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The solar system presents us with a number of planetary bodies with shallow atmospheres that are sufficiently Earth-like in their form and structure to be termed “terrestrial.” These atmospheres have much in common, in having circulations that are driven primarily by heating from the Sun and radiative cooling to space, which vary markedly with latitude. The principal response to this forcing is typically in the form of a (roughly zonally symmetric) meridional overturning that transports heat vertically upward and in latitude. But even within the solar system, these planets exhibit many differences in the types of large-scale waves and instabilities that also contribute substantially to determining their respective climates. Here we argue that the study of simplified models (either numerical simulations or laboratory experiments) provides considerable insights into the likely roles of planetary size, rotation, thermal stratification, and other factors in determining the styles of global circulation and dominant waves and instability processes. We discuss the importance of a number of key dimensionless parameters, for example, the thermal Rossby and the Burger numbers as well as nondimensional measures of the frictional or radiative timescales, in defining the type of circulation regime to be expected in a prototypical planetary atmosphere subject to axisymmetric driving. These considerations help to place each of the solar system terrestrial planets into an appropriate dynamical context and also lay the foundations for predicting and understanding the climate and circulation regimes of (as yet undiscovered) Earth-like extrasolar planets. However, as recent discoveries of “super-Earth” planets around some nearby stars are beginning to reveal, this parameter space is likely to be incomplete, and other factors, such as the possibility of tidally locked rotation and tidal forcing, may also need to be taken into account for some classes of extrasolar planet.

We present a photometric detection of the first brightness dips of the unique variable star KIC 8462852 since the end of the Kepler space mission in 2013 May. Our regular photometric surveillance started in October 2015, and a sequence of dipping began in 2017 May continuing on through the end of 2017, when the star was no longer visible from Earth. We distinguish four main 1-2.5% dips, named "Elsie," "Celeste," "Skara Brae," and "Angkor", which persist on timescales from several days to weeks. Our main results so far are: (i) there are no apparent changes of the stellar spectrum or polarization during the dips; (ii) the multiband photometry of the dips shows differential reddening favoring non-grey extinction. Therefore, our data are inconsistent with dip models that invoke optically thick material, but rather they are in-line with predictions for an occulter consisting primarily of ordinary dust, where much of the material must be optically thin with a size scale <

Tosedostat, an oral aminopeptidase inhibitor, has synergy with cytarabine and hypomethylating agents. We performed a Phase II trial to determine rates of complete remission (CR) and survival using tosedostat with cytarabine or decitabine in older patients with untreated acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS). Thirty-four patients ≥60 years old (median age 70 years; range, 60-83) were randomized to receive tosedostat (120 mg on days 1-21 or 180 mg continuously) with 5 d of either cytarabine (1 g/m2 /d) or decitabine (20 mg/m2 /d) every 35 d. Twenty-nine patients (85%) had AML, including 15 (44%) with secondary AML/MDS, and 5 (15%) had MDS-refractory anaemia with excess blasts type 2. The CR/CR with incomplete count recovery (CRi) rate was 53% [9 in each arm; 14 CR (41%) and 4 CRi (12%)], attained in 6 of 14 patients with adverse cytogenetics and 4 of 7 with FLT3-internal tandem duplication mutations. Median follow-up was 11.2 months (range, 0.5-22.3), and median survival was 11.5 months (95% confidence interval, 5.2-16.7). Twenty-three patients (67.6%) were treated as outpatients and 10 of these patients required hospitalization for febrile neutropenia. No Grade 3-4 non-haematological toxicities required withdrawal from study. Tosedostat with cytarabine or decitabine is tolerated in older patients with untreated AML/MDS, results in a CR/CRi rate of >50%, and warrants further study in larger trials.

The prevalence of diseases such as AML or myelodysplastic syndromes increases with the aging of the population. Only intensive chemotherapy or hematopoietic cell transplantation have curative potential. However, comorbid conditions may interfere with effective therapy. Although transplantation following low-intensity conditioning is being carried out in patients even in their 70s, these are highly selected patients, and the data cannot be extrapolated to the population at large. Further, such a therapy in older individuals may be associated with considerable morbidity and the need for prolonged hospitalization and rehabilitation, stressing the system and draining family resources. As the focus of many older individuals is on quality of life, it is important to emphasize that, for various advanced malignancies, emerging data indicate that quality of life may be better and survival may be longer with palliative care. A re-assessment of treatment decisions in older patients is in order. We tend to 'oversell', and particularly older patients do not have a full understanding of the impact of the proposed therapy on their lives. Our conversations with these patients must include a discussion of supportive/palliative care and must address end-of-life issues. Talking about death may mean talking about life.

