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Myelofibrosis with myeloid metaplasia (MMM) is a disorder characterized by clonal myeloproliferation, ineffective erythropoiesis, extramedullary hematopoiesis and bone marrow fibrosis. Between 4/1998 and 1/2006, 17 patients with MMM were treated with allogeneic hematopoietic stem cell transplantation. Patients included 8 males and 9 females with a median age of 51.8 years (range 37–66). All patients were transfusion-dependent at the time of transplantation, 3 (18%) had abnormal cytogenetics and 4 (24%) had a prior splenectomy. Six patients (35%) received a reduced intensity conditioning regimen consisting of either fludarabine and busulfan (1 pt), fludarabine and low dose total body irradiation (1 pt), fludarabine and melphalan (3 pts) or fludarabine and cyclophosphamide (1 pt). Eleven patients (65%) received an ablative regimen of either busulfan and cyclophosphamide (10 pts) or cyclophosphamide and total body irradiation (1 pt). Patients with unrelated donors also received ATG as part of their conditioning. The hematopoietic cell source was peripheral blood in 12 pts (71%) and bone marrow in 5 pts (29%). Six pts (35%) received cells from an HLA-identical sibling, 1 pt (6%) had a 1 Antigen mismatch sibling and 10 pts (59%) received stem cells from an unrelated donor. Graft-versus-host disease prophylaxis consisted of tacrolimus in 15 pts (88%) and cyclosporine in 2 pts (12%). Transplant-related mortality was 17% (sepsis 1 pt, VOD 1 pt, acute GVHD 1 pt) all occurring in the group treated with a myeloablative regimen. Of the remaining 14 patients, all achieved hematological recovery and transfusion independence. There were 2 relapses and one patient died of disease recurrence; both relapses occurred in the group receiving a reduced intensity regimen. The other 12 patients remain alive and in remission. The 6-year actuarial survival is 67% with no statistical difference between the groups who received a reduced intensity versus a myeloablative regimen. In conclusion, Myelofibrosis with Myeloid Metaplasia can be successfully treated with allogeneic hematopoietic stem cell transplantation with a significant proportion of patients achieving long-term survival. Hematopoietic recovery can be achieved despite the presence of marrow fibrosis. The optimal preparative regimen remains to be determined with more relapses observed in the reduced intensity regimen group and a higher mortality seen in the myeloablative group. A risk-stratification strategy for regimen selection should be considered in future studies.

