High incidence of relapse after autologous stem-cell transplantation for B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma.

BACKGROUND: High-dose therapy followed by autologous stem-cell transplantation (autoSCT) induces complete remissions in the majority of patients with advanced B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma (B-CLL). However, the long-term utility of this therapy for B-CLL is unknown. PATIENTS AND METHODS: Sixteen previously treated patients with B-CLL were transplanted using autologous blood (n = 13) or bone marrow (n = 3). The median age of the patients was 49 f1p4s (range 44-60 years), and the median number of prior chemotherapy regimens was two. Patients were eligible for transplantation if they had chemosensitive disease and no morphologic evidence of malignant cells in the graft. Preparative regimens included cyclophosphamide and total-body-irradiation, with or without cytarabine, or BEAC. RESULTS: All patients engrafted and achieved a complete remission posttransplant. Ten patients were alive at a median of 41 months (range 22-125 months), and five were disease-free. Eight patients have relapsed and six have died (three from progressive malignancy). The projected three-year overall survival, failure-free survival and relapse rates were 68%, 37%, and 56%, respectively. CONCLUSIONS: AutoSCT for advanced B-CLL is associated with a high relapse rate. Whether this therapy can prolong life or produce cures is uncertain.

Ex vivo treatment of bone marrow with phosphorothioate oligonucleotide OL(1)p53 for autologous transplantation in acute myelogenous leukemia and myelodysplastic syndrome.

Effective ex vivo purging techniques can decrease the likelihood of infusing bone marrow contaminated with leukemic cells during autologous transplantation. In preliminary studies, OL(1)p53, a 20-mer phosphorothioate oligonucleotide directed against p53 mRNA, decreased the number of acute myelogenous leukemia (AML) cells in vitro, suggesting a possible role for OL(1)p53 in purging bone marrow harvests of leukemia cells. To demonstrate that OL(1)p53 was nontoxic to hematopoietic progenitor cells, normal bone marrow cells were incubated with 10 microM OL(1)p53 for 36 h, and hematopoietic progenitor cell survival was determined by in vitro colony assays. OL(1)p53 had no toxic effect on the growth of either myeloid (CFU-GM) or erythroid (BFU-E) progenitor cells. OL(1)p53 was then used to ex vivo purge bone marrow harvests from nine patients with either AML or myelodysplastic syndrome (MDS). Bone marrow cells were incubated with 10 microM OL(1)p53 for 36 h before transplantation. The median times posttransplantation for the patient to recover an absolute neutrophil count greater than 0.5 x 10(9)/L and a platelet transfusion independence were 30 days and 56 days, respectively. Incubation of bone marrow cells with OL(1)p53 had no detrimental effect on the growth of hematopoietic progenitor cells, and transplantation of autologous bone marrow cells treated with the phosphorothioate oligonucleotide, OL(1)p53, resulted in successful recovery of circulating neutrophils following high-dose therapy in patients with AML or MDS. The data show that OL(1)p53 can be used safely to purge autologous bone marrow harvests from patients with leukemia.

Effect of improved cementing techniques on the longevity of fixation in revision cemented femoral arthroplasties. Average 8.8-year follow-up period.

Forty-six revision cemented femoral arthroplasties in which second-generation cementing techniques were used have been reviewed. After an average follow-up period of 8.8 years, 91% of the femoral components remained in place and 87% remained well fixed. Only 7% were rerevised for aseptic loosening. These results demonstrate a marked improvement over those of first-generation cementing techniques.

Cytogenetic abnormalities in B-immunoblastic lymphoma.