The bone marrow microenvironment influences malignant hematopoiesis but how it promotes leukemogenesis has not been elucidated. Additionally, the role of the bone marrow stroma in regulating clinical responses to DNA methyltransferase inhibitors (DNMTi) is also poorly understood. In this study, we conducted a DNA methylome analysis of bone marrow-derived stromal cells from myelodysplastic syndrome (MDS) patients and observed widespread aberrant cytosine hypermethylation occurring preferentially outside CpG islands. Stroma derived from 5-azacytidine-treated patients lacked aberrant methylation and DNMTi treatment of primary MDS stroma enhanced its ability to support erythroid differentiation. An integrative expression analysis revealed that the WNT pathway antagonist FRZB was aberrantly hypermethylated and underexpressed in MDS stroma. This result was confirmed in an independent set of sorted, primary MDS-derived mesenchymal cells. We documented a WNT/ß-catenin activation signature in CD34+ cells from advanced cases of MDS where it associated with adverse prognosis. Constitutive activation of ß-catenin in hematopoietic cells yielded lethal myeloid disease in a NUP98-HOXD13 mouse model of MDS, confirming its role in disease progression. Our results define novel epigenetic changes in the bone marrow microenvironment which lead to ß-catenin activation and disease progression of MDS.

We treated patients under age 50 years with iodine-131 (131I)–anti-CD45 antibody combined with fludarabine and 2 Gy total body irradiation to create an improved hematopoietic cell transplantation (HCT) strategy for advanced acute myeloid leukemia or high-risk myelodysplastic syndrome patients. Fifteen patients received 332 to 1561 mCi of 131I, delivering an average of 27 Gy to bone marrow, 84 Gy to spleen, and 21 Gy to liver. Although a maximum dose of 28 Gy was delivered to the liver, no dose-limiting toxicity was observed. Marrow doses were arbitrarily capped at 43 Gy to avoid radiation-induced stromal damage; however, no graft failure or evidence of stromal damage was observed. Twelve patients (80%) developed grade II graft-versus-host disease (GVHD), 1 patient developed grade III GVHD, and no patients developed grade IV GVHD during the first 100 days after HCT. Of the 12 patients with chronic GVHD data, 10 developed chronic GVHD, generally involving the skin and mouth. Six patients (40%) are surviving after a median of 5.0 years (range, 4.2 to 8.3 years). The estimated survival at 1 year was 73% among the 15 treated patients. Eight patients relapsed, 7 of whom subsequently died. The median time to relapse among these 8 patients was 54 days (range, 26 to 1364 days). No cases of nonrelapse mortality were observed in the first year after transplantation. However, 2 patients died in remission from complications of chronic GVHD and cardiomyopathy, at 18 months and 14 months after transplantation, respectively. This study suggests that patients may tolerate myeloablative doses >28 Gy delivered to the liver using 131I-anti-CD45 antibody in addition to standard reduced-intensity conditioning. Moreover, the arbitrary limit of 43 Gy to the marrow may be unnecessarily conservative, and continued escalation of targeted radioimmunotherapy doses may be feasible to further reduce relapse.

The intrinsic anti-leukemic effect of allogeneic hematopoietic cell transplantation (HCT) is dependent on genetic disparity between donor and recipient, intimately associated with graft-versus-host disease (GVHD), and mediated by lymphocytes contained in or derived from the donor hematopoietic cell graft. Three decades of intense effort have not identified clinical strategies that can reliably separate the graft-versus-leukemia (GVL) effect from the alloimmune reaction that drives clinical GVHD. For patients who require HCT and for whom two or more human leukocyte antigen (HLA)-A, -B, -C, and -DRB1-matched donor candidates can be identified, consideration of donor and recipient genotype at additional genetic loci both within and outside the major histocompatibility complex may offer the possibility of selecting the donor [candidate(s)] that poses the lowest probability of GVHD and the highest probability of a potent GVL effect. Strategies for engineering conventional donor lymphocyte infusion also hold promise for prevention or improved treatment of post-transplant relapse. The brightest prospects for selectively enhancing the anti-leukemic efficacy of allogeneic HCT, however, are likely to be interventions that are designed to enhance specific antitumor immunity via vaccination or adoptive cell transfer, rather than those that attempt to exploit donor alloreactivity against the host. Adoptive transfer of donor-derived T cells genetically modified for tumor-specific reactivity, in particular, has the potential to transform the practice of allogeneic HCT by selectively enhancing antitumor immunity without causing GVHD.

