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1.  Verbal Feedback in Therapeutic Communities: Pull-ups and Reciprocated Pull-ups as Predictors of Graduation 
The most important proximal outcomes for residents of therapeutic communities (TCs) are retention and successful completion of the program. At this point there has been no quantitative analysis of the relationship between the exchange of corrective reminders, or pull-ups, between peers in TCs and graduation. This study draws on a database of pull-ups exchanged between 5,464 residents of three Midwestern TCs. Residents who send more pull-ups to peers and who reciprocate pull-ups with a larger percentage of peers are more likely to graduate. Residents who receive more pull-ups from peers and staff and a larger percentage of whose peers reciprocate pull-ups that they send are less likely to graduate. Implications of these findings for program theory and program improvement are discussed.
PMCID: PMC3556212  PMID: 23068980
Therapeutic Communities; Retention; Graduation; Social Network Analysis; Corrections
2.  Improved non-relapse mortality and infection rate with lower dose of antithymocyte globulin in patients undergoing reduced intensity conditioning allogeneic transplantation for hematologic malignancies 
We sought to reduce the risk of infectious complications and non-relapse mortality (NRM) associated with the use of antithymocyte globulin (ATG) without compromising control of acute graft-versus-host disease (GVHD) in patients undergoing reduced intensity conditioning (RIC) transplantation.
As part of an ongoing quality improvement effort, we lowered the dose of rabbit ATG from 7.5 mg/kg of ATG (R-ATG) (n=39) to 6.0 mg/kg of ATG (r-ATG) (n=33) in association with fludarabine and busulfan RIC transplantation and then monitored patients for adverse events, relapse, and survival.
Of the 72 mostly high risk (82%) patients studied, 89% received unrelated donor allografts, 25% of which were HLA-mismatched. No differences in post-transplantation full donor-cell chimerism rates were observed between the two ATG-dose groups (p>0.05). When R-ATG vs. r-ATG patients were compared, we observed no significant difference in the cumulative incidence of grade II–IV acute GVHD (32% vs. 27%; p-=0.73) or grade III–IV acute GVHD (23% vs. 11%; p=0.28). However, the r-ATG group had significantly less CMV reactivation (64% vs. 30%; p=0.005) and bacterial infections (56% vs. 18%; p=0.001), a better 1-year cumulative incidence of NRM (18% vs. 3%; p=0.03) and a trend for better 1-year overall survival (64% vs. 84%; p=0.07) compared to R-ATG patients.
A seemingly modest reduction in the dose of rabbit ATG did not compromise control of acute GVHD or achievement of donor chimerism but led to a significant decrease in the risk of serious infections and NRM in high risk RIC allograft recipients.
PMCID: PMC3953136  PMID: 19822302
Fludarabine; busulfan; thymoglobulin; antithymocyte globulin; allogeneic stem cell transplantation; graft-versus-host disease
3.  Autoantibodies in chronic idiopathic urticaria and nonurticarial systemic autoimmune disorders 
Chronic idiopathic urticaria (CU) has been associated with other autoimmune diseases and basophil-activating autoantibodies to FcεRI or IgE. It is unknown whether patients with systemic-autoimmune diseases have a similar prevalence of these autoantibodies.
To compare the prevalences of basophil-activating autoantibodies (elevated CU Index) in patients with CU, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Clinical characteristics and laboratory studies were examined for an association with the CU Index.
Adult patients, 27 with CU, 27 with RA, and 26 with SLE, and 20 healthy controls were compared on the basis of the CU Index panel, anti-IgE, and antithyroid antibodies.
The CU Index values were significantly higher in the CU group when compared with the RA group but not when compared with the SLE group. 33% of CU, 23% of SLE, 3.7% of RA, and 15% of controls had apositive CU Index. Elevated antithyroid antibody levels did not correlate with a positive CU Index in any of the groups. An elevated CU Index in the SLE group was not associated with age, sex, ethnicity, disease severity, or history of atopy.
The CU Index values were elevated in patients with CU and SLE. The presence of these autoantibodies did not correlate with disease activity or presence of thyroid antibodies. Functional autoantibodies may not be specific for chronic idiopathic urticaria, and their role in nonurticarial systemic autoimmune diseases requires further investigation.
PMCID: PMC3901433  PMID: 23244655
4.  Short-Run Prosocial Behavior in Response to Receiving Corrections and Affirmations in Three Therapeutic Communities 
Therapeutic communities (TC s) have a strong record of maintaining a high quality social climate on prison units. One possible reason for this is the system of mutual monitoring among TC residents, based on the assumption that peer affirmation of behavior in accord with TC norms and peer correction of behavior contrary to TC norms will lead to increased resident prosocial behavior. Laboratory experiments have demonstrated that such peer monitoring can lead to cooperation, but there has been no quantitative test of this hypothesis in an actual TC. In this article we test this assumption by using the affirmations that residents of three different TCs send as a measure of prosocial behavior following the reception of peer affirmations and corrections. At all three facilities residents send more affirmations following the reception of both affirmations and corrections, with this relationship being stronger and longer lasting after receiving affirmations. No other variable consistently predicts the number of affirmations that residents send to peers. These findings imply that mutual monitoring among TC residents can lead to increased levels of prosocial behavior within the facility, and that prosocial behavior in response to peer affirmations plays a key role.