We have considered the cytogenetic abnormalities present in 27 unpublished cases of B-immunoblastic lymphoma. Among these 27 patients, the chromosome changes were heterogeneous and complex. The chromosomes most commonly gained were 3 (44% of cases), 18 (44%), 6 (30%) and 11 (30%). The most common structural abnormalities involved band 14q32 (26%), band 18q21 (15%) and bands 6q16-21 (19%). Study of these 27 immunoblastic lymphomas did not allow us to tentatively identify a common primary cytogenetic abnormality unique to B-immunoblastic lymphoma, however, a translocation at 14q32 may be the primary cytogenetic lesion in some of the cases. Rather, we have added to the number of abnormalities reported in immunoblastic lymphoma and in non-Hodgkin's lymphoma in general.

Cemented revision for femoral osteolysis in cemented arthroplasties. Results in 29 hips after a mean 8.5-year follow-up.

We reviewed 29 consecutive patients after cemented femoral revision of cemented hip arthroplasties for osteolysis. After an average follow-up of 8.5 years, osteolysis had recurred in only two cases (6.9%) and 25 femoral components (86%) remained well fixed.

Techniques of extraction of well-fixed cemented and cementless implants in revision total hip arthroplasty.

Removal of well-fixed cemented and cementless components in total hip arthroplasty is technically demanding and requires a multitude of surgical techniques and tools. The wide array of modular prostheses currently in use adds to the complexity of this task. The authors describe the several techniques that facilitate extraction of well-fixed cemented and cementless total hip prostheses, as well as the bone cement. A working knowledge of these techniques should result in easier implant extraction and less bone destruction during this process.

Mantle zone lymphoma. A clinicopathologic study of 22 cases.

A clinicopathologic analysis of 22 cases of mantle zone lymphoma (MZL) was performed. In lymph node sections, MZL was characterized by the proliferation of neoplastic small lymphoid cells in wide mantles around benign germinal centers. Eighteen cases were of the intermediate lymphocytic type and four cases were of the small lymphocytic type. Immunohistologic analysis of paraffin sections revealed the following characteristic immunophenotype of MZL: L26, LN2, NUB1 and T2/48 positive, and LN5, LN1, AF6 and UCHL1 negative. The immunophenotype of MZL was identical to that of normal primary lymphoid follicles and the mantle zones of secondary follicles, except for the absence of staining with LN5 in MZL. The median age of the patients was 63 years, and the male-to-female ratio was 1.2:1. B symptoms were present in 55% of the patients, and 81% had splenomegaly. An absolute lymphocytosis was present at the time of initial diagnosis in 13% of the patients, and 67% had bone marrow involvement by lymphoma. Thirteen percent of the patients had Stage II disease, 23% had Stage III disease, and 64% had Stage IV disease. All 22 patients received some form of therapy, with 73% receiving multiagent chemotherapy. Eleven patients achieved a complete remission at some time during their course. The overall median survival of the entire group was 88 months. Clinical features which appeared to influence survival adversely included an absolute lymphocyte count above 4000/microliters, a platelet count less than 100,000/microliters, and male sex. Achievement of a complete remission at any time favorably influenced survival. Pathologic features which appeared to influence survival adversely were a mitotic rate of 10 or more per 10 high-power fields (HPF) and the presence of 40 or more large lymphoid cells per 10 HPF. These findings lead the authors to conclude that MZL is a distinctive form of low-grade non-Hodgkin's lymphoma.

Changes in survival after transient ischemic attacks: observations comparing the 1970s and 1980s.

We compared survival following transient ischemic attack (TIA) in 2 prospective cohorts of TIA patients admitted to Wake Forest University Medical Center. The 1st consisted of 177 patients admitted between 1961 and 1973, and the 2nd of 185 patients admitted between 1980 and 1983. Patients in the 2nd cohort had significantly greater longevity than patients in the 1st cohort, both univariately and after adjustment for cerebrovascular risk factors. The adjusted 1-year survival estimate increased from 91% in the 1st cohort to 98% in the 2nd, and the adjusted 3-year survival estimate increased from 83% in the 1st to 94% in the 2nd. The underlying causes for this dramatic improvement in survival may include early identification and aggressive management of TIAs or coexisting diseases, improved management of subsequent completed strokes or myocardial infarctions, or unadjusted differences in these cohorts. The data imply that reports of TIA survival from different periods may not be comparable.