Introduction: Treatment of the elderly AML patient remains challenging. Standard induction chemotherapy may not be well tolerated and increased rates of higher risk disease have led to poor long-term outcomes. New strategies are needed in this population. Methods: A retrospective review of consecutive Acute Myelogenous Leukemia patients age >60 years treated with either 5-azacitidine 75mg/m2/d 7 days per month (5-aza) or 3 days idarubicin 12 mg/m2 with 7 days cytarabine 100 mg/m2 continuous infusion (3+7). Patients were offered both treatments, and supportive care alone, and chose their own therapy. Results: Between November 2004 and August 2006, 33 elderly patients with AML underwent therapy with either 5-aza (n=11, median age = 74 years) or 3+7 (n=22 median age = 67) (p=0.07) at Hackensack University Medical Center. Consolidation therapy in the 3+7 cohort consisted of high-dose cytarabine (n=12) and allogeneic transplantation (n=2). Rates of secondary leukemia were balanced between groups (27% 5-aza and 36% 3+7; p=0.9). SWOG cytogenetic risk categories were high-risk in 36% 5-aza and 45% 3+7, and intermediate risk in 64% 5-aza and 55% 3+7 (p=0.9). Marrow blast counts (median) at initiation of therapy were 42% in 5-aza and 65% in 3+7 (p=0.01). Median survival from diagnosis was similar between both therapies at 397 days for 5-aza and 276 days for 3+7 (Log-rank p=0.7). Patients with high-risk cytogenetics fared poorly in the entire cohort with a median survival of 154 days versus 435 days with intermediate risk cytogenetics (p=0.002). Patients with high-risk cytogenetics did not benefit from 5-aza therapy (median survival 35 days) compared to 3+7 (median survival 214 days) (p=0.09), but the trend was reversed among intermediate-risk cytogenetic patients (5-aza median survival 435 days; 3+7 median survival 276 days; p=0.13). Early mortality (<100 days) occurred in 36% 5-aza (2 infection, 1 disease, 1 cardiac) and 18% 3+7 (2 infection, 2 organ toxicity) (p=0.47). Using IWG MDS criteria for hematologic responses, red cell responses among 5-aza pts were CR:36%, PR:18% and among 3+7 pts were CR:68% (p=0.17 for CR rate and p=0.69 for ORR). Platelet responses among 5-aza were CR:36%, PR:18% and among 3+7 were CR:68% (p=0.17 for CR rate and p=0.69 for ORR rate). Median red cell transfusions from diagnosis were 7 units in 5-aza and 15 units in 3+7 (p=0.03). Median platelet transfusions were 4 units in 5-aza and 11 units in 3+7 (p=0.02). Bacteremia occurred in 2 of 11 (18%) 5-aza patients (3 episodes) and 17 of 22 (77%) 3+7 patients (30 episodes) (p=0.002). Patients receiving 5-aza induction spent a median of 11% of their at-risk days in the hospital compared to 33% median at-risk days for patients receiving 3+7 (p=0.12). Overall for the entire cohorts, 5-aza patients spent 213 days in hospital among 2651 at risk days (8%) versus 1229 days in hospital among 3759 at risk days (33%) (p=0.001). Conclusions: In this series of elderly (>60 year old) patients with AML, 5-azacitidine yielded similar survival outcomes compared to standard 3+7 induction and was associated with significantly less transfusional support, bacteremias, and hospital days. Although not a curative therapy, poor outcomes with standard chemotherapy in the elderly AML patient make consideration of the well tolerated outpatient 5-azacitidine therapy attractive.

A sequential nucleation and growth process has been developed to construct complex nanostructured films step‐by‐step from aqueous solutions, as reported by Liu, Voigt, and co‐workers on p. 335. This method can be applied to a wide range of materials, and can be combined with top–down techniques to create spatially resolved micropatterns. The cover figure shows images of oriented nanowires, nanoneedles, nanotubes, nanoplates and stacked columns, wagon‐wheels, hierarchical films based on wagon‐wheels, hierarchically ordered mesophase silicate, and micropatterned flower‐like structures.

Application of unrelated multi-antigen mismatched transplant is limited by a high risk of severe GvHD. Pan-T-Cell depletion successfully limits GvHD in this setting, but graft failure, early disease relapse and prolonged immunodeficiency have prevented broad use of this approach. In an attempt to limit GvHD, obtain engraftment and early disease control, we evaluated the effect of adding back 1 x 105bone marrow derived CD3+cells/kg patient body weight, following full conditioning, to a pan-T-cell depleted (Isolex, Baxter, Chicago IL) marrow graft (1 x 106CD34+cells/kg). In this pilot trial, three consecutive male patients with high risk malignancies without matched donors (disease/age: ALL-CR2/22, refractory AML/31 and CML blast crisis/55 failed imatinib) consented to receive multi-antigen mismatched unrelated marrow grafts (ALL at B/C, AML at B/DR/DQ and CML at A/DQ). Two patients (AML/CML) received transplant conditioning with busulfan/cyclophosphamide and one received TBI/cyclophosphamide (ALL). In addition, all patients received rabbit derived ATG (3 mg/kg days -3 and -2). GvHD prophylaxis included standard tacrolimus and methotrexate with prednisone (0.5 mg/kg starting day +7 tapered off by day + 90). All patients achieved neutrophils 1000/ul (days +15, 21 and 26). No patient developed detectable acute or chronic GvHD. One patient (ALL) died on day +110 in remission, from drug resistant CMV pneumonia. The other two are long term clinical disease-free survivors at 25 (CML) and 40 months (AML) with complete blood counts and differentials within the normal range. Neither survivor has experienced any serious late infection and both have undetectable EBV DNA. Immunoglobulin levels (IgG, A and M) are within the normal range for both patients except for a low IgA level (29 mg/dl) in the CML patient. At 40 months post-transplant, the AML patient is 100% female by FISH, and has normal T and B cell counts (CD3, CD8, helper/suppressor ratio, CD19) with a borderline low CD4 count(507; nl range >666cells/cu.mm). At 25 months, the CML patient has normal CD3 and CD8 counts, increasing CD4 counts (260) and improving chimerism (CD33+100% donor; CD3+33% donor). TCR Vb CDR3-size spectratype analysis of CD4 and CD8 subsets of these two patients were compared to 6 healthy donors to assess the complexity of their reconstituting T cell repertoire. Of 24 Vb families, 21–23 were resolvable revealing an overall complexity in the CD4 compartment of 91% (AML) and 82% (CML), and in the CD8 compartment 86% (AML) and 73% (CML). Limited T-cell add back at the time of unrelated multi-antigen transplant did not cause GvHD, was associated with prompt and stable engraftment and appears to facilitate comprehensive immune reconstitution. Further study is warranted.

