Intracoronary acetylcholine produces endothelium-dependent dilation of normal coronary arteries and paradoxical constriction of atherosclerotic vessels. Regional differences in endothelium-dependent vasomotion, however, have not been studied in relation to the nonuniform development of atherosclerosis. We compared the vasomotor response to increasing doses of acetylcholine of angiographically smooth coronary artery segments prone to atherosclerosis (coronary branch points) with segments remote from branch points (straight segments). In patients with entirely smooth coronary arteries and a dilator response to acetylcholine (group 1, n=7), branch points and straight segments demonstrated equal and significant dosedependent dilation to acetylcholine (14.7±8.9%o and 12.3±12.7%, respectively; p_NS). In patients with early atherosclerosis as manifest by luminal coronary irregularities, the lowest dose of acetylcholine (10-8 M) produced constriction at branch points and slight dilation at straight segments (-6.3 ±7.4% vs. +2.2+7.3%, p <0.05). At higher doses of acetylcholine, both branch point and straight segments constricted, but constriction remained more pronounced at branch points. Both branch point and straight segments, however, retained the ability to dilate to the non-endothelium-dependent agent, nitroglycerin. In a third group of patients with angiographically entirely smooth coronary arteries but without dilation to acetylcholine, constriction to acetylcholine again occurred first at branch points. Thus, coronary branch points demonstrate increased sensitivity to acetylcholine-induced constriction in patients with angiographic evidence of early coronary atherosclerosis and in middle-aged patients with smooth coronary arteries. These segments, however, retain the ability to dilate to nitroglycerin.Whether this early evidence of defective endothelium-dependent vasodilation predicts the later development of occlusive atherosclerosis is not yet known. (Circulation 1990;82:1169-1173 C oronary atherosclerosis has a long asymptomatic phase of development,1'2 and only the later phases, particularly segmental narrowing and stenosis, can be assessed by coronary arteriography. Furthermore, atherosclerosis is a focal disease with specific sites of predilection that include branch points and other regions of disturbed flow.3 Experimental studies suggest that alterations in local arterial wall shear stress produce morphological changes in the vascular endothelium that may play a central role in atherogenesis.4-6

Summary:We report a series of 37 consecutive patients with multiple myeloma (MM) who received an allograft between 1990 and 2000 at our institution. Median age was 47 years, and nearly 70% of patients were Durie-Salmon stage III. A median of five cycles of chemotherapy were given before transplant, with a median interval between diagnosis and transplant of 9.3 months. We report a nonrelapse mortality rate of 22% with a median followup period of 40 months, whereas complete remission (CR) rate at 12 months is estimated at 57%. Treatment failure rate and overall survival at 40 months are estimated at 52% and 32%, respectively. The number of chemotherapy cycles prior to allotransplantation achieved borderline statistical significance as a poor prognosis factor for overall survival (P ‫؍‬ 0.05), while the presence of chronic graft-versus-host disease (cGVHD) was significantly correlated with CR achievement (P ‫؍‬ 0.036). Our study confirms that early allografting in MM can yield toxicity rates significantly lower than those associated with historical cohorts, and supports the hypothesis that cumulative chemotoxicity has a negative influence on mortality and survival rates. More importantly, our study clearly demonstrates an association between cGVHD and CR and brings further evidence in favor of a graft-versus-myeloma effect. Bone Marrow Transplantation (2001) 28, 841-848.

