Internal medicine

Simultaneous optical absorption and laser-induced fluorescence measurements have been used to map the three-dimensional number densities of ground-state ions and neutrals within a low-temperature KrF laser-produced magnesium plasma expanding into vacuum. Data is reported for the symmetry plane of the plasma, which includes the laser interaction point at a delay of 1 ms after the ; 30 ns KrF laser ablation pulse and for a laser fluence of 2 J cm y2 on target. The number density distributions of ion and neutral species within this plane indicate that two distinct regions exist within the plume; one is a fast component containing ions and neutrals at maximum densities of ; 3 = 10 13 cm y3 and ; 4 = 10 12 cm y3 , respectively and the second is a high-density region containing slow neutral species, at densities up to ; 1 = 10 15 cm y3 . q 1998 Elsevier Science B.V.

Autologous stem cell transplantation (ASCT) for primary systemic amyloidosis (AL) produces high hematologic and organ responses. However, treatment-related mortality remains high and reported series are subject to selection bias. In all, 48 of 80 amyloid patients referred to our center had AL in the absence of myeloma, 26 of these 48 were deemed transplant candidates and 20 actually underwent ASCT. Transplant-related mortality has fallen from 50 to 20% since January 1999 due to better patient selection and prophylactic measures. Intent-to-treat organ responses were renal (46%), cardiac (25%) and liver (50%). Organ responses in patients who survived transplantation were renal (75%), cardiac (40%) and liver (100%). The 3-year OS post-ASCT was 56% with improved outcome predicted by a better performance status (P ¼ 0.08), normal ALP (P ¼ 0.08), nephrotic syndrome (P ¼ 0.01) and the absence of severe hypotension (P ¼ 0.01). The 3-year OS for all referred patients was 44% and this was not significantly better for transplant candidates. Patients with significant hypotension (systolic blood pressure p90 mmHg) or poor performance status (ECOG 42) have an exceedingly high treatment-related mortality and should not be transplanted. For those undergoing ASCT, organ response rates appear promising, but conclusive evidence of improved survival for this select group of patients is still lacking and will require randomized trials.

disease characteristics at diagnosis were as follows (no. of patients): male (22), female (11), median age 56 years (range 39 -70), Stage II (9), Stage III (24), IgG (22), IgA (9), free light chain (2). Median paraprotein at initiation of consolidation was 0 (range 0 -3.6) (n ϭ 33), day 1 cycle 4 was 0.1 (range 0 -2.1) (n ϭ 23), and at end of study was 0.35 (range 0 -3.4) (n ϭ 20). With a median follow up of 14 months, disease progression has occurred in 5 patients with 1 death. Fourteen patients (42%) experienced reactivation of VZV, 2 patients had human herpes virus 6 reactivation, and 1 patient had oral herpes simplex virus reactivation, all requiring therapy. The median absolute lymphocyte count at the onset of viral reactivation was 1336/mcl (range ϭ 600 -4800/mcl). A significant difference was seen in the mean CD8 count just prior to transplantation between those patients with viral reactivation (243, range 77-685) and the rest of the study population (392, range 87-1339) (P ϭ .03). The median time from enrollment to VZV reactivation was 189 days (range 25-375). Ten patients had grade 1/2 and none had grade 3/4 neuropathy at study enrollment. At initiation of post transplant bortezomib 21 (64%) had grade 1/2 neuropathy and 1 (3%) had grade 3/4 neuropathy. Treatment emergent neuropathy on once weekly bortezomib was seen in only 3 patients (9%), necessitating dose reduction (1 patient) or discontinuation of therapy (2 patients). No grade 3/4 thrombocytopenia or neutropenia was observed with consolidation bortezomib. We conclude that bortezomib when administered pre-and post HDCT in MM patients results in a very high rate of viral reactivation. This finding may be explained by a decrease in circulating CD8 T cells and has implications for future clinical trials of bortezomib in this setting.

