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The use of computational structural models that include geometrical non-linearity in many application cases may require high reliability in prediction of displacements. Nevertheless, large differences up to 60% on maximum total displacement have been found among results of static large-deformation analyses performed by means of the major commercial software packages in a simple benchmark study with linear material properties. In order to investigate the causes of such disagreement, the present work compares different finite element formulations including well-established stress update schemes. The various formulations are tested, and results are compared in three test cases. Rodriguez stress update algorithms have shown the best performance among methods reported in literature. Finally, the cause of the large differences found in the predictions of commercial codes is identified. It is linked to the energetic inconsistency of some stress update methods in the simulation of extension/compression loading conditions. Such inaccuracy is reproduced analytically by formulating and integrating the corresponding inconsistent constitutive equations. The identified problem is very important for designers, as it affects almost all the static simulations, which are the most common type of large-deformation analyses and usually involve extension/compression loading.

AbstractThis article addresses Giorgio Agamben’s radicalization of the category of use, attempting to map out some of the key insights this yields, and seeking to establish the importance that this longstanding preoccupation of the Italian philosopher can have for design studies. It will be proposed that rethinking use with Agamben means rethinking the way we relate not only to artifacts but also to each other, thus possibly inspiring the design of experimental practices of sociality. In other words, it means reconsidering the way we organize and reorganize our senses and movements throughout everyday instances of entanglement with the world. Design debates have tended to subordinate the question of use to concerns over users, artifacts, and production. This exploration pledges instead to focus on alternative potentialities for use itself, ultimately interpreting Agamben’s articulation as the interplay of a certain attitude and a certain relationality that might, if only intermittently, take us beyond the individuating logic of sovereign intentionality.

Goal. Assess the progress and pitfalls of current United Kingdom (U.K.) policies to reduce health inequalities. Objectives. (1) Describe the context enabling health inequalities to get onto the policy agenda in the United Kingdom. (2) Categorize and assess selected current U.K. policies that may affect health inequalities. (3) Apply the "policy windows" model to understand the issues faced in formulating and implementing such policies. (4) Examine the emerging policy challenges in the U.K. and elsewhere. Data Sources. Official documents, secondary analyses, and interviews with policymakers. Study Design. Qualitative, policy analysis. Data Collection 2001-2002. The methods were divided into two stages. The first identified policies which were connected with individual inquiry recommendations. The second involved case-studies of three policies areas which were thought to be crucial in tackling health inequalities. Both stages involved interviews with policymakers and documentary analysis. Principal Findings. (1) The current U.K. government stated a commitment to reducing health inequalities. (2) The government has begun to implement policies that address the wider determinants. (3) Some progress is evident but many indicators remain stubborn. (4) Difficulties remain in terms of coordinating policies across government and measuring progress. (5) The "policy windows" model explains the limited extent of progress and highlights current and possible future pitfalls. (6) The U.K.'s experience has lessons for other governments involved in tackling health inequalities. Conclusions. Health inequalities are on the agenda of U.K. government policy and steps have been made to address them. There are some signs of progress but much remains to be done including overcoming some of the perverse incentives at the national level, improving joint working, ensuring appropriate measures of performance/progress, and improving monitoring arrangements. A conceptual policy model aids understanding and points to ways of sustaining and extending the recent progress and overcoming pitfalls. Key Words: Health inequalities, policy, implementation, U.K., central government, This article is based on the premise that many of the causes and manifestations of health inequalities in the United Kingdom and the United States have been described and are [...]

A comparison was made of the effectiveness of two approaches for treating acute lymphoblastic leukemia (ALL), a malignancy of blood cells in which bone marrow (where blood cells are made) becomes replaced by malignant tissue. The two approaches are chemotherapy and bone marrow transplantation; the latter method transplants bone marrow from a tissue-compatible donor (usually a sibling) into the patient. The study was retrospective and involved hospitals throughout the world; it evaluated the effects of treatment for 484 patients who underwent chemotherapy and 251 patients who received bone marrow transplants. All patients were treated during their first remission (period when the signs of the disease are no longer evident). The length of time after treatment that patients survived without a recurrence of leukemia was assessed. Results showed that the probability of surviving five years without leukemia was similar for both treatment groups (approximately 40 percent). Neither treatment conferred a survival advantage. While most treatment failures with chemotherapy were the result of relapse, the majority of failures with transplantation were due to complications of the procedure (graft-versus-host disease). It is likely that an effective approach to treating ALL is to administer chemotherapy first, saving transplantation for those who relapse. As many as 20 percent of relapsing patients after chemotherapy are cured by transplantation. At present, it cannot be said that bone marrow transplants offer advantages over chemotherapy for treating adult ALL in first remission. (Consumer Summary produced by Reliance Medical Information, Inc.)