Association of DNA content and proliferative activity with clinical outcome in patients with diffuse mixed cell and large cell non-Hodgkin's lymphoma.

Formalin-fixed and paraffin-embedded lymph node biopsy specimens from 52 untreated patients with newly diagnosed diffuse large cell (n = 48) or mixed cell (n = 4) non-Hodgkin's lymphoma (NHL) were analyzed for DNA content and proliferative activity (PA) by flow cytometry. The results obtained by flow cytometry were compared with the results of cytogenetic studies performed on 28 of the specimens. The median age of the patients was 65 years (range, 15-84 years) and the male to female ratio was 3 to 2. All patients were uniformly staged and uniformly treated with cyclophosphamide, doxorubicin, procarbazine, bleomycin, vincristine, and prednisone. The flow cytometric results were compared statistically by univariate analysis with the rate and duration of complete remission and survival. Tumors with low PA (greater than or equal to 80% of cells in G0/G1 phase) were found in 65% of the patients; 74% of those with low PA versus only 44% of those with high PA achieved an initial complete remission (P less than 0.02). DNA aneuploidy was detected in tumors of 56% of the patients and was associated with a significantly longer duration of complete remission (P less than 0.01). Both low PA and aneuploidy independently predicted longer survival. The predicted 2-year actuarial survival for patients with tumors with low PA was 68% versus 10% for those with high PA (P less than 0.01). Similarly, the 2-year survival of patients with aneuploid tumors was 60% versus 36% for those with diploid tumors (P less than 0.01). The combination of PA and DNA content categorized the patients into four groups with decreasing 2-year survivals: low PA/aneuploid (n = 20), 77%; low PA/diploid (n = 14), 57%; high PA/aneuploid (n = 9), 32%; high PA/diploid (n = 9), 0%. The flow cytometric results correlated well with those of the cytogenetic studies. We conclude that low PA and DNA aneuploidy, both separately and in combination, predict a favorable clinical outcome for patients with diffuse mixed cell and large cell NHL.

Increased hepatic efflux of glutathione after chronic ethanol feeding.

Chronic ethanol feeding increases hepatotoxicity of drugs, such as acetaminophen, which form electrophilic metabolites. Availability of glutathione (GSH) is important in preventing liver damage from reactive metabolites. Chronic ethanol feeding has been reported to increase turnover of hepatic GSH in rats. The results of the present study show that the total hepatic efflux of GSH was increased from 5.95 +/- 0.42 nmoles/min/g liver (control) to 9.96 +/- 0.57 nmoles/min/g (P less than 0.001) in isolated perfused livers from rats 24 hr after withdrawal from chronic ethanol feeding. The increase in total efflux of GSH was due to a significant increase in sinusoidal GSH efflux from 4.76 +/- 0.49 nmoles/min/g liver in control rats to 9.07 +/- 0.47 nmoles/min/g (P less than 0.001) in ethanol-fed rats, while biliary efflux decreased slightly, 1.20 +/- 0.11 (control) vs 0.89 +/- 0.31 (ethanol). The increase in cellular efflux of GSH was similar in magnitude to the increase in hepatic GSH turnover that we reported previously. Biliary GSSG was similar in both groups of animals. Hepatic GGT activity was increased slightly, but not significantly, whereas renal GGT activity was similar in ethanol-fed rats. Hepatic GSH and GSSG levels were also similar. The increase in turnover of hepatic GSH in rats withdrawn from chronic ethanol feeding was most likely due to increased cellular efflux of GSH. This finding suggests that chronic ethanol feeding may increase cellular requirements for GSH, although the mechanism remains unknown. This alteration in GSH turnover may have important consequences for detoxification of xenobiotics or their metabolites by the liver.