We examined whether lenalidomide exposure up-regulates miRNAs and mRNAs, previously shown to play a role in the disease phenotype of del(5q) myelodysplastic syndrome, in pre-treatment CD34(+) marrow cells. We hypothesized that increased expression would predict for clinical response. Changes in miR-143, miR-145, miR-146a, miR-146b, miR-378, miR-584, SPARC and RPS14 were examined in del(5q) (n=10) and non-del(5q) (n=18) myelodysplastic syndrome patient samples. Significantly increased expression of miR-143 (1.8-fold and 1.5-fold in del(5q) and non-del(5q), respectively), and miR-145 (1.9-fold and 1.6-fold in del(5q) and non-del(5q), respectively) was observed. In the del(5q) myelodysplastic syndrome cohort, transfusion independence correlated with a 1.3-fold or more increase in miR-145 expression and response over 12 months correlated with a 1.5-fold or more increase. Knockdown of miR-143 and miR-145 in cord blood CD34(+) cells resulted in increased erythroid progenitor activity. Lenalidomide selectively abrogated progenitor activity in cells depleted of miR-143 and miR-145 supporting a key role for miR-143/145 in the sensitivity to lenalidomide of del(5q) myelodysplastic syndrome patients.

These suggested practice guidelines are based on extensive evaluation of the reviewed risk-based data and indicate useful current approaches for managing patients with MDS. Four drugs have recently been approved by the FDA for treating specific subtypes of MDS: lenalidomide for MDS patients with del(5q) cytogenetic abnormalities; azacytidine and decitabine for treating patients with higher-risk or nonresponsive MDS; and deferasirox for iron chelation of iron overloaded patients with MDS. However, because a substantial proportion of patient subsets with MDS lack effective treatment for their cytopenias or for altering disease natural history, clinical trials with these and other novel therapeutic agents along with supportive care remain the hallmark of management for this disease. The role of thrombopoietic cytokines for management of thrombocytopenia in MDS needs further evaluation. In addition, further determination of the effects of these therapeutic interventions on the patient's quality of life is important.(116,119,120,128,129) Progress toward improving management of MDS has occurred over the past few years, and more advances are anticipated using these guidelines as a framework for coordination of comparative clinical trials.

The frequencies of 12 DLA-D alleles in a random canine population were determined in one-way mixed lymphocyte cultures using a panel of homozygous typing cells established in this laboratory. The homozygous typing cells served as stimulators for responder lymphocytes obtained from 160 random dogs. The results of these studies were compared to those with lymphocytes from 75 dogs in our research laboratory. DLA-D allelic frequencies were estimated by maximum likelihood techniques. The use of a relative response (RR) less than or equal to 5% as a definition of a typing response resulted in the recognition of a total allele frequency of 59% in dogs from the research laboratory. Three of the 12 DLA-D alleles were not detected. Typing responses of cells from random dogs to the 12 DLA-D alleles were determined using RRs less than or equal to 5%, less than or equal to 10%, less than or equal to 15%, and less than or equal to 20%. With RRs of less than or equal to 5%, less than or equal to 10%, and less than or equal to 15%, the total allele frequencies recognized were 39%, 47%, and 55%, respectively. Within each of these % RR ranges all but one of the DLA-D alleles were detected. With an RR less than or equal to 20% the total allele frequency recognized was 58% and all 12 alleles were detected. Our results indicate that an RR of less than or equal to 10% could be used to define a phenotypic DLA-D typing response in the dog. The level of allelic frequencies detected in both the research and random canine populations indicates the need to identify additional DLA-D alleles through expanded family studies using mixed lymphocyte culture and homozygous cell typing.

Allogeneic hematopoietic cell transplantation (HCT) represents a potentially curative approach for patients with myelodysplastic syndromes (MDSs). While a large proportion of HCT recipients become long-term disease-free survivors, recurrence of MDS remains the leading cause of mortality after HCT. The role of donor lymphocyte infusion (DLI) in patients with relapsed MDS after HCT is unclear. We report results among 16 patients treated with DLI for relapsed MDS after HCT at a single institution between March 1993 and February 2004. The cohort contained 10 men and 6 women with a median age of 49 (range, 22-67) years. CR with resolution of cytopenias and prior disease markers occurred in 3 of 14 patients who could be evaluated. Two patients survived without MDS for 68 and 65 months after DLI, respectively, but died with pneumonia. Grades II-IV acute GVHD and chronic GVHD occurred after DLI in 6 (43%) and 5 (36%) patients, respectively. All three responders developed grades III-IV acute GVHD and extensive chronic GVHD after DLI. Our results confirm prior reports that DLI can result in CR in some patients with recurrent MDS after transplant, but long-term survival is infrequent.

Transplant outcome was analyzed in 150 patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia transformed from MDS (tAML) conditioned with nonmyeloablative or myeloablative regimens. A total of 38 patients received nonmyeloablative regimens of 2 Gy total body irradiation alone (n=2) or with fludarabine (n=36), 90mg/m2. A total of 112 patients received a myeloablative regimen of busulfan, 16mg/ kg (targeted to 800-900 ng/ml), and cyclophosphamide 120 mg/ kg. Nonmyeloablative patients were older (median age 62 vs 52 years, P

The incidence, etiology, outcome, and risk factors for developing pneumonia late after hematopoietic stem cell transplantation (SCT) were investigated in 1359 patients transplanted in Seattle. A total of 341 patients (25% of the cohort) developed at least one pneumonic episode. No microbial or tissue diagnosis (ie clinical pneumonia) was established in 197 patients (58% of first pneumonia cases). Among the remaining 144 patients, established etiologies included 33 viral (10%), 31 bacterial (9%), 25 idiopathic pneumonia syndrome (IPS, 7%), 20 multiple organisms (6%), 19 fungal (6%), and 16 Pneumocystis carinii pneumonia (PCP) (5%). The overall cumulative incidence of first pneumonia at 4 years after discharge home was 31%. The cumulative incidences of pneumonia according to donor type at 1 and 4 years after discharge home were 13 and 18% (autologous/syngeneic), 22 and 34% (HLA-matched related), and 26 and 39% (mismatched related/unrelated), respectively. Multivariate analysis of factors associated with development of late pneumonia after allografting were increasing patient age (RR 0.5 for20 years, 1.2 for40 years, P=0.009), donor HLA-mismatch (RR 1.6 for unrelated/mismatched related, P=0.01), and chronic graft-versus-host disease (GVHD; RR 1.5, P=0.007). Our data suggest that extension of PCP prophylaxis may be beneficial in high-risk autograft recipients. Further study of long-term anti-infective prophylaxis based on patient risk factors after SCT appear warranted.

Combinations of agents may improve outcomes among elderly acute myeloid leukaemia (AML) and high-risk myelodysplastic syndrome (MDS) patients. We performed an adaptive phase I/II trial for newly-diagnosed AML or high-risk MDS patients aged ≥50 years using a Bayesian approach to determine whether 1 of 3 doses of bendamustine (45, 60, 75 mg/m(2) days 1-3), together with idarubicin (12 mg/m(2) days 1-2), might provide a complete response (CR) rate ≥40% with30% grade 3-4 non-haematological toxicity. We treated 39 patients (34 AML; five MDS with10% marrow blasts; median age 73 years). None of the three bendamustine doses in combination with idarubicin met the required CR and toxicity rates; the 75 mg/m(2) dose because of excess toxicity (two of three patients) and the 60 mg/m(2) dose because of low efficacy (CR rate 10/33), although no grade 3-4 non-haematological toxicity was seen at this dose. Median survival was 7·2 months. All patients began treatment as outpatients but hospitalization was required in 90% (35/39). Although we did not find a dose of bendamustine combined with idarubicin that would provide a CR rate of40% with acceptable toxicity, bendamustine may have activity in AML/MDS patients, suggesting its addition to other regimens may be warranted.

The term myelodysplastic syndrome (MDS) describes a spectrum of disorders that are characterized by dysplastic marrow cell morphology, the development of peripheral blood cytopenias, and a tendency to evolve into acute myeloid leukemia. MDS has been recognized as a stem-cell disease, and hemopoietic stem-cell transplantation is currently the only potentially curative therapy. In patients with less advanced MDS (

BACKGROUND We studied whether blocking of the T cell costimulatory signal from B7-->CD28 by cytotoxic T lymphocyte antigen 4-immunoglobulin fusion protein would, either by itself or when added to methotrexate/cyclosporine, result in improved graft-versus-host disease prevention after dog leukocyte antigen nonidentical canine hematopoietic stem cell transplantation after 920 cGy total body irradiation. RESULTS AND CONCLUSIONS Survivals of cytotoxic T lymphocyte antigen 4-immunoglobulin fusion protein-treated dogs were only slightly prolonged over controls. It appeared that the addition of cytotoxic T lymphocyte antigen 4-immunoglobulin fusion protein failed to induce graft-host tolerance in this model beyond that achieved with methotrexate/cyclosporine alone.