Here we evaluated whether sequential high-dose chemotherapy (sHD) increased the early complete remission (CR) rate in acute myelogenous leukemia (AML) compared with standard-intensity idarubicin-cytarabine-etoposide (ICE) chemotherapy. This study enrolled 574 patients (age, 16-73 years; median, 52 years) who were randomly assigned to ICE (n = 286 evaluable) or sHD (2 weekly 3-day blocks with cytarabine 2 g/m2 twice a day for 2 days plus idarubicin; n = 286 evaluable). Responsive patients were risk-stratified for a second randomization. Standard-risk patients received autograft or repetitive blood stem cell-supported high-dose courses. High-risk patients (and standard-risk patients not mobilizing stem cells) underwent allotransplantation. CR rates after 2 induction courses were comparable between ICE (80.8%) and sHD (83.6%; P = .38). sHD yielded a higher single-induction CR rate (69.2% vs 81.5%; P = .0007) with lower resistance risk (P < .0001), comparable mortality (P = .39), and improved 5-year overall survival (39% vs 49%; P = .045) and relapse-free survival (36% vs 48%; P = .028), despite greater hematotoxicity delaying or reducing consolidation blocks. sHD improved the early CR rate in high-risk AML (odds ratio, 0.48; 95% confidence interval [CI], 0.31-0.74; P = .0008) and in patients aged 60 years and less with de novo AML (odds ratio, 0.46; 95% CI, 0.27-0.78; P = .003), and also improved overall/relapse-free survival in the latter group (hazard ratio, 0.70; 95% CI, 0.52-0.94; P = .01), in standard-risk AML, and postallograft (hazard ratio, 0.61; 95% CI, 0.39-0.96; P = .03). sHD was feasible, effectively achieved rapid CR, and improved outcomes in AML subsets. This study is registered at www.clinicaltrials.gov as #NCT00495287.

Patients and methods: We designed a study mainly directed towards investigating MRI and laboratory changes after autologous PBPC transplantation in patients affected by advanced, poor prognosis and refractory MS. The [...]

Abstract Background--Systemic sclerosis (SSc, scleroderma) in either its diffuse or limited skin forms has a high mortality when vital organs are affected. No treatment has been shown to influence the [...]

Several letters to the editor are presented in response to articles in previous issues on topics including free will, renewable energy and the role of carbon dioxide on plant growth.

Background/Introduction:COVID-19 tremendously affected Papua New Guinea in late 2021, which accompanied by a low vaccination rate (<4%), lead to an International EMT Request for Assistance.Objectives:Study’s aim is to share how UK-Med, a part of the UK EMT, developed best practices related to risk communication and community engagement integration within a COVID-19 emergency response.Method/Description:A participatory health promotion program was piloted in Western Highland Province among 71 health care workers. Training of trainers approach was adopted to build the capacity of health workers in advocating for vaccines uptake. Perception survey was used at the baseline and at the end of the program to assess the knowledge, skills, and attitude of the participants towards COVID-19 vaccine acceptance. A descriptive analysis and paired t-test were used.Results/Outcomes:Health care professionals are not well-equipped with accurate, scientific, and up-to-date information related to COVID-19 vaccines; which leads to increase in concern and fear among them. Health care workers affect community members’ decision to take the COVID-19 vaccine, being viewed as referents within their communities. The paired t-test showed a significant increase in the knowledge, skills, and attitude (P value <.001) of the participants toward COVID-19 vaccines. Participants described being ready to engage community influencers and cascade training to further reach out to community groups.Conclusion:Integrating RCCE within EMT deployments plays a crucial role in leveraging health care capabilities to influence community members and advocate for COVID-19 vaccines uptake; which will ultimately decrease morbidity and mortality. Further research is required to strengthen the role of health promotion in emergencies.

Background/Introduction:UK-Med, as part of our UK EMT project, deployed a team to respond to the overwhelming surge in COVID-19 cases in Papua New Guinea in late 2021. Such deployment was associated with several risks, including natural hazards; earthquakes; societal crisis; tribal fighting and civil unrest; and health risks such as extreme temperatures and poor sanitation infrastructure presented further hazards to personnel safety.Objectives:To share lessons learned on enhancing the well-being of an EMT in a challenging context such as PNG.Method/Description:Satisfaction survey, bilateral meetings, in addition to weekly meetings with the headquarters held throughout the deployment.Results/Outcomes:All deployed team members felt exhausted early in the deployment, including an early lack of clarity on the deployment location which eventually ended up being Mount Hagen, a very risky area only accessible by plane. Utilizing emotional and social support, diversity acceptance within the team, and coherent coordination between team members the deployment delivered upon all agreed objectives. Local staff were integrated and a successful workplan was well-received and evaluated as making a real difference to the staff and patients, with a request for an extension of activities received from the Provincial Health Authority.Conclusion:Considerations for staff well-being need to counter-balance the need for strict security protocols. Solid feedback mechanisms should be designed and implemented at an early stage of deployments to avoid any adverse effect on the team’s well-being. Deployment of an assessment team should strengthen coordination, ensuring required needs are being responded to and operational planning is location/context specific.

Several letters to the editor are presented in response to the articles published in a previous issue including "The White House Garden Sets a Powerful Example," in the April/ May 2013 issue, "Doing Well by Doing Good: The Better Business Paradigm" and "The U.S. Army Net-Zero Initiative," April/ May 2013.

All-trans-retinoic acid (ATRA) has greatly modified the prognosis of acute promyelocytic leukemia; however, the role of maintenance in patients in molecular complete remission after consolidation treatment is still debated. From July 1993 to May 2000, 807 genetically proven newly diagnosed acute promyelocytic leukemia patients received ATRA plus idarubicin as induction, followed by 3 intensive consolidation courses. Thereafter, patients reverse-transcribed polymerase chain reaction–negative for the PML-RARA fusion gene were randomized into 4 arms: oral 6-mercaptopurine and intramuscular methotrexate (arm 1); ATRA alone (arm 2); 3 months of arm1 alternating to 15 days of arm 2 (arm 3); and no further therapy (arm 4). Starting from February 1997, randomization was limited to ATRA-containing arms only (arms 2 and 3). Complete remission was achieved in 761 of 807 (94.3%) patients, and 681 completed the consolidation program. Of these, 664 (97.5%) were evaluated for the PML-RARA fusion gene, and 586 of 646 (90.7%) who tested reverse-transcribed polymerase chain reaction–negative were randomized to maintenance. The event-free survival estimate at 12 years was 68.9% (95% confidence interval, 66.4%-71.4%), and no differences in disease-free survival at 12 years were observed among the maintenance arms.

The Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) 0496 protocol, through the central handling of bone marrow samples at presentation, allowed us to combine cytogenetic and molecular information on a large series of adults with acute lymphoblastic leukemia (ALL) treated homogeneously, enabling us to define as broadly as possible their genetic profile and to determine the impact on outcome of the cytogenetic-molecular signature. Of 414 patients centrally processed, 325 were considered for the categorization into the following cytogenetic-molecular subgroups: normal, t(9;22)/BCR-ABL, t(4;11)/MLL-AF4, t(1;19)/E2A-PBX1, 9p/p15-p16deletions, 6q deletions, miscellaneous structural abnormalities, and hyperdiploid. The inclusion into each subgroup was based on a hierarchical approach: molecular abnormalities with adverse prognosis had precedence over karyotypic changes with less-defined prognosis and the latter over ploidy. Patients without abnormalities and those with isolated 9p/p15-p16deletions showed a relatively favorable outcome (median disease-free survival [DFS], > 3 years). The t(9;22)/BCR-ABL, t(4;11)/MLL-AF4, t(1; 19)/E2A-PBX1defined a group with dismal prognosis (median DFS, 7 months), whereas 6q deletions, miscellaneous aberrations, and hyperdiploidy predicted an intermediate prognosis (median DFS, 19 months). This study highlights the importance of a combined cytogenetic-molecular profiling of adult ALL at presentation as a critical independent determinant of their outcome, providing further evidence of the necessity of a risk-adapted therapeutic algorithm for an optimal management of these patients.

Hematopoietic stem cell transplantation (HSCT) has been proposed for the treatment of severe multiple sclerosis (MS). In a phase 2 multicenter study we selected 19 non–primary progressive MS patients showing high disease activity on the basis of both brain magnetic resonance imaging (MRI) and sustained clinical deterioration despite conventional treatments. After stem cell mobilization with cyclophosphamide (CY) and filgrastim, patients were conditioned with BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea), cytosine arabinoside, etoposide, and melphalan (BEAM) followed by antithymocyte globulin (ATG). Unmanipulated peripheral blood stem cells (PBSCs) were then infused. No maintenance treatment was administered with a median follow-up of 36 months (range, 12 to 72 months). All patients showed clinical stabilization or improvement; 3 subsequently deteriorated, 1 beyond the baseline. No MRI active lesions were detected after the HSCT except in 1 patient who showed a new lesion at 4.5 years. Infections were limited and restricted to 3 months after HSCT. Health-related quality of life was assessed through the 54-item MS quality of life (MSQOL-54) questionnaire, showing a statistically significant improvement in both composite scores and in most of the individual domains. HSCT is able to induce a prolonged clinical stabilization in severe progressive MS patients, resulting in both sustained treatment-free periods and quality of life improvement.

We analyzed the clinicobiological features and treatment outcome of a series of acute promyelocytic leukemias (APLs) occurring as a second tumor (APL-st's, n = 51) and compared these with a large group of de novo APL cases (n = 641), both observed by the Italian cooperative group GIMEMA. In the APL-st group, 37 patients had received radiotherapy and/or chemotherapy for their primary malignancy (PM), while 14 had been treated by surgery alone. Compared with de novo APL patients, APL-st patients were characterized by a predominance of females (P < .003), higher median age (P < .05), and worse performance status (P < .005). The median time elapsed between PM and APL-st was 36 months, with a longer latency for patients treated with surgery alone. No significant differences were found with regard to karyotypic lesions or type of promyelocytic leukemia/retinoic acid receptor α (PML/RARα) fusion in the 2 cohorts. A high prevalence of PMs of the reproductive system was observed among the female APL-st population (24 [71%] of 34 patients in this group had suffered from breast, uterine, or ovarian cancer). Thirty-one APL-st and 641 de novo APL patients received homogeneous APL therapy according to the all-trans retinoic acid (ATRA) and idarubicin regimen (the AIDA regimen). The complete remission (CR), 4-year event-free survival (EFS), and 4-year overall survival (OS) rates were 97% and 93%, 65% and 68%, and 85% and 78% in the APL-st and de novo APL groups, respectively. In spite of important clinical differences (older age and poorer performance status), the APL-st group responded as well as the de novo APL group to upfront ATRA plus chemotherapy, probably reflecting genetic similarity.

Hematopoietic stem cells (HSCs) are the earliest cells of the immune system, giving rise to B and T lymphocytes, monocytes, tissue macrophages, and dendritic cells. In animal models, adoptive transfer of HSCs, depending on circumstances, may cause, prevent, or cure autoimmune diseases. Clinical trials have reported early remission of otherwise refractory autoimmune disorders after either autologous or allogeneic hematopoietic stem cell transplantation (HSCT). By percentage of transplantations performed, autoimmune diseases are the most rapidly expanding indication for stem cell transplantation. Although numerous editorials or commentaries have been previously published, no prior review has focused on the immunology of transplantation tolerance or development of phase 3 autoimmune HSCT trials. Results from current trials suggest that mobilization of HSCs, conditioning regimen, eligibility and exclusion criteria, toxicity, outcome, source of stem cells, and posttransplantation follow-up need to be disease specific. HSCT-induced remission of an autoimmune disease allows for a prospective analysis of events involved in immune tolerance not available in cross-sectional studies.