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512 Delayed immune reconstitution following intensive T cell depletion of the stem cell graft is the main complication limiting broad utilization of haplo-mismatched donors for stem cell transplantion (SCT). Indeed, it results in frequent and rapidly lethal infectious events. The ability to accelerate immune reconstitution following haplo-SCT would provide a unique opportunity to transplant the large number of patients who cannot find an HLA-matched donor. We present results of our Phase I clinical trial of haploidentical allogeneic SCT followed by an “add-back of donor T cells to accelerate immune reconstitution” (ATIR). This donor lymphocyte infusion (DLI) underwent photodynamic depletion (PD) of host-reactive T cells using dibromorhodamine as photosensitizer (Kiadis Pharma). Nineteen patients (11 M, 8 F) with very high-risk hematologic malignancies (mostly refractory or relapsed acute myeloid leukemia (10) and myelodysplastic syndromes (4), and refractory ALL (1), CLL (2), CML (1) and NHL (1)) entered the trial. Median age at SCT was 54 years (range: 19-62). HLA compatibility was 3/6 in 6 pts, 4/6 in 12 pts and 5/6 (DR mismatch) in 1 pt. Increasing doses of PD-treated donor cells (ATIR: 1×104 to 5.0 ×106 CD3+ cells/kg) were administered on day 34±6 after transplant. In the ATIR, greater than 95% of CD4+CD25+ and CD8+CD25+ T cells as well as anti-host cytotoxic T lymphocyte precursors (CTLp) were depleted from DLIs. All stem cell grafts underwent in vitro immunomagnetic T cell depletion using CD34+ positive cell selection (Miltenyi). The myeloablative regimen consisted of TBI (1200 cGy), thiotepa (5 mg/kg) and fludarabine (200 mg/m2). No GVHD prophylaxis was administered. All patients showed complete donor chimerism and durable hematologic engraftment. Five patients developed grade II GVHD affecting skin (n = 5 pts), liver (2 pts) and gastrointestinal tract (1 pt) at a median of 101 days post-SCT. No patient developed grade III-IV acute GVHD. Chronic GVHD developed in 9 pts, mostly in those receiving higher T cell doses. Treatment of acute and chronic GVHD involved steroids, tacrolimus and mycophenolate mofetil in 3 patients, steroids and tacrolimus in 3 pts, and steroids only in 3 pts. GVHD responded rapidly to treatment since the median duration of total immunosuppressive therapy in each patient was 187 days (range: 61-319 d). All 7 patients in cohorts 1-3, who received 1.3×105 or less CD3+ cells/kg, developed infectious complications (100% of pts), with 5 lethal episodes in these 7 pts. In sharp contrast, only 6 (50%) of the following 12 patients (cohorts 4-7) receiving ATIR with the highest CD3+ cell doses (3.2×105 to 5.0×106 CD3+ cells/kg) developed infections (p <0.05), none resulting in a fatal event (p<0.001). Interestingly, CD3 lymphocytes recovered earlier in the last 2 cohorts (6 and 7) receiving 2-5×106 CD3+ cells/kg than in the first 5 cohorts (7.9×105 or less CD3+ cells/kg) (p<0.01). Eight patients died: 4 of relapsed leukemia (3 AML; 1 ALL) and 4 of infections. Overall treatment related mortality (TRM) is 27% at 2 years post-SCT, with a TRM of 0% in patients receiving the highest CD3+ cell doses (cohorts 4-7). The overall survival is 60% at 2 years (median f-up: 12.1 mo; 95% confidence interval at 2 years: 37-83%). The 12 patients in cohorts 4-7 receiving the higher CD3+ cell doses had an improved survival (82% at 2 yrs) over the 7 patients in cohorts 1-3 administered a lower CD3+ cell dose (14% at 2 yrs) (p<0.05). Our results indicate that the post-transplant infusion of an ATIR-PD treated DLI is feasible, results in accelerated T cell reconstitution, and decreases the incidence and severity of infections without inducing severe GVHD. These results suggest a clinical benefit for patients receiving the highest ATIR doses and form the basis of an international pivotal clinical trial to decrease TRM in patients undergoing haploidentical stem cell transplantation. Disclosures: Roy: Kiadis Pharma: Research Funding. Egeler:Kiadis Pharma: Employment.

Summary:Autopsy series have revealed patterns of injury in graftversus-host disease and provided insight into infectious and toxic complications following hematopoietic stem cell transplantation (HSCT). Overall autopsy rates have declined significantly in recent decades including specialized services such as neonatal medicine and cardiac care. However, rates of post-mortem exams at HSCT centers have not been specifically documented. We reviewed hospital records between 1992 and 2002 to determine overall autopsy rates at our hospital and within the HSCT program. Although the overall autopsy rate declined steadily from 24% in 1992 to 9% in 2002, rates of postmortem exams in the HSCT program remained relatively stable at 32% (24-46%). Autopsy rates were not significantly different for recipients of allogeneic vs autologous transplants and no clear difference was observed for the proportion of autopsies requested on weekdays compared with weekends. Autopsies confirmed major clinical diagnoses and/or suspected causes of death in 45 of 61 autopsies (74%) and yielded major or minor disagreements in clinical diagnosis in 10 cases (16%) and seven cases (11%), respectively. The preservation of high rates of autopsy within our HSCT program demonstrates that specialized programs are able to maintain elevated rates of post-mortem examinations despite overall declining rates. Bone Marrow Transplantation (2005) 35, 781-785.

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