Multi-antigen HLA mismatched transplantation is associated with a high risk of graft failure and graft-vs.-host disease (GVHD), particularly in the unrelated setting. Strategies used to overcome these barriers include high CD34+ dose and T-cell depletion respectively. However, this often results in increased relapse rates and delayed immune reconstitution. We previously reported on four patients without matched donors who were transplanted using a multi-antigen mismatched, pan T-cell depleted donor graft with limited (1x105 CD3+ cells/kg unrelated donor, 1x106 CD3+ cells/kg related donor) T-cells added back on the day of transplant. Two additional patients have been transplanted using this strategy. The results are summarized in the table below. Post-graft immunosuppression consisted of tacrolimus and prednisone with short course methotrexate. Patients who received a full myeloablative conditioning regimen demonstrated neutrophil engraftment (ANC > 500/uL) at day +15, +15, +16 and +21. One patient had secondary graft failure attributed to resistant herpes infection, and promptly recovered graft function after an additional infusion of CD34+ cells. Of the patients who received a reduced intensity conditioning regimen, one never attained neutrophil engraftment while the other had neutrophil recovery at day +32, but had secondary graft failure at day +107. None of the patients receiving an unrelated donor graft developed GVHD. Of the six patients, there are two survivors at 12 months and 29 months. Analysis of the immune reconstitution of these patients reveal persistent graft function with recovery of T-cell function with absolute CD4+ counts of 225 and 472 cells/μL respectively. Both patients remain in complete remission. In summary, limited T-cell add-back at the time of immune reconstitution in pan T-cell depleted, multi-antigen HLA mismatched grafts can result in engraftment without GVHD, adequate disease control, and immune reconstitution. However, a requirement for this effect is a fully myeloablative conditioning regimen. We postulate that the degree of immuosuppression provided by a reduced intensity conditioning regimen is not enough to overcome the host-vs.-graft reactions, resulting in graft rejection. Further study is warranted among patients requiring mismatched donor transplantation. Diagnosis Mismatch Stem Cell Source Conditioning WBC > 500 Plt >20k Complications Pt. Status Notes: BC= blast crisis, CR= complete remission, R= relapse, U= unrelated donor, R= related donor, BM= bone marrow, PBSC= peripheral blood stem cell, Bu= busulfan, CY= cyclophosphamide, ATG= rabbit ATG, Flu= fludarabine, Mel= melphalan 2° AML-CR1 B/DR/DQ U-BM Bu/CY/ATG D+14 D+104 EBV, Influenza Alive @ 19 Mo ALL-CR2 B/C U-BM TBI/CY/ATG D+21 - CMV Pneumonia Died D+110, CMV CML-BC A/DQ U-BM Bu/CY/ATG D+25 −/D+17 after CD34 boost Graft failure 2° HSV, CD34 boost D+128 Alive @ 12 Mo 2° AML-CR1 DR/DQ R-PBSC Flu/Bu/ATG D+15 D+24 GVHD gut D+40, Relapse D+118 Died D+212, relapse 2° AML-CR1 B/C U-PBSC Flu/Mel/ATG - - 1° graft failure Died D+42, graft failure AML-R1 A/C U-PBSC Flu/Mel/ATG D+32 - 2° graft failure D+107, melanoma Died D+148, graft failure