Autologous hematopoietic stem cell transplantation (ASCT) has been recently utilized with encouraging results in patients with poorly controlled MS.

T-cell depletion of donor marrow decreases graft–versus–host disease resulting from transplants from unrelated and human leukocyte antigen (HLA)-mismatched related donors. However, there are diverse strategies for T-cell–depleted transplantation, and it is uncertain whether any improve leukemia-free survival (LFS). To compare strategies for T-cell–depleted alternative donor transplants and to compare T-cell depleted with non-T-cell–depleted transplants, we studied 870 patients with leukemia who received T-cell–depleted transplants from unrelated or HLA-mismatched related donors from 1982 to 1994. Outcomes were compared with those of 998 non-T-cell–depleted transplants. We compared LFS using different strategies for T-cell–depleted transplantation considering T-cell depletion technique, intensity of pretransplant conditioning, and posttransplant immune suppression using proportional hazards regression to adjust for other prognostic variables. Five categories of T-cell depletion techniques were considered: narrow-specificity antibodies, broad-specificity antibodies, Campath antibodies, elutriation, and lectins. Strategies resulting in similar LFS were pooled to compare T-cell–depleted with non-T-cell–depleted transplants. Recipients of transplants T-cell depleted by narrow-specificity antibodies had lower treatment failure risk (higher LFS) than recipients of transplants T-cell depleted by other techniques. Compared with non-T-cell–depleted transplants (5-year probability ± 95% confidence interval [CI] of LFS, 31% ± 4%), 5-year LFS was 29% ± 5% (P?=?NS) after transplants T-cell depleted by narrow-specificity antibodies and 16%?±?4% (P?

The treatment of severe autoimmune diseases has been recently revitalized by the introduction of intense immune suppression with immune ablative intent followed by three different procedures. These are allogeneic hematopoietic stem cell transplantation (HSCT), autologous HSCT (using either marrow or peripheral blood), and intense immune suppression without stem cell support. Current trials suggest that high dose immune suppressive therapy with or without autologous hematopoietic stem cell support can induce remission of previously refractory disease. Follow-up is too brief to determine if intense immune suppression, and more specifically autologous HSCT, will ultimately cure SLE. It is conceivable that an allogeneic source of stem cells from a normal donor (e.g. HLA matched sibling) will be required to achieve a cure. It is also possible that autologous HSCT, even if not curative, may prolong the life of patients with otherwise high-risk features. In carefully selected patients, the potential benefits of this procedure may outweigh the risks.

Transplant outcome was analyzed in 690 recipients of bone marrow transplants (BMTs) for acute lymphoblastic leukemia (ALL) in first (n = 299) or second remission (n = 391). Actuarial 5-year leukemia-free survival was 42% ± 9% (95% confidence interval) and 26% ± 6%, respectively; relapse rates were 29% ± 9% and 52% ± 8%, respectively. Five-year leukemia-free survival was 56% ± 18% in children and 39% ± 10% in adults (P≪ .02) transplanted in first remission. In first-remission adults, non-T-cell phenotype, male to female donor-recipient sex-match and grafts-host disease (GVHD) were associated with decreased leukemia-free survival; inclusion of corticosteroids in the regimen to prevent GVHD was associated wth increased leukemia-free survival. Variables associated with decreased leukemia-free survival after second-remission transplants were age ≫16 years and relapse occurring while on therapy. Variables associated with increased probability of relapse were similar for first- and secondremission transplants and included GVHD prophylaxis without methotrexate and absence of GVHD. In firstremission transplants, leukocyte count ≫50 x 109/L at diagnosis was also associated with increased relapse; in second remission, relapse while receiving chemotherapy was also associated with increased posttransplant relapse. These data emphasize the importance of both disease- and transplant-related variables in predicting outcome after BMT. They may be used to explain differences between studies, design future trials, and identify persons most likely to benefit from BMT. © 1989 by Grune & Stratton, Inc.

Peripheral blood mononuclear cells of 21 patients undergoing allogeneic bone marrow transplantation (BMT) were monitored post-BMT for immunologic markers (E rosettes OKT3, OKT8, DR, and BT5/9, a monoclonal antibody which stains helper T cells), cytochemical markers (acid phosphatase [AP], beta-glucuronidase [BGLU], and acid alpha naphthyl acetate esterase [ANAE] ), and morphology. The cytochemical T score, was obtained from typical AP, BGLU, and ANAE reactivity. The same was done for the cytochemical non-T score and macrophage (Mo) score. All patients received cyclosporine A (CyA) for graft-v-host disease (GvHD) prophylaxis. In univariate analysis there was no significant correlation between the proportion of E rosettes, OKT3-, OKT8-, DR-, and BT5/9-positive cells, and GvHD. The first three showed instead a positive correlation with time from transplant: E rosettes (P = .02), OKT3 (P = .01), and OKT8 (P = .003). In contrast, a significant negative correlation was found in univariate analysis, between the cytochemical T score and GvHD (P = .0001), and a positive correlation between non-T score and GvHD (P = .0008), as well as between the Mo score and GvHD (P = .03). There was no influence of time from transplant on the T (P = .8), non-T (P = .8), or Mo score (P = .4). In multivariate analysis comparing E rosettes, OKT3, T score, non-T score, GvHD, and time from BMT, the only variable associated with GvHD was the T score (P less than .05). These results suggest that T cell activation during GvHD is associated with a loss of hydrolase expression in T cells, but does not imply relevant modifications of immunologic surface markers. In addition, lysosomal enzymes appear early (before day 10) after transplantation, indicating that T cells at this stage are well differentiated.