PMCID: PMC3735223  PMID: 23935258
5.  Screening for Exercise-Induced Bronchoconstriction in College Athletes 
Previous studies have reported that the prevalence of exercise-induced bronchoconstriction (EIB) in athletes is higher than that of the general population. There is increasing evidence that athletes fail to recognize and report symptoms of EIB. As a result, there has been debate whether athletes should be screened for EIB, particularly in high-risk sports.
We prospectively studied 144 athletes from six different varsity sports at a large National Collegiate Athletic Association Division I collegiate athletic program. Baseline demographics and medical history were obtained and the presence of asthma symptoms during exercise was documented. Each athlete subsequently underwent a eucapnic voluntary hyperventilation (EVH) test to document the presence of EIB. Exhaled nitric oxide (eNO) quantification was performed immediately before EVH testing. EIB was defined as a ≥10% decline in forced expiratory volume in 1 second compared with baseline.
Only 4 of 144 (2.7%) athletes were EIB-positive after EVH testing. The presence of symptoms was not predictive of EIB as only 2 of the 64 symptomatic athletes (3%) were EIB-positive based on EVH testing. Two of the four athletes who were found to be EIB-positive denied such symptoms. The mean baseline eNO in the four EIB-positive athletes was 13.25 parts per billion (ppb) and 24.5 ppb in the EIB-negative athletes.
Our data argue that screening for EIB is not recommended given the surprisingly low prevalence of EIB in the population we studied. In addition, the presence or absence of symptoms was not predictive of EIB and eNO testing was not effective in predicting EIB.
PMCID: PMC3832203  PMID: 22276571
asthma; athletes; bronchoconstriction; exercise; screening
6.  Chemotherapeutic Agents Increase the Risk for Pulmonary Function Test Abnormalities in Patients With Multiple Myeloma 
Case reports of pulmonary toxicity have been published regarding bortezomib, lenalidomide, and thalidomide but there are no published reports looking at the possible long-term pulmonary effects of these medications. This article describes a possible relationship between the administration of bortezomib and thalidomide and the development of pulmonary function test (PFT) abnormalities. It also suggests that routine pulmonary function testing may be required in patients receiving these medications until larger studies can be performed to confirm this observation.
Multiple myeloma is a common malignancy accounting for approximately 1% of all malignancies worldwide. Bortezomib, lenalidomide, and thalidomide are immunomodulatory derivatives that are used in the treatment of multiple myeloma (MM). There have been case reports of pulmonary disease associated with these agents, but the effect of these agents on pulmonary function test (PFT) results is unknown.
Patients and Methods
We reviewed the records of 343 patients with MM who underwent PFTs before autologous stem cell transplantation. One hundred nine patients had not received any of the 3 medications, whereas 234 had received 1 or more of these agents.
Patients exposed to bortezomib were more likely to have obstructive PFT results (P = .015) when compared with patients not exposed to this medication. Restrictive PFT results were more likely after exposure to thalidomide (P = .017). A logistic regression model was performed and when adjusted for age, sex, Durie-Salmon (DS) stage, body mass index (BMI), time from diagnosis to transplantation in days, and smoking history, the odds of obstruction were 1.96 times higher for patients who received bortezomib. The odds of restriction were 1.97 times higher after exposure to thalidomide.
There appears to be a risk of PFT abnormalities developing in patients treated with bortezomib and thalidomide.
PMCID: PMC3481157  PMID: 22986117
Airflow obstruction; Bortezomib; Lenalidomide; Multiple myeloma; Pulmonary function tests; Thalidomide
7.  Pilot study on the efficacy of an ondansetron-versus palonosetron-containing antiemetic regimen prior to highly emetogenic chemotherapy 
Nausea and vomiting are among the most feared complications of chemotherapy reported by patients. The objective of this study was to establish the overall complete response (CR; no emesis or use of rescue medication 0–120 h after chemotherapy) with either ondansetron- or palonosetron-containing antiemetic regimens in patients receiving highly emetogenic chemotherapy (HEC).
This was a prospective, open-label, randomized, single-center, pilot study that enrolled patients receiving their first cycle of HEC. Patients were randomized to receive either palonosetron 0.25 mg IV (PAD) or ondansetron 24 mg orally (OAD) on day 1 prior to HEC. All patients received oral aprepitant 125 mg on day 1, then 80 mg on days 2 and 3, and oral dexamethasone 12 mg on day 1, then 8 mg on days 2, 3, and 4. Descriptive statistics were used to summarize the data.
A total of 40 patients were enrolled, 20 in each arm. All patients were female, and 39 received doxorubicin/cyclophosphamide chemotherapy for breast cancer. For the primary endpoint, 65 % (95 % CI, 40.8–84.6 %) of patients in the PAD arm and 40 % (95 % CI, 19.1–63.9 %) of patients in the OAD arm achieved an overall CR.
While CR rates for aprepitant and dexamethasone plus palonosetron or ondansetron-containing regimens have been published previously, this is the first documentation of CR rates with these regimens in the same patient population. These results may be used to design a larger, adequately powered, prospective study comparing these regimens.
PMCID: PMC3769492  PMID: 23748485
Ondansetron; Palonosