patients older than 65 years.     

BEAM chemotherapy and autologous haemopoietic progenitor cell transplantation as front-line therapy for high-risk patients with diffuse large cell lymphoma

In two consecutive and unselected cohorts of diffuse large cell lymphoma (DLCL) patients with advanced stage disease (IIB or bulk or more) and aged < 60 years, we compared a standard (MACOP-B for 12 weeks, 60 patients) versus a high-dose chemotherapy programme (8 weeks of MACOP-B plus one or two cycles of intensification with mitoxanthrone, dexamethasone, high-dose Ara-C, and finally BEAM chemotherapy with autologous haemopoietic progenitor cell transplantation, 61 patients). 41 patients (68%) in the standard group and 51 (84%) in the high-dose chemotherapy group, achieved a complete remission (CR) or an uncertain complete remission (CRu) (P = 0.0491). With a median follow-up time of 28 months for the high-dose group and 63.5 months for the standard group, the actuarial estimate of event-free survival (EFS) at 2 years demonstrates a significant benefit (70% v 50%, P = 0.03) for patients treated with the intensive regimen. The analysis of subgroups of patients showed that only high-risk patients (two or three risk factors) benefitted from the high-dose chemotherapy programme. Nevertheless, the overall survival does not show a significant difference between the two treatment modalities. The treatment-related morbidity was similar and the mortality rate was 8% in the standard (MACOP-B) group and 3% in the high-dose chemotherapy programme. In conclusion, our results show that high-dose chemotherapy and autologous stem cell transplantation is a safe procedure which should be considered for the front-line treatment of non-Hodgkin lymphoma patients with poor prognostic features.     

Perioperative risk factors affecting hospital stay and hospital costs in open heart surgery for patients > or = 65 years old

OBJECTIVE: Demographic changes, associated with increased demands for open heart surgery in the elderly, place increased burden on financial resources. To evaluate perioperative risk factors affecting incidence of hospital events and estimation of hospital charges, 2577 patients > or = 65 years (range 65-91), operated on from January 1991 to December 1994, were compared with a concurrent cohort of 2642 younger patients. METHODS: Statistical analysis, by surgical procedure, focused on hospital mortality, key postoperative complications affecting length of hospital stay and hospital charges. RESULTS: Overall hospital mortality was 4.7%, 3.5% in younger patients versus 6.1% in the older group (P < 0.01). Mortality was significantly lower in patients less than 65 years undergoing coronary artery bypass grafting (3% versus 5%, P < 0.01) and valve replacement (4% versus 9%, P = 0.01). Significant risk factors for hospital death in the elderly: diabetes (P < 0.01), hypertension (P < 0.01), myocardial infarction (P < 0.01) and congestive heart failure (P < 0.01). Significant postoperative events, more common in older patients, included prolonged ventilation (P < 0.01), congestive heart failure (P < 0.01), infection (P < 0.01), cerebrovascular accident (P < 0.01), and intra aortic balloon pump (P < 0.01). Incremental risk factors for morbidity in the elderly were: higher New York Heart Association class, congestive heart failure, emergent operation, and female gender. Mean length of hospital stay for the < 65 group was 15.3 versus > 19.5 days for the > 65 group (P < 0.01). Length of stay over 18 days positively correlated with increased morbidity in both age groups. For patients > or = 65 years of age, the average hospital charge for open heart surgery was 172% higher for patients with a length of stay greater than 18 days compared with 165% for patients less than 65 years of age. CONCLUSIONS: Higher operative mortality and longer length of stay in elderly patients, resulting in increased health care costs, was associated with more co-morbidities. These results suggest interventions designed to reduce congestive heart failure and other co-morbidities may improve patient's recovery and reduce costs.     

Petrous bone approach for the surgery of petroclival meningiomas

Adult patients with acute lymphoblastic leukemia (ALL) were treated according to the ALL90 study, the second prospective study for ALL of the Japan Adult Leukemia Study Group (JALSG). Its characteristics included response-oriented individualized induction therapy with six drugs (doxorubicin, mitoxantrone, vincristine, prednisolone, [corrected] cyclophosphamide and L-asparaginase), and a prospective comparison between allogeneic bone marrow transplantation (allo-BMT) and chemotherapy alone in patients below 45 years of age. The protocol consisted of one or two courses of induction, four courses of consolidation, and three courses of intensification including 12 month maintenance and six times of central nervous system (CNS) prophylaxis. Of 180 evaluable patients (median age, 43), 125 (69%) achieved complete remission (CR). Predicted overall survival (OAS), event-free survival and disease-free survival (DFS) were 15, 10 and 14%, respectively at the median follow-up period of 62 months. No specific toxicities were observed. Leukocytes < 30,000/microliter, normal karyotype, and blasts < 10% in bone marrow at day 15 of induction therapy were significantly favorable prognostic factors for the achievement of CR, DFS and OAS by univariate analysis. Multivariate analysis showed leukocytes < 30,000/microliter and blasts < 10% on day 15 was a significant factor for the achievement of CR, DFS and OAS. Ph-chromosome was found in 28% (36/130) of patients examined and was one of the worst prognostic factors. All Ph positive patients were predicted to die within 600 days. Allo-BMT was not significantly superior to chemotherapy with respect to DFS (P = 0.226). The overall results were inferior to those of the former ALL87 protocol. As reasons, the older median age of 43 years old (vs. 38 years old) and lower dose intensity, especially of l-asparaginase, etc. were suggested. However, patients with good prognostic factors (leukocyte < 30,000/microliter and age < 30 years old) showed better survival than others (P < 0.0001), and the result was similar to that of older children, the high risk group of childhood ALL, suggesting that ALL could be a disease of single entity, showing higher resistance to chemotherapy as patients become older.     

Tamsulosin 0.4 mg once daily: tolerability in older and younger patients with lower urinary tract symptoms suggestive of benign prostatic obstruction (symptomatic BPH). The European Tamsulosin Study Group

OBJECTIVES: To compare the safety and tolerability of tamsulosin 0.4 mg once daily in younger (< 65 years) and older (> or = 65 years) patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO). METHODS: In a retrospective analysis of two European double-blind, randomized, placebo-controlled trials, safety was assessed in 574 younger or older patients treated with tamsulosin or placebo for 12 weeks. RESULTS: The incidence of adverse events, drug-related adverse events, serious adverse events and discontinuations due to adverse events was similar in older and younger tamsulosin-treated patients and was not significantly different from placebo. Although abnormal ejaculation was slightly more common in younger than older men receiving tamsulosin, the difference was not statistically significant from the placebo groups in both age groups. The incidence of adverse events possibly associated with vasodilation in tamsulosin-treated younger and older patients was 8.4 and 4.2%, respectively; these were comparable with the values for placebo-treated patients: 7.5 and 6%, respectively. Baseline systolic blood pressure was higher in older than younger patients, but there were minimal changes in blood pressure or pulse rate in tamsulosin- or placebo-treated patients in either age group. CONCLUSIONS: Tamsulosin is well tolerated and suitable for use in older and younger patients with LUTS suggestive of BPO (symptomatic BPH).     

Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype

Advances in the treatment of acute myeloid leukemia (AML) have occurred with the introduction of new therapies including high-dose cytarabine and the identification of powerful prognostic factors such as cytogenetics that predict for long-term outcome. To date, the prognostic impact of cytarabine dose escalation within various cytogenetic groups of AML has not been assessed. We describe 285 newly diagnosed patients with primary AML who had adequate karyotypes and were enrolled on a prospective Cancer and Leukemia Group B cytogenetic study. All patients were randomly assigned to postremission treatment with standard-, intermediate-, or high-dose cytarabine intensification. Patients were categorized to one of three cytogenetic groups: (a) core binding factor type [(CBF); ie., t(8;21) inv(16), t(16;16), and del(16)]; (b) normal; and (c) other abnormality karyotype. An evaluation of these patients after a median follow-up time of over 7 years was performed to determine the relationship of intensification to outcome by cytogenetic group. Patients included 57 patients with CBF AML, 140 patients with normal karyotype AML, and 88 patients with other cytogenetic abnormalities. The treatment outcome of CBF AML patients was superior, with an estimated 50% still in complete remission (CR) after 5 years as compared with 32 and 15% for patients with normal karyotype AML and other abnormality AML, respectively (P < 0.001). Univariate analysis showed the following nonkaryotype factors to predict a prolonged CR duration: (a) younger age (P < 0.008); (b) lower leukocyte count (P=0.01); (c) the presence of Auer rods (P=0.004); (d) a lower percentage of bone marrow blasts (P=0.001) at the time of diagnosis, (e) and a higher postremission cytarabine dose (P < 0.001). The impact of cytarabine dose on long-term remission was most marked (P < 0.001) in the CBF AML group (after 5 years, 78% of those with a dose of 3 g/m2 were still in CR, 57% of those with a dose of 400 mg/m2 were still in CR, and 16% of those with a dose of 100 mg/m2 were still in CR) followed by normal karyotype AML (P=0.01; after 5 years, 40% of those with a dose of 3 g/m2 were still in CR, 37% of those with a dose of 400 mg/m2 were still in CR, and 20% of those with a dose of 100 mg/m2 were still in CR). In contrast, cytarabine at all doses produced only a 21% or less chance of long-term continuous CR for patients with other cytogenetic abnormalities. A multivariate analysis of CR duration assessed the independent impact of each of these variables on cure. Significant factors entering this model in descending order of importance were cytogenetic group (CBF > normal > other abnormality; P=0.00001), cytarabine dose (3 g/m2 > 400 mg/m2 > 100 mg/m2; P=0.00001), logarithm of leukocyte count at the time of diagnosis (P=0.0005), and histological subtype of AML (P=0.005). This study demonstrates that the curative impact of cytarabine intensification varies significantly among cytogenetic groups and results in a substantial prolongation of CR among patients with CBF and normal karyotypes, but not in those with other karyotypic abnormalities. These findings support the use of pretreatment cytogenetics in risk stratification of postremission AML therapy.     

GABAergic stimulation regulates the phenotype of hippocampal interneurons through the regulation of brain-derived neurotrophic factor

PURPOSE: Information concerning the differences between older and younger women with breast cancer, treated with standard therapy, is lacking from many prospective series. The purpose of this study is to identify factors that influence treatment decisions and determine if women age 65 and older are treated differently than younger women. The outcomes of older women would then be compared to younger to determine if treatment differences influence outcome. METHODS AND MATERIALS: The records of 558 women with early invasive breast cancer who were treated with breast conserving surgery and radiation therapy were retrospectively reviewed. Four hundred thirty-two women under the age of 65 (range: 24-64) and 126 women age 65 and older (range: 65-85) were assessed for treatment differences including breast reexcision, extent of axillary dissection, extent of breast and nodal irradiation, and the use of chemotherapy or hormonal therapy. Differences in the treatment of the two groups were determined and the end points of local control, disease-free survival, and overall survival were compared. Median follow-up was 5.5 years. RESULTS: The two treatment groups had identical pathologic TNM staging with the exception that 21% of the older age group and 5% of the younger group did not undergo axillary dissection. Women age 65 and older were less likely to have a reexcision, extensive axillary dissection, chemotherapy, or nodal irradiation. They were more likely to receive hormonal therapy. Reexcision in older women was positively influenced by a family history of breast cancer and negatively influenced by a history of previous malignancy. None of the patients who were treated without and axillary dissection suffered a regional recurrence. Although local control was better in older patients, there were no differences in disease-free or overall survival for the two groups. DISCUSSION: The findings of this study reveal that older patients have significant treatment differences as compared to younger patients; however, despite these differences, similar local control and survival were achieved at 5 to 10 years. With the expected survival of older women increasing, the prospective evaluation of treatment options for older women should be considered.