T cells were derived from the bone marrow of 8 healthy donors and fractionated, according to their receptors for the Fc fragment of IgG, into TG+ and TG- lymphocytes. These were then cocultured with autologous or allogeneic bone marrow cells in agar in the CFU-C assay. No significant suppresion of colony formation could be detected. Total T, TG+, and TG- cells were then incubated for 18 hr with PWM, washed, and cocultured with bone marrow cells. PWM-treated TG- cells showed no significant CFU-C suppressor activity, whereas PWM-treated total T and TG+ cells inhibited colony formation of both autologous and allogeneic marrow cells. The supernatant of PWM-treated total T and TG+ cells also inhibited colony formation. PWM alone enhanced colony formation. The results of this study indicate that normal T cells can be activated in vitro to become CFU-C/suppressor cells after PWM stimulation, and that this effect is mediated by T cells with the Fc receptor for IgG.

Thirty-six patients with severe aplastic anemia or acute leukemia undergoing bone marrow transplantation or intensive hematologic treatments were randomized to receive gentamicin (1 mg/kg/iv q8h) or tobramycin (1 mg/kg/iv q8h) in combination with carbenecillin (500 mg/kg/day i.v. in 4 doses) and cephalotin (200 mg/kg/day i.v. in 6 doses), at the onset of fever during granulocytopenia. Patients in the gentamicin group were treated for a total of 541 patient days (minimum 5, maximum 106), and patients in the tobramycin group for 426 patient days (minimum 9, maximum 48). All patients received oral decontamination, which included the amino glycoside (either gentamicin or tobramycin) given intravenously. This study showed that 1) no patient had an increase in creatinine level above 1.3 mg % and no patient developed renal failure, 2) there was no difference between gentamicin and tobramycin in the efficacy of treating febrile episodes and/or major infections, 3) prolonged intravenous administration (up to 48 consecutive days in the tobramycin group and 106 consecutive days in the gentamicin group) was well tolerated and effective in treating fever of unknown origin in granulocytopenic patients: 45 of 72 febrile episodes resolved while the patients had a granulocyte count below 500/mm3.

Autologous stem cell transplantation with or without in vitro lymphocyte depletion has been suggested as a new treatment option for severe autoimmune diseases. We describe five patients with autoimmune diseases (CREST syndrome, myasthenia gravis and Hashimoto's thyroiditis, systemic lupus erythematosus, atopic dermatitis, and rheumatoid arthritis) who underwent autologous bone marrow (n = 1) or peripheral blood progenitor cell (n = 4) transplantation with unmanipulated grafts as treatment for the autoimmune disease in one case or as treatment for a malignant disorder with a concomitant autoimmune disorder in four cases. In all patients serological and clinical signs of the autoimmune disease recurred early or persisted. These observations should be regarded as a cautionary note concerning the efficacy of high-dose therapy followed by transplantation of unmanipulated autologous stem cells for treatment of severe autoimmune diseases.

Peripheral blood (PB) T cells from 56 patients with B-cell chronic lymphocytic leukemia (B-CLL) were analyzed by two- and three-color immunofluorescence (IF) to determine the expansion of distinct T-cell subsets and their relationship with the clinical and biological features of the disease. We detected the expansion of an unusual T-cell subpopulation expressing lower CD4 or CD8 levels (CD4lo, CD8lo) than classic T cells (CD4hi, CD8hi). This subpopulation also expressed low levels of the CD3/TCR alpha/beta complex and was CD19-CD13-CD14-. A phenotypic analysis probing the activation level of CD4lo, CD8lo, CD4hi, and CD8hi cells showed that they comprised increased counts of HLA-DR+, CD11b+, CD45R0+, and CD45RA+ cells. Subset expansion ranged from 2.1- to 13.6-fold. Statistical analysis showed that the size of some of these subsets was correlated to intrinsic features of the tumor. First, CD4loHLA-DR+ cell counts were higher in patients with stage A than those with stages B and C disease. Second, CD8loHLA-DR+ cell counts were higher in patients in stable remission than in those at diagnosis. Third, CD4loHLA-DR+, CD4loCD45R0+, CD4loCD45RA+, and CD4hiCD11b+ cell counts were higher in patients whose tumor cells expressed high levels of surface immunoglobulin (sIg) than in those expressing low levels. The involvement of CD4lo and CD8lo cells in most of these correlations suggests that they may be tumor-reactive cells. Similar cells described in human and murine autoimmune disease have been shown to be autoreactive anergic cells, which may derive from nonclassic pathways of T-cell development.

The argyrophilic nucleolar organizer regions (AgNORs) were analysed in bone marrow biopsies from 80 patients with multiple myeloma (MM) at presentation. The mean AgNOR number per MM cell (AgNOR counts) and their distribution within the nucleus (configuration) were assessed. AgNOR counts were significantly associated with several recognized prognostic factors: Durie and Salmon clinical staging system (p = 0.02), percentage of plasma cells (PCs) in aspirates (p = 0.01) and in bone marrow biopsies (p = 0.0000), pattern of bone marrow involvement (p = 0.0003), calcaemia (p = 0.0005) and creatininaemia (p = 0.0003). AgNOR counts were also associated with the degree of PC differentiation (p = 0.0000). A single central cluster of 2-3 large-sized AgNORs (configuration A) was evident in most Gl MM; one cluster of 4-5 medium-sized dots or two clusters of 2-4 dots (configuration B) were seen in most G2 MM; many small-sized, scattered dots were present in G3 MM (configuration C).AgNOR counts and configuration were related to the prognosis: in the univariate analysis, the 5 year survival rate was 7% for cases with >4.5 AgNORs/cell and 46% for cases with ≤4.5 AgNORs/cell (p = 0.01), 53% for configuration A, 12% for configuration B and 0% for configuration C (p = 0.0000). AgNOR counts (p = 0.02) and configuration (p = 0.000) were independent prognostic variables in the multivariate analysis. The AgNOR counts were significantly higher in "fulminant myeloma" than in less aggressive cases (p = 0.002).The plasma cell labelling index (LI%), evaluated in 44 MM patients, showed significant correlation with prognosis: the 5 year survival rate was 51% for LI% ≤1 and 17% for LI% >1 (p = 0.02). More than 70% of patients with low LI% had low AgNOR counts and more than 70% of patients with high LI% had high AgNOR counts (p = 0.007).AgNOR counts and configuration reflect the myeloma cell mass, the degree of differentiation and the kinetics of the myeloma cells. They offer an exact evaluation of the tumour characteristics and can be useful additional parameters for MM prognosis.

Eighty-one patients with acute myeloid leukemia (ANLL, n = 44) or acute lymphoblastic leukemia (ALL, n = 37), aged 10 to 50 years were randomized to receive 1 mg/kg per day (n = 41, group A) or 5 mg/kg per day (n = 40, group B) of cyclosporine A (CyA) from day –1 to day +20 after bone marrow transplant (BMT). All patients received CyA orally thereafter. All patients were prepared with cyclophosphamide (CY) 120 mg/kg and fractionated total body irradiation (TBI), and received unfractionated BM from an HLA-identical sibling. The two groups were comparable for diagnosis, disease status, French-American-British (FAB) classification, WBC count at diagnosis, cytogenetic abnormalities, ex-tramedullary disease before BMT, donor/recipient age and sex, number of cells infused, and number of days with intravenous (IV) CyA. Median follow-up for surviving patients in group A was 983 v632 days in group B. Patients in group A had lower serum levels of CyA (295 v686 ng/mL, P =.004), lower bilirubin levels (1.9 v2.6 mg/dL, P= .07), lower creatinine levels (0.9 v1.4 mg/dL, P =.06), and a lower proportion of CD8+cells in the peripheral blood (PB) within day +21 (19% v28%, P= .07). First day to 0.5 × 109/L neutrophils was comparable in the two groups (13 v14 days; P= .1). In a Cox model, the actuarial risk of acute graft-v-host disease (GVHD) grade II+, after stratification for age (<20 years >) was significantly lower in group B patients (0.54, P =.04). The actuarial risk of developing chronic GVHD was comparable (P =.9). Actuarial transplant-related mortality (TRM) at 240 days was 28% and 26% (P= .8) in group A and B: the major cause of death was GVHD in group A (P =.02) and multiorgan toxicity in group B (P =.07). The actuarial risk of relapse at 2 years overall was 20% in group A and 52% in group B (P =.001); it was 9% v43%, respectively, for patients in first remission (P= .0001) and 48% v63% for patients in non-first complete remission (CR) [P =.1). Actuarial 2-year disease-free survival (DFS) in group A and B was 58% v32% (P= .02) for all patients, 71% v35% (P =.01), in first remissions, and 30% v23% (P =.2) in advanced disease. In conclusion, protection from GVHD-related death with high-dose CyA is offset by significant organ toxicity and leukemia relapse: As a consequence, long-term DFS is clearly superior in patients receiving low-dose CyA after Cy and fractionated TBI.

In a previous study, we showed that patients undergoing allogeneic hemopoietic stem cell transplantation (HSCT) who had cytomegalovirus (CMV) antigenemia with more than 4 CMV antigen-positive cells/200,000 have a high transplant-related mortality (TRM) rate, despite treatment with ganciclovir or foscarnet. In an attempt to reduce TRM, 32 allogeneic HSCT recipients, between the ages of 16 and 55 years (median, 35 years), with CMV antigenemia (≥5 positive cells) developing at a median interval from HSCT of 49 days, were given combination treatment with foscarnet and ganciclovir for 15 days. The prescribed dose was 180 mg/kg/day of foscarnet and 10 mg/kg/day of ganciclovir: the median administered dose in the first 15 days, after adjusting for creatinine levels and peripheral blood counts, was 64% for foscarnet and 53% for ganciclovir. Maintenance was given with foscarnet and ganciclovir on alternate days for an additional 2 weeks. Thirty-one of 32 patients were on cyclosporine, 30 were on systemic antibiotics, and 9 were on intravenous amphotericin.

Summary Argyrophilic nucleolar organizer region (Ag-NOR) analysis was performed on bone marrow biopsies from 90 patients with multiple myeloma (MM) at presentation. The pattern of AgNOR expression and its relationship to histological features were evaluated. The mean AgNOR number per plasma cell was directly correlated with the degree of MM differentiation (3.18 for G1, 4.36 for G2, 6.13 for G3;P<0.0001), with the per-centage of bone marrow plasma cells (BMPC%) (3.06 for BMPC%=20, 4.28 for BMPC% 21–50, 5.14 for BMPC%>50;P<0.0001), with the pattern of medullary involvement (3.63 for interstitial, 4.44 for nodular, 5.17 for diffuse involvement;P<0.001) and with medullary fibrosis (5.23 for cases with fibrosis, 4.29 for cases without fibrosis;P<0.05). The plasma cells of G1 MM showed 2–3 large AgNORs, tightly grouped in a central nuclear cluster; those of G2 MM showed a central nuclear cluster composed of 4–5 medium-size dots and/or two clusters of 2–3 dots; the G3 MM plasma cells showed many small dots scattered in the nucleolus or dispersed in the nucleus. Our results indicate the diagnostic value of AgNOR analysis in MM and suggest the use of this method for identifying clones of atypical plasma cells with different proliferative activity in bone marrow biopsies. It allows simultaneous evaluation of the morphology and kinetics of MM cells in routinely fixed, decalcified, paraffin-embedded material.