disease characteristics at diagnosis were as follows (no. of patients): male (22), female (11), median age 56 years (range 39 -70), Stage II (9), Stage III (24), IgG (22), IgA (9), free light chain (2). Median paraprotein at initiation of consolidation was 0 (range 0 -3.6) (n ϭ 33), day 1 cycle 4 was 0.1 (range 0 -2.1) (n ϭ 23), and at end of study was 0.35 (range 0 -3.4) (n ϭ 20). With a median follow up of 14 months, disease progression has occurred in 5 patients with 1 death. Fourteen patients (42%) experienced reactivation of VZV, 2 patients had human herpes virus 6 reactivation, and 1 patient had oral herpes simplex virus reactivation, all requiring therapy. The median absolute lymphocyte count at the onset of viral reactivation was 1336/mcl (range ϭ 600 -4800/mcl). A significant difference was seen in the mean CD8 count just prior to transplantation between those patients with viral reactivation (243, range 77-685) and the rest of the study population (392, range 87-1339) (P ϭ .03). The median time from enrollment to VZV reactivation was 189 days (range 25-375). Ten patients had grade 1/2 and none had grade 3/4 neuropathy at study enrollment. At initiation of post transplant bortezomib 21 (64%) had grade 1/2 neuropathy and 1 (3%) had grade 3/4 neuropathy. Treatment emergent neuropathy on once weekly bortezomib was seen in only 3 patients (9%), necessitating dose reduction (1 patient) or discontinuation of therapy (2 patients). No grade 3/4 thrombocytopenia or neutropenia was observed with consolidation bortezomib. We conclude that bortezomib when administered pre-and post HDCT in MM patients results in a very high rate of viral reactivation. This finding may be explained by a decrease in circulating CD8 T cells and has implications for future clinical trials of bortezomib in this setting.

patients received autologous hematopoietic cell transplants (AHCT) at Canada's largest transplant center. In this retrospective cohort study of AHCT patients admitted to the intensive care unit (ICU), we describe the outcomes following ICU admission and the variables measured in the first 24 h of ICU admission associated with overall ICU mortality. Results indicate a 3.3% ICU admission rate (n ¼ 34) with 13 deaths (1% overall mortality rate, 38% in ICU mortality rate). The worst outcome was in AL amyloid patients of whom 28% were admitted to the ICU, with an ICU mortality rate of 55%. The Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation (APACHE II) score in the first 24 h were statistically associated with mortality by univariate analysis. Other variables measured at 24 h and associated with ICU mortality included multiorgan failure, mechanical ventilation, inotropic support 44 h and Gram-negative sepsis. Our data indicate that ICU admission in the autotransplant population is rare and that it is influenced by underlying diagnosis, with AL amyloid patients having the highest risk. Our observations may assist clinical decision-making regarding the continuation of intensive care delivered 24 h after ICU admission.

The use of high-dose chemotherapy and autologous stem-cell transplantation in patients with relapsed Hodgkin's lymphoma is supported by two randomized clinical trials but its benefit in patients with primary refractory disease is less clear. Aiming to shed light on this issue, we analyzed and compared the outcomes of patients with relapsed or refractory Hodgkin's lymphoma treated with second-line chemotherapy and planned autologous stem-cell transplantation.

CD28 is required for the development of regulatory T cells (Tregs, CD41CD251Foxp31) in the thymus and also contributes to their survival and homeostasis in the periphery. We studied whether and how CD28 and ICOS control the differentiation of Tregs from naive T cells. By using WT, CD28-, ICOS-or CD28/ICOS-knockout mice on C57BL/6 background as T-cell sources, we found that CD28 is essential, while ICOS is dispensable, for the development and homeostasis of Tregs as well as for the generation of Tregs from naive CD41CD25-T cells in vivo. The requirement of CD28 for Treg differentiation was mediated by IL-2, because neutralization of IL-2 with its specific mAb blocked Treg differentiation from wild-type CD41CD25-T cells and addition of IL-2 restored Treg differentiation from CD28-/-T cells. Other common g-chain cytokines, IL-4, IL-7 or IL-15, do not share such a role of IL-2. However, a strong CD28-signal promotes expansion of T effector cells (CD251Foxp3-) while inhibiting differentiation of Tregs. Our study demonstrates that CD28 delicately controls the process of Treg differentiation and T effector cell expansion in the periphery, which provides the ''fine-tuning'' of the balance between immune activation and suppression.