Background: Previous reports have suggested that patients with aggressive histology lymphoma who fail to respond to standard-dose salvage chemotherapy are unlikely to become long-term survivors with high-dose therapy. Thus, chemotherapy-refractory disease has traditionally been considered a contraindication for autologous transplantation. Whether the use of dose-intensified salvage chemotherapy prior to transplantation will alter outcomes is unknown. Patients and Methods: 207 patients with aggressive lymphoma (diffuse large cell B cell NHL n=137, Hodgkins Disease n=70) underwent autologous peripheral blood (n=192), bone marrow (n=7) or combined (n=8) transplantation at Hackensack University Medical Center between January 1997 and June 2004 using a regimen of BCNU 600 mg/m2, Etoposide 1600 mg/m2, Cytarabine 24 gms/m2 and Cyclophosphamide 90 mg/m2 (with dose attenuations for advanced age/poor performance status). All patients received a single cycle of DICE (Dexamethasone 160 mg, Ifosphamide 4 gm/m2, Cisplatin 100 mg/m2, Etoposide 400 mg/m2 in divided doses over 4 days) chemotherapy at the time of initial relapse. Restaging was performed and responding patients (n=142) received a second cycle of DICE prior to collection of stem cells. Patients not achieving at least a PR (>50% reduction in tumor bulk or only minimal residual for low volume disease) were considered to have chemotherapy refractory disease (n=65) and were given an intensified salvage regimen of DICEP (dose intensive Cyclophosphamide 5000 mg/m2, Etoposide 1500 mg/m2, Cisplatin 120 mg/m2 in divided doses over 3 days) prior to stem cell collection. Results: Chemotherapy refractory patients receiving dose intensified DICEP prior to autologous transplantation were able to achieve long-term survival. The 3 and 7-year Kaplan-Meier survival rates for DICEP treated refractory patients were 43% and 39%, respectively. This compares favorably, although less than, chemosensistive lymphoma patients treated with DICE salvage (3-yr: 65%, 7-yr: 52%; versus DICEP log-rank p=0.004). This difference in survival between refractory/sensitive patients held in both non-Hodgkins (refractory 3-yr: 47%, 7-yr 47%; sensitive 3-yr 61%, 7-yr: 47%; p=0.017) and Hodgkins Disease (refractory 3-yr: 48%, 7-yr: 39%; sensitive 3-yr: 74%, 7-yr: 61%; p=0.07). The most significant difference in outcomes by chemosensitivity was noted among patients with 1st relapse, with 3 and 7-year survivals of 70% and 58% in DICE sensitive and 32% and 32% in refractory patients requiring DICEP (p=0.0016). Minimal differences (p=0.36) were noted in Primary Induction Failure patients (7 yr survivals of 47% in both). Early (<100 day) all-cause mortality was similar among refractory (21.5%) and sensitive (14%; z=1.15; p=0.25) patients, although early relapse death rates trended higher in the refractory patients (15% vs 7%; z=1.63; p=0.10). Conclusions: Aggressive histology lymphoma patients not responding to standard-dose DICE salvage therapy may become long-term survivors with DICEP salvage followed by autologous transplantation, although outcomes are slightly inferior. A risk adapted strategy of dose intensified salvage in refractory lymphomas should be considered and transplant offered to chemotherapy refractory patients.