Immune mechanisms superimposed to the myeloablative conditioning regimens exert an additional powerful effect in eradicating leukemia and in achieving immunological control of minimal residual disease. The impact of GVHD-independent GVL has been evaluated to be absent, or near absent, in ALL, about 30% in AML and about 40% in CML. While until little time ago most of the evidence in favor of an immune antileukemia mechanism exerted by allo BMT in CML was indirect, based on the lack of GVL, there is now solid evidence of a positive type, based on the antileukemia effect of donor lymphocyte infusions in patients having relapsed after transplant.There are three lines of indirect clinical evidence for GVL in CML: they include the classical linkage between GVHD and reduced relapse rate, increased relapse rate after identical twin allografts, and increased relapse risk after effective GVHD prophylaxis, with T lymphocyte depletion in the foreground. The eradicating effects of donor lymphocyte infusions in relapsed patients are the ultimate demonstration that allogeneic immune competent cells are capable of recognizing and destroying the Ph-positive clone. However the frequency of irreversible aplasia indicates that donor lymphocytes act in the same way on residual host hematopoiesis, so that a second graft, without repeat conditioning, should be programmed for such cases.

We analyzed the effects of T-cell depletion on the outcome of HLA-identical sibling bone marrow transplants for leukemia by comparing 731 T-cell-depleted transplants with 2,480 non-T-cell-depleted transplants. T-cell depletion decreased acute graft-versus-host disease (GVHD) (relative risk [RR] 0.45; P <. 0001) and chronic GVHD (RR 0.56; P <. 0001). However, it increased graft failure (RR 9.29; P <. 0001). Leukemia relapse also was increased. In first remission acute leukemia or chronic phase chronic myelogenous leukemia, leukemia relapse was 2.75 times more likely after T-cell-depleted transplants (P <. 0001). T-cell depletion increased the risk of treatment failure (RR 1.35; P <. 0003) and decreased leukemia-free survival. We also studied controllable variables associated with outcome of T-cell-depleted trans- plants. The unique findings were that among recipients of T-cell-depleted transplants for early leukemia, radiation doses ≥11 Gy (RR 0.54; P < .01), dose rates greater than 14 cGy/min (RR 0.56; P < .002), and additional posttransplant immune suppression with cyclosporine alone (RR 0.53; P < .0006) or cyclosporine plus methotrexate (RR 0.36; P < .01) were associated with fewer treatment failures. Use of monoclonal antibodies rather than physical techniques for T-cell depletion (RR 2.01; P < .03) and fractionated radiation (RR 1.69; P < .05) were associated with increased treatment failure and lower leukemia-free survival. These data may be useful in designing strategies to improve results of T-cell- depleted transplants.© 1991 by The American Society of Hematology. 0006-4971/91/7808-0024$3.00/0

T lymphocytes were derived by E rosetting from the peripheral blood (PB) and bone marrow (BM) of 15 patients with chronic granulocytic leukemia (CGL) in the chronic phase of their disease. T cells were also obtained from 12 healthy individuals. T cells were incubated overnight either in culture medium (RPMI) or RPMI plus pokeweed mitogen (PWM). The supernatants were then recovered and the cells washed in fresh RPMI. T cells from normal donors and from CGL patients were then cocultured with normal allogeneic marrow cells grown in soft agar for CFU-C colony formation. Target marrow cells were also grown in agar in the presence of T-derived supernatants. The results of this study can be summarized as follows. (1) Normal PB and BM T cells efficiently suppressed autologous and allogeneic CFU-C growth after PWM stimulation. (2) T cells derived from peripheral blood or marrow of CGL patients failed to inhibit CFU-C growth, whether pretreated with PWM or not. (3) The supernatants of PWM-treated normal T cells strongly inhibited CFU-C colony formation, whereas the supernatants of PWM- treated CGL T cells had no CFU-C/suppressor activity. These data indicate that T cells from CGL patients cannot be primed to become CFU- C suppressor cells after PWM: stimulation in vitro and cannot release a soluble inhibitor of granulopoiesis produced by PWM-primed normal T cells.

A 46 year woman with severe long-lasting SLE received an autologous bone marrow transplantation utilising CD34+haematopoietic progenitors following a 3 log T-lymphocyte depletion. The immunosuppressive regimen (conditioning) consisted of 15mg/kg Thiotepa followed by 100 mg/kg of cyclophosphamide over 2 d. Granulocytic recovery was aided by G- CSF. The post-transplant course was uneventful, and a good clinical and immunologic remission (ANA negativisation) was achieved. This is the first case of SLE having received an autologous progenitor cell transplant for the autoimmune disease by itself, unaccompanied by a haematologic condition requiring transplantation.The potential, advantages and limits of this procedure, which are currently being explored worldwide, are briefly discussed.