Bacterial contamination of bone marrow or peripheral blood stem cell transplant products typically occurs with skin flora or, rarely, gram-negative organisms. We describe a clonal outbreak of contamination in transplant products caused by contamination with an aerobic actinomycete that occurred at our institution during the summer of 2001. From 1 July through 12 September 2001, 73 peripheral blood or bone marrow stem cell products were obtained from 39 patients, and 34 products were found to be contaminated with the outbreak strain. Fourteen patients were reinfused with contaminated cells, and the outbreak strain was isolated from the blood cultures for one patient. Investigation revealed multiple potential sources for contamination during the product cryopreservation process. The outbreak of contamination was aborted upon modification of the cryopreservation process.

Our purpose was to assess efficacy and toxicity of highdose chemotherapy (HDCT) and ASCT in patients with relapsed and refractory Hodgkin's lymphoma (HL) aged 60 years and older and compare the results with a group of younger HL patients treated in a similar manner. We identified 15 consecutive patients, with HL aged 60 years and older who underwent HDCT (etoposide 60 mg/kg þ melphalan 160 mg/m 2 ) and ASCT at our institution from May 2001 to March 2008. The results were compared with a cohort of 157 younger HL patients treated in a similar manner from January 1999 to December 2006. After a median follow-up of 2.5 years, PFS at 3 years after ASCT was 73% (95% confidence interval (CI) 37-90) for the older group and 56% (95% CI 46-64) for the younger group (P ¼ 0.45); OS after ASCT was 88% (95% CI 39-98) for the older group and 84% (95% CI 75-90) for the younger group (P ¼ 0.80). No transplantrelated deaths were seen. Our study suggests that ASCT is feasible for selected elderly patients with HL, giving similar results to younger patients in terms of survival and toxicity.

disease characteristics at diagnosis were as follows (no. of patients): male (22), female (11), median age 56 years (range 39-70), Stage II (9), Stage III (24), IgG (22), IgA (9), free light chain (2). Median paraprotein at initiation of consolidation was 0 (range 0-3.6) (n ϭ 33), day 1 cycle 4 was 0.1 (range 0-2.1) (n ϭ 23), and at end of study was 0.35 (range 0-3.4) (n ϭ 20). With a median follow up of 14 months, disease progression has occurred in 5 patients with 1 death. Fourteen patients (42%) experienced reactivation of VZV, 2 patients had human herpes virus 6 reactivation, and 1 patient had oral herpes simplex virus reactivation, all requiring therapy. The median absolute lymphocyte count at the onset of viral reactivation was 1336/mcl (range ϭ 600-4800/mcl). A significant difference was seen in the mean CD8 count just prior to transplantation between those patients with viral reactivation (243, range 77-685) and the rest of the study population (392, range 87-1339) (P ϭ .03). The median time from enrollment to VZV reactivation was 189 days (range 25-375). Ten patients had grade 1/2 and none had grade 3/4 neuropathy at study enrollment. At initiation of post transplant bortezomib 21 (64%) had grade 1/2 neuropathy and 1 (3%) had grade 3/4 neuropathy. Treatment emergent neuropathy on once weekly bortezomib was seen in only 3 patients (9%), necessitating dose reduction (1 patient) or discontinuation of therapy (2 patients). No grade 3/4 thrombocytopenia or neutropenia was observed with consolidation bortezomib. We conclude that bortezomib when administered pre-and post HDCT in MM patients results in a very high rate of viral reactivation. This finding may be explained by a decrease in circulating CD8 T cells and has implications for future clinical trials of bortezomib in this setting.

CD28 is required for the development of regulatory T cells (Tregs, CD41CD251Foxp31) in the thymus and also contributes to their survival and homeostasis in the periphery. We studied whether and how CD28 and ICOS control the differentiation of Tregs from naive T cells. By using WT, CD28-, ICOS-or CD28/ICOS-knockout mice on C57BL/6 background as T-cell sources, we found that CD28 is essential, while ICOS is dispensable, for the development and homeostasis of Tregs as well as for the generation of Tregs from naive CD41CD25-T cells in vivo. The requirement of CD28 for Treg differentiation was mediated by IL-2, because neutralization of IL-2 with its specific mAb blocked Treg differentiation from wild-type CD41CD25-T cells and addition of IL-2 restored Treg differentiation from CD28-/-T cells. Other common g-chain cytokines, IL-4, IL-7 or IL-15, do not share such a role of IL-2. However, a strong CD28-signal promotes expansion of T effector cells (CD251Foxp3-) while inhibiting differentiation of Tregs. Our study demonstrates that CD28 delicately controls the process of Treg differentiation and T effector cell expansion in the periphery, which provides the ''fine-tuning'' of the balance between immune activation and suppression.