This report updates the results of marrow transplantation at the Fred Hutchinson Cancer Research Center for patients with severe aplastic anemia whose donors were HLA-nonidentical relatives. Between 1970 and 1993, 40 patients received transplants for severe aplastic anemia from related donors other than HLA genotypically matched siblings. Nine patients (group 1) were conditioned with cyclophosphamide (Cy) at 50 mg/kg for 4 doses and received marrow from phenotypically HLA-matched relatives. With the exception of one accidental death, all patients are alive and disease free 3-18 years after transplantation. Thirty-one patients received marrow from HLA-mismatched relatives who differed by one or more loci. Fifteen of these patients (group 2) received Cy at 50 mg/kg for 4 doses without total body irradiation (TBI) and none survived. Because of failure to sustain engraftment in 9 of 14 evaluable patients in group 2, the regimen for HLA-mismatched patients was changed in 1984 to include Cy at 60 mg/kg for 2 doses and TBI was added at 1200 cGy to increase immunosuppression (group 3). Sixteen patients in group 3 received marrow grafts after failure to respond to immunosuppressive therapy. Eight of the 16 patients in group 3 remain alive without disease between 1.5 and 11.3 years after transplantation. In conclusion, transplants from phenotypically HLA-identical related donors can be carried after Cy alone and results are comparable to those observed with genotypically HLA-identical siblings. Transplants from related donors mismatched for one or more HLA loci require a more intensive conditioning regimen, for example, one containing TBI, to achieve sustained engraftment.

Allogeneic hematopoietic cell transplantation (HCT) can be curative for both myelodysplastic syndromes (MDS) and lymphoid malignancies. Little is known about the efficacy of allogeneic HCT in patients in whom both myeloid and lymphoid disorders are present at the time of HCT. We analyzed outcomes in 21 patients with MDS and concurrent lymphoid malignancy when undergoing allogeneic HCT. Seventeen patients had received extensive prior cytotoxic chemotherapy, including autologous HCT in seven, for non-Hodgkin lymphoma (NHL, n=7), Hodgkin lymphoma (HL, n=2), chronic lymphocytic leukemia (CLL, n=5), NHL plus HL (n=1), multiple myeloma (n=1), or T-cell acute lymphocytic leukemia (ALL) (n=1), and had, presumably, developed MDS as a consequence of therapy. Four previously untreated patients had CLL. Nineteen patients were conditioned with high-dose (n=14) or reduced-intensity regimens (n=5), and transplanted from HLA-matched or one antigen/allele mismatched related (n=10) or unrelated (n=9) donors; two patients received HLA-haploidentical related transplants following conditioning with a modified conditioning regimen. Currently, 2 of 4 previously untreated, and 2 of 17 previously treated patients are surviving in remission of both MDS and lymphoid malignancies. However, the high non-relapse mortality among previously treated patients, even with reduced-intensity conditioning regimens, indicates that new transplant strategies need to be developed.

Bone marrow transplantation is associated with several risk factors that may predispose patients to the development of a new malignancy post-transplant. Several types of malignancies, including lymphoproliferative disorders, new leukemias, and solid tumors have been observed. Risk factors include treatment of acute graft-versus-host disease with monoclonal or polyclonal antibodies, total body irradiation, HLA nonidentity, and T-cell depletion. It is currently unknown whether longer follow-up will show a further increase or decline in the incidence of secondary tumors.

Thirty-six patients with advanced hematologic malignancy were entered into a Phase I study designed to define the maximum tolerated dose of unshielded total body irradiation delivered from dual 60 Cobalt sources at an exposure rate of 8 cGy/min and given in fractions twice daily for total doses ranging from 12 Gy to 17 Gy. All patients received cyclophosphamide, 120 mg/kg administered over 2 days before total body irradiation. Allogeneic marrow was infused from HLA-identical siblings (n = 29) or one locus HLA incompatible family members (n = 3); three patients received cryopreserved autologous marrow and one patient received syngeneic marrow. The maximum tolerated dose of total body irradiation given as 2 Gy fractions twice a day was 16 Gy. One of eight patients receiving 12 Gy, none of four receiving 14 Gy, three of 20 receiving 16 Gy, and two of four receiving 17 Gy developed severe (Grade 3–4) regimen-related toxicity. The primary dose limiting toxicity was pneumonitis, followed by veno-occlusive disease of the liver, renal impairment, and mucositis. Five patients (14%) are alive, four disease-free 798–1522 days posttransplant. Twenty (56%) relapsed posttransplant. Further investigation of regimens containing 16 Gy of hyperfractionated total body irradiation is warranted to assess anti-tumor efficacy.

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A short overview of the motivation and techniques of the ground-based photometric follow-up program of the CoRoT mission is given. © 2009 International Astronomical Union.

We investigated in a murine model whether UVB irradiation of lymphohemopoietic cells would prevent the development of graft-versus- host disease (GVHD). Preliminary experiments showed that spleen colony (CFU-S) formation by hemopoietic cells was preserved at UVB doses that eliminated lymphocyte proliferation. In a parent into F1 model, UVB irradiation (5 to 15 mJ/cm2) of spleen cells added to normal marrow cells prevented the development of GVHD, whereas all recipients given untreated spleen cells developed GVHD. Syngeneic recipients of marrow exposed to 2.5 to 10 mJ/cm2 of UVB achieved normal hemopoietic reconstitution. Based on these observations, B6D2 F1 (H-2b x H-2d) recipients were given 1,000 cGy of total body irradiation (TBI) followed by transplantation of 5 x 10(6) parental B6 (H-2b) bone marrow cells and 10 x 10(6) B6 spleen cells, either unirradiated or exposed to UVB before infusion. All mice transplanted with cells exposed to 10 or 12.5 mJ/cm2 of UVB survived without GVHD. At 2.5 and 5.0 mJ/cm2, mice showed signs of GVHD, beginning at day 30, and 100% and 80%, respectively, eventually developed chronic GVHD. At 7.5 mJ/cm2, mice had weight loss, from which 60% recovered and survived without GVHD, while 40% died with GVHD. At 15 mJ/cm2, some recipients died from graft failure, while some survived without GVHD. All surviving mice were complete donor-type chimeras. Spleen size and cellularity and in vitro lymphocyte responses correlated inversely with the development of GVHD. Mice without GVHD showed specific tolerance to skin grafts from the second parent strain, while animals with GVHD rejected their skin grafts. Thus, in a murine model UVB irradiation of transplanted hemopoietic stem cells allows for hemopoietic reconstitution and prevents GVHD.

Most patients receiving bone marrow transplantation are being conditioned with high-dose chemotherapy, either alone or combined with total body or total lymphoid irradiation. This treatment is associated not only with acute toxicities, but also with delayed complications, including lung and airway disease, ocular and dental problems, endocrine dysfunction, impaired growth, infertility, problems of the genitourinary tract and the nervous system, bone marrow dysfunction, autoimmune disorders, and secondary malignancies. Although many of these problems are thought to be related to irradiation, chronic GVHD and associated complications may contribute. Patients may be cured of their disease, but their quality of life may be unsatisfactory. Using fractionated (rather than single dose) total body irradiation of non-irradiation conditioning regimens may reduce the incidence of many of these problems. We have only two decades of experience with this form of treatment, and it is not unlikely that additional problems will emerge, particularly in children.

Numerous reduced-intensity conditioning regimens for allogeneic hematopoietic cell transplantation are currently being explored, primarily in older patients and in individuals with comorbid conditions who are not eligible for conventional myeloablative conditioning regimens. There is agreement that these approaches have reduced early transplant-related (non-relapse) toxicity and mortality. It is unclear, however, whether these strategies improve long-term survival. Furthermore, as most trials with reduced-intensity regimens have enrolled older patients and patients with comorbid conditions, it is not appropriate to compare the results of these trials to those obtained with more conventional approaches. It remains to be determined whether younger patients, and patients without comorbid conditions, will derive significant long-term benefits from reduced-intensity regimens when compared to conventional strategies. It may be that the different approaches are complementary and in the end will preferentially serve specific patient populations based on age, comorbid conditions and malignancy type. To determine the role of reduced-intensity approaches, controlled prospective trials are needed, with enrolled patients being stratified according to comorbid conditions, disease characteristics, pre-transplant therapy and source of stem cells, at a minimum.