Autologous transplant has emerged as the standard of care for the treatment of relapsed B-cell non-Hodgkin’s lymphomas (NHL). However, for the treatment of T-cell NHL, the role is not as clear. We report our experience with 24 patients with T-cell NHL who underwent autologous transplantation at time of first relapse. Lymphoma types were varied (peripheral T-cell = 8, lymphoblastic = 6, anaplastic large cell = 5, not otherwise specified = 5). All patients received CHOP as primary therapy, except one patient who received ProMACE/CytaBOM, one who received Stanford V, and two who received HyperCVAD. Patients had either relapsed disease (14 patients) or primary refractory disease (9 patients). One patient underwent autologous transplant as consolidation therapy. Mobilization regimens varied, consisting of dexamethasone, ifosphamide, etoposide, and cisplatin (DICE, 12 patients), dose intensive cyclophosphamide, etoposide, cisplatin (DICEP, 5 patients), cyclophosphamide/etoposide (3 patients), cyclophosphamide (2 patients), or other regimens (2 patients). Adequate collection of stem cells was seen in all but one case, which required bone marrow collection. The conditioning regimen used was BVAC (BCNU 600 mg/m2, etoposide 1600 mg/m2, cytarabine 24 g/m2, and cyclophosphamide 90 mg/kg) in 23 patients. One patient received melphalan conditioning. For the entire group, the overall survival at 3 years was 50%. This compares favorably with 336 relapsed B-cell NHL patients who underwent autologous transplant with the identical conditioning regimen (BVAC) in the same period of time (OS = 52%). At 5 years, the overall survival of the B-cell lymphoma group was stable at 49%. However, the overall survival for the T-cell NHL group declined to 30%. The primary cause of death post transplant was disease relapse. When divided among specific lymphoma subtypes, 3 of 8 patients with peripheral T-cell lymphoma, 4 of 5 patients with anaplastic large cell lymphoma, 3 of 6 patients with lymphoblastic lymphoma and 3 of 5 patients with other T-cell lymphoma subtypes remain alive. Although there are too few patients to draw any definite conclusions, it appears that autologous stem cell transplant for relapsed or refractory T-cell NHL results in similar 3-year overall survivals when compared to B-cell NHL using the same conditioning regimen. However, T-cell NHL appear to be associated with a higher late relapse rate which is reflected in the lower overall survivals at 5 years. Although there may be a benefit to autologous transplant in relapsed anaplastic large cell lymphomas, relapsed/refractory T-cell NHL had inferior long term overall survival compared to their B-cell counterpart transplanted with the same regimen. Novel approaches should be considered in the treatment of relapsed or refractory T-cell NHL.

The dichloroalkyl‐Cr complexes (I) react with Tl cyclopentadienide to give the chloride‐bridged dimers (II).

The prognostic value of tumor proliferative indices in meningiomas was assessed by mitotic counts and by immunocytochemistry using a monoclonal antibody against the proliferating cell nuclear antigen (PCNA) (clone 19A2), a 36-kd nuclear protein involved in DNA synthesis. Sixty-three intracranial meningiomas were classified as benign (26), with atypical features (24) or as malignant (13). The patients included 24 men and 39 women, mean age 54.2 ± 1.7 (mean ± SEM) (range 15–78) at initial presentation. Twenty-four of the 63 primary tumors recurred locally, including 23.1% (6/26) of the benign, 37.5% (9/24) of the atypical, and 69.2% (9/13) of the malignant meningiomas. Among tumors that recurred, 1/9 (11%) of the atypical and 5/9 (55.5%) of the malignant tumors had had macroscopical total excision at the initial surgery. The mean interval to recurrence was 52 ± 11.8 months. The mean progression-free follow-up period for patients without tumor recurrence was 82 ± 8.5 months. Analysis of variance revealed that significant differences existed between tumor grades for both PCNA indices (1.16 ± 0.29% for benign; 14.14 ± 2.07% for atypical and 21.37 ± 5.47% for malignant) and mitotic indices (total counts per ten high power fields) (0.08 ± 0.05 for benign, 4.75 ± 0.91 for atypical and 19.00 ± 4.07 for malignant). Multivariate regression analysis indicated that mitotic index >6 was the single most important factor (p < 0.05) for shorter disease-free interval. Age, sex and total surgical excision were not significant factors. PCNA index was a significant factor in the univariate model, but not in the multivariate model. However, a two-factor-interaction model with PCNA >5% and mitoses >6 was highly significant as a predictor of outcome (p < 0.0001). We conclude that PCNA index may be used as an adjunct with mitotic counts in predicting the clinical course of patients with meningiomas.