Autologous stem cell transplantation (ASCT) for primary systemic amyloidosis (AL) produces high hematologic and organ responses. However, treatment-related mortality remains high and reported series are subject to selection bias. In all, 48 of 80 amyloid patients referred to our center had AL in the absence of myeloma, 26 of these 48 were deemed transplant candidates and 20 actually underwent ASCT. Transplant-related mortality has fallen from 50 to 20% since January 1999 due to better patient selection and prophylactic measures. Intent-to-treat organ responses were renal (46%), cardiac (25%) and liver (50%). Organ responses in patients who survived transplantation were renal (75%), cardiac (40%) and liver (100%). The 3-year OS post-ASCT was 56% with improved outcome predicted by a better performance status (P ¼ 0.08), normal ALP (P ¼ 0.08), nephrotic syndrome (P ¼ 0.01) and the absence of severe hypotension (P ¼ 0.01). The 3-year OS for all referred patients was 44% and this was not significantly better for transplant candidates. Patients with significant hypotension (systolic blood pressure p90 mmHg) or poor performance status (ECOG 42) have an exceedingly high treatment-related mortality and should not be transplanted. For those undergoing ASCT, organ response rates appear promising, but conclusive evidence of improved survival for this select group of patients is still lacking and will require randomized trials.

patients received autologous hematopoietic cell transplants (AHCT) at Canada's largest transplant center. In this retrospective cohort study of AHCT patients admitted to the intensive care unit (ICU), we describe the outcomes following ICU admission and the variables measured in the first 24 h of ICU admission associated with overall ICU mortality. Results indicate a 3.3% ICU admission rate (n ¼ 34) with 13 deaths (1% overall mortality rate, 38% in ICU mortality rate). The worst outcome was in AL amyloid patients of whom 28% were admitted to the ICU, with an ICU mortality rate of 55%. The Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation (APACHE II) score in the first 24 h were statistically associated with mortality by univariate analysis. Other variables measured at 24 h and associated with ICU mortality included multiorgan failure, mechanical ventilation, inotropic support 44 h and Gram-negative sepsis. Our data indicate that ICU admission in the autotransplant population is rare and that it is influenced by underlying diagnosis, with AL amyloid patients having the highest risk. Our observations may assist clinical decision-making regarding the continuation of intensive care delivered 24 h after ICU admission.

Prospective population-based surveillance to assess the epidemiology of invasive pneumococcal disease (IPD) in hematopoietic stem cell transplant (HSCT) patients is limited and a comparison to the general population is lacking. By using a population-based Invasive Bacterial Diseases Network surveillance program, we studied the incidence, clinical significance, serotypes and antimicrobial resistance of IPD in a large cohort of adult HSCT patients and the general population. Streptococcus pneumoniae isolates and patient data were collected prospectively from 1995 to 2004. We identified 14 cases of IPD (based on sterile site isolates) in our HSCT population over a 10-year period. This translated to an incidence rate of 347 infections per 100 000 persons per year. This compared to an incidence of 11.5 per 100 000 persons per year in the general population (regression ratio ¼ 30.2; 95% confidence interval (CI) 17.8-50.8, Po0.00001). If nonsterile site isolates (respiratory tract) were included, the incidence rate in transplant patients was 446 per 100 000 persons per year. Serotypes 23F and 6B were most common; 100 and 69.2% of isolates were a serotype included in the pneumococcal polysaccharide and conjugate vaccines, respectively. The antimicrobial resistance rates were high, especially for trimethoprim/ sulfamethoxazole. HSCT recipients are at significantly greater risk for IPD than the general population. Preventative strategies are necessary.