The objective of this prospective study was to determine whether amifostine (Ethyol) reduced conditioning-related toxicity following a regimen of busulfan (7 mg/kg) and fractionated total body irradiation (6 x 200 cGy). In all, 12 patients with advanced myelodysplastic syndrome transplanted from HLA-identical siblings were enrolled. Patients received 340 mg/m(2) amifostine i.v. twice daily during conditioning (days -7 through -1). All patients developed oropharyngeal mucositis. Six patients had evidence of sinusoidal obstruction syndrome of the liver. Six patients experienced pulmonary toxicity of grades II-III. A total of 11 patients died, one with relapse and 10 with infectious complications or regimen-related toxicity. Nonrelapse causes of death included invasive aspergillosis in three, multiorgan failure in three, and idiopathic interstitial pneumonitis in two patients. One patient each died of organizing pneumonia and CMV pneumonia. One patient is alive in complete remission 31 months after transplantation. These results were not superior to those in patients conditioned with busulfan plus fractionated total body irradiation and not given amifostine, and suggest that amifostine, as administered here, has no protective effect against toxicity from this myeloablative regimen.

Donor-cell leukemia post bone marrow transplantation is a rare event. Most of the cases reported to date have developed in cells from an HLA-matched sibling, who had no evidence of malignant disease before or following the occurrence of donor-origin leukemia. We describe a 17-year-old female who developed B-cell lymphoma 9 years following the occurrence of donor-origin acute myeloid leukemia in her brother for whom she had donated marrow. Cytogenetic analysis of the tumor revealed multiple chromosomal aberrations. The donor was heterozygous for the Ashkenazi mutation of Bloom's syndrome, suggesting that donor-type leukemia could have resulted from genomic instability in the donor cells.

Blockade of tumor necrosis factor (TNF)alpha by a soluble TNF receptor fusion protein (etanercept; Enbrel) improved in vitro hemopoiesis from the marrow of patients with myelodysplastic syndrome (MDS). Therefore, we enrolled 14 MDS patients (4 RA, 2 RARS, 6 RAEB, 2 CMML), 44-80 (median 60) years old, in a pilot trial. Etanercept, 25 mg, was given twice a week s.c. for 16 weeks (increased to three times a week if no response at 8 weeks). Among 12 evaluable patients, four had rises in hemoglobin by 1-1.5 gm/dl (three) or decreased transfusion requirements (one). Two patients had increased platelet counts (54% and 73%), and two increased neutrophils (63% and 120%). Baseline TNFalpha levels, determined in all patients, did not correlate with responses. Among eight marrows available for sequential in vitro assays, four showed increases in CFU-GM of 1.5- to 5-fold at 8 weeks, whereas three showed 3- to 10-fold decrements relative to baseline. Thus, etanercept treatment resulted in moderate improvements of cytopenias in some patients, while cell counts declined in others. Additional trials are needed to evaluate its clinical efficacy in MDS.

Patients who develop secondary leukemia face a poor prognosis for survival. Chemotherapy to induce a remission has been complicated by prolonged leukopenia, infection, and a low likelihood of achieving a complete remission. Once achieved, the remissions are of short duration [1]. Combination chemotherapy with cytosine arabinoside and fludarabine, or treatment with topotecan show promise to increase the remission rate and duration of remission [2,3]. However, longterm survival is not likely for patients with secondary leukemia. Treatment of secondary acute leukemia by bone marrow transplantation from a family member or unrelated donor suitably matched for HLA has resulted in long term disease free survival for less than 30 % of patients due to a high relapse rate and significant non-relapse mortality [4,5,6]. We previously reported no statistically significant improvement in outcome whether patients with secondary acute myeloid leukemia (AML) were transplanted as initial therapy or following induction chemotherapy

We have undertaken a formal study to evaluate the reproducibility of retrospective assessments for grading the severity of acute GVHD. Using criteria previously established by the Seattle group, three reviewers independently assigned GVHD severity grades for a set of 100 marrow transplant patients. Significant differences were found in the distribution of GVHD grades assigned by one of the reviewers as compared to the other two reviewers. In only 40% of cases did all three reviewers assign the same GVHD grade, and in only 68-71% of cases did all three reviewers assign the same grade within 0-I vs II-IV or 0-II vs III-IV categories. Despite the high rate of disagreement between any two reviewers, at least two reviewers assigned the same overall GVHD grade in 93% of cases. These results suggest that current criteria for assessing the severity of GVHD by a single reviewer are not sufficiently reliable for rigorous clinical studies. As an alternative to the original criteria, we have developed and tested simplified criteria that summarize the clinical course of GVHD as reflected by the progression of disease and the amount of immunosuppressive treatment used to control the disease. Our results suggest that the revised criteria might yield more reproducible retrospective grading than the original criteria. Although the original criteria and the revised criteria might produce different results for individual patients, the overall distributions of grades with the two systems were similar. The proposed revised criteria could be implemented without disrupting the continuity and consistency with previous grading assigned by the original criteria.

The influence of busulfan (BU) plasma concentration on outcome of transplantation from HLA identical family members for the treatment of chronic myelogenous leukemia (CML) was examined in 45 patients transplanted in chronic phase (CP) (n = 39) or accelerated phase (AP) (n = 6). All patients received the same regimen of BU, 16 mg/kg orally and cyclophosphamide (CY), 120 mg/kg intravenously. Plasma concentrations of BU at steady state (CSSBU) during the dosing interval were measured for each patient. The mean CSSBU was 917 ng/mL (range, 642 to 1,749; median, 917; standard deviation, 213). Of patients with CSSBU below the median, seven (five of 18 in CP and two of four in AP) developed persistent cytogenetic relapse and three of these patients died. There were no relapses in patients with CSSBU above the median. The difference in the cumulative incidence of relapse between the two groups was statistically significant (P = .0003). CSSBU was the only statistically significant determinant of relapse in univariable or multivariable analysis. The 3-year survival estimates were 0.82 and 0.64 for patients with CSSBU above and below the median (P = .33). There was no statistically significant association of CSSBU with survival or nonrelapse mortality, although the power to detect a difference in survival between 0.82 and 0.64 was only 0.24, similarly CSSBU above the median was not associated with an increased risk of severe regimen-related toxicity. We conclude that low BU plasma levels are associated with an increased risk of relapse.

Eight patients with aplastic anaemia associated with dyskeratosis congenita received allogeneic marrow grafts from either HLA-identical siblings (six patients) or HLA-matched unrelated donors (two patients). Patients who received marrow from HLA-identical siblings were conditioned with cyclophosphamide (140-200 mg/kg), with or without antithymocyte globulin. Patients who received unrelated donor marrow were conditioned with cyclophosphamide (120 mg/kg) and total body irradiation (1200 cGy). The six patients who survived for >2 weeks following transplant all had haematological evidence of engraftment, and all three patients who survived for at least a year following transplant recovered normal haematological function. Three patients died with respiratory failure and pulmonary fibrosis at 70 d. 8 years and 20 years posttransplant; three patients died during the neutropenic period of invasive fungal infections; one patient died on day 44 of refractory acute graft-versus-host disease; and one patient remains alive 463 d following transplant. The surviving patient recently underwent surgical resection of a Dukes' stage C rectal carcinoma diagnosed 14 months posttransplant. The aplastic anaemia associated with dyskeratosis congenita can be successfully treated by allogeneic bone marrow transplantation; however, this approach does not reverse the other systemic manifestations of the syndrome. The pathogenesis of the intestinal lung disease observed in dyskeratosis congenita patients following marrow transplantation is not understood.

PURPOSE To evaluate a high-dose treatment regimen of fractionated total-body irradiation (TBI), etoposide, and cyclophosphamide (Cy) followed by autologous stem-cell transplantation (ASCT) in patients with malignant lymphoma. PATIENTS AND METHODS Fifty-three patients with non-Hodgkin's lymphoma (NHL; n = 43) or Hodgkin's disease (HD; n = 10) received 12.0 Gy of fractionated TBI, etoposide 60 mg/kg, and Cy 100 mg/kg followed by infusion of autologous hematopoietic stem cells. RESULTS Thirty-one of 53 patients are alive a median of 643 (range, 177 to 1,144) days after transplant. The 2 year Kaplan-Meier (K-M) estimates of survival, event-free survival (EFS), and relapse for all 53 patients were 54%, 45%, and 43%, respectively. Sixteen of 24 patients with less advanced disease and 10 of 29 patients with more advanced disease survive free of disease for K-M estimates of EFS of 61% and 31%, respectively (P = .006). The K-M estimates of relapse were 34% for patients with less advanced disease and 53% (P = .05) for patients with more advanced disease. The K-M estimates of dying from causes other than relapse were 8% in patients with less versus 25% in patients with more advanced disease (P = .09). CONCLUSION These data indicate that approximately 60% of patients transplanted early after failure of initial therapy for malignant lymphoma are projected to be disease-free more than 2 years after treatment with fractionated TBI, etoposide, and Cy and infusion of autologous hematopoietic stem cells. The transplant-related mortality rate is low and relapse is the main cause of treatment failure in patients with less advanced disease. For patients with more advanced disease, the K-M estimates of both transplant-related deaths (25%) and relapse (53%) remain major problems.