Summary In the attempt to evaluate the role of Autologous and Allogeneic Bone Marrow Transplantation, we have retrospectively analyzed 159 patients with Acute Myeloid Leukemia in first complete remission treated in our Unit, most of whom were referred from other Institutions. High-dose therapy was uniform and consisted of cyclophosphamide 60 mg/kg/d on two consecutive days and TBI in a single dose (10 Gy) for ABMT patients and in fractionated doses (3.3 Gy × 3 days) for BMT patients. Eight years actuarial survival was similar in two groups (52% for BMT and 49% for ABMT). The actuarial risk of relapse for BMT and ABMT was 29% and 43%, respectively. Considering that none of ABMT patients was “purged” with in vitro technique, this review seems to confirm the importance of “in vivo” purging with postremission intensification, immediately before the harvesting. Of course, more patients and a longer follow-up are needed to drow final conclusions.

The administration of anti-lymphocyte globulin in a patient with pure red cell aplasia completely abrogated the PHA-induced T colony forming capacity of peripheral blood mononuclear cells. The possible mechanisms of the ALG-induced suppression are discussed. It is proposed that T-colony assays may represent an useful tool for monitoring some effects of immunosuppressive drugs on T cells.

Nineteen patients with acute graft versus host disease (GvHD) following bone marrow transplantation (BMT) were treated with high dose bolus 6-methylprednisolone (BMPr), at the dose of 20 mg/kg/day i.v. for the first 3 days, 10 mg/kg/day i.v. for the following 4 days, and then at doses gradually tapered down to 1 mg/kg/day. All patients except one, who was given preventive BMPr 5 mg/kg/day i.v. on alternate days, were placed on preventive methotrexate therapy after BMT. Sixteen patients were grafted with an HLA matched, and three patients with an HLA mismatched marrow.

Three cases of adult pure red cell aplasia (PRCA) are reported. All patients proved refractory to various combinations of androgens and corticosteroids. The first case, harboring a thymoma, showed a complete clinical remission following cyclophosphamide therapy. The second and third responded similarly to either a combined cyclophosphamide + antilymphocyte globulin (ALG) treatment or to ALG administration preceded by a small dosage of cyclophosphamide, which had proved ineffective when administered alone. Serum IgG inhibitors to erythropoiesis were demonstrated in all cases by means of in vivo and/or in vitro techniques. The inhibitors), although directed against the erythroid marrow in both the first and third patients (PRCA type A), apparently functioned as an antibody to circulating erythropoietin (Ep) in the second case (PRCA type B). The inhibitor(s) was always absent in postremission samples. Additionally, experimental models for both types of human PRCA were established in normal rodents. The present studies support the contention that adult PRCA is an autoimmune disease. The therapeutic role of cytotoxic-immunodepressive agents in PRCA patients is confirmed. It is emphasized that ALG may represent an additional therapeutic tool in cases resistant to cyclophosphamide and/or steroids. In addition, cyclophosphamide proved effective in a patient harboring a thymoma not amenable to surgery. Finally, it is postulated that IgG serum auto-antibodies, directed against either an early erythroid precursor (PRCA type A) or, more rarely, circulating Ep (PRCA type B), play a major role in the pathogenesis of the disease.

Objective:comparative assessment of sensitivity and specificity of regional Cerebral Blood Flow (rCBF) by 133-Xenon inhalation and quantitative Electroencephalography (qEEG) in patients with Neuropsychiatric Systemic Lupus Erythematosus (NP-SLE).Methods:Sixty-two combined rCBF and qEEG examinations were performed in fifty-two SLE patients. Group A: 27 SLE patients without NP-SLE; group B: 17 patients with florid (within 1 month) NP-SLE; group C: 12 patients with previous NP-SLE examined in the remission phase (four patients of which already considered in group B). The study also included data deriving from two sets of examinations in ten patients who were observed twice, in different phases of the clinical course of NP-SLE.Results:in comparison to healthy controls, rCBF was lower (p < .001) in group B only, whereas qEEG showed similar increases of both δ and 0 relative powers together with a reduction of α relative power in groups A-C. As compared to group A, sensitivity and specificity in detecting cerebral abnormalities in group B were 76% and 78% for rCBF, and 59% and 44% for qEEG, respectively. In the ten patients examined twice, rCBF was consis tent with clinical course in 90% of cases and qEEG in 60%.Conclusion:total accuracy in detecting cerebral functional abnormalities during florid NP-SLE is better by rCBF than by qEEG. rCBF and, in selected cases, qEEG examinations are reliable markers of NP-SLE.

The impressive prolongation of survival has been the most important progress made in clinical systemic lupus erythematosus (SLE). Quality of life has also greatly improved, including pregnancy. However, persisting disease and therapy-related morbidity outcomes justify new approaches, different from the usual long-term palliative immunosuppression. Haematopoietic stem cells (HSCs) from healthy histocompatible mice are capable of curing murine SLE after eradication of the original HSCs with total body irradiation. Syngeneic and even autologous HSCs are also capable of curing induced experimental autoimmune diseases such as adjuvant arthritis and experimental allergic encephalomyelitis. In man allogeneic bone-marrow transplantation (BMT) is becoming progressively safer, but cannot yet be offered to SLE patients. However, syngeneic transplants from twins non-concordant for the disease would be justified.Conditioning with high-dose cyclophosphamide followed by autologous HSC rescue, from the marrow and/or from the peripheral blood, may already be regarded as a powerful immunosuppressive procedure for selected cases of SLE and other severe autoimmune diseases. Autologous transplant procedures are not saddled with the immunologic problems of allo-BMT. Although eradication of SLE may not be achieved by auto-BMT, minimal residual immunologic disease can be suppressed or controlled, and long-term self-maintained remissions may be expected.