The effects of hypoglycemia on cerebrovascular permeability to a protein, horseradish peroxidase (HRP), were studied in mice given 3 or 8 units of crystalline zinc insulin intraperitoneally. HRP (10 mg in 0.1 ml saline) was injected intravenously 15 to 20 minutes prior to sacrifice. Both mildly and severely hypoglycemic groups of mice showed a drastic reduction in the normal transit of HRP across cerebral arterioles. The number of normally-stained vessel segments and of HRP-filled endothelial vesicles decreased in insulin-treated mice. In the brains of severely hypoglycemic mice, however, increased parenchymal HRP accumulation occurred. A ruptured blood vessel was found in the center of one-fourth of the focal exudates examined. Electron microscopic examination revealed thrombi, sometimes extending through the vessel wall, and hemorrhage, yet inter-endothelial tight junctions remained intact. Seizures were associated with severe hypoglycemia in 6 out of 10 mice with serum glucose levels below 40 mg/100 ml following 8 units of insulin, but the number of focal exudates per brain was similar in all 10 mice. We conclude that insulin-induced hypoglycemia is associated with decreased HRP transit across cerebral arterioles, and that severe insulin shock is also accompanied by actual rupture of vessel walls and extravasation of blood and HRP into the parenchyma of the brain.

The grading of glial tumors has traditionally relied on histological assessment, but the distinction between grade II and grade III gliomas is still a subject of debate. We examined the value of the monoclonal antibody MIB-1 (Ki-67) labeling index (LI) in the differentiation between grade II and grade III gliomas by either the 1993 WHO grading scheme or the St. Anne-Mayo grading scale. The MIB-1 LI in the most densely labeled areas from 80 diffuse cerebral hemispheric gliomas was determined. The tumors included 16 grade II, 31 grade III and 33 grade IV gliomas by the WHO scale. The mean LIs (%) were 0.88 ± 0.29 for grade II, 8.75 ± 1.71 for grade III, and 9.12 ± 1.55 for grade IV gliomas. Analysis of variance indicated a significant difference in mean LIs between grades II and III and grades II and IV (p :≤ 0.0001), but not between grades III and IV. Seven tumors were classified differently by the 2 systems (grade III by WHO, but grade 2 by St. Anne-Mayo), and all had MIB-1 LI over 3%. Univariate analysis showed that MIB-1 LI with a cut-off point at 1.5% was a significant prognostic factor (p ≤ 0.0005). High tumor grade (WHO, p ≤ 0.0002; St. Anne-Mayo, p ≤ 0.0006) and patient age >50 (p ≤ 0.0001) were also significant factors for shorter survival. Using Cox Regression Multivariate Analysis, MIB-1 LI>1.5% was a significant independent predictor of shorter disease survival when paired with tumor grade (p :≤ 0.032), patient age (p ≤ 0.0065), or gender (p ≤ 0.0007). We conclude that the MIB-1 immunoreactivity is useful in distinguishing grade II from grade III gliomas, and maybe more sensitive in assigning aggressive gliomas to grade III than the St. Anne-Mayo grading system.

The tin-substituted superconducting system DyBa2Cu3-3xSn3xOywas investigated from x=0.025 to x=0.4 by measurements of electrical resistivity and ac susceptibility, X-ray diffraction, and Mössbauer spectroscopy. It was found that the substitution of Cu by Sn does not affect the zero-resistance temperature until x?0.25 and results in the presence of a second phase. An anomaly in the temperature dependence of the Mössbauer recoil-free fraction near 70 K was observed for the sample with nominal composition DyBa2Sn3Oy.

Stable and reproducible superconductivity in the Tl(Ba2-xLax)CuO5-?(0.0?x?0.6) system with the tetragonal TlBa2CuO5-?-type (1021) structure was reported. A Prototype compound TlBa2CuO5-?had shown a metastable superconducting onset around 25 K, with zero resistivity at 10 K. With partial substitution of La for Ba ions, Tc(50% resistivity drop) increases to 45 K, Tc0(zero resistivity) to 42 K and onset around 50 K. A diamagnetic signal was observed with onset as high as 57 K. Tetragonal lattice parameters decrease with the increasing La concentration due to the partial replacement of larger Ba2+ions by smaller La3+ions. The Pairing field energy of 170 K and electron-elementary excitation coupling constant ? of 0.76 were derived from the BCS-like Tcformula through comparison with other single Tl-O layer systems TlCan-1Ba2CunO2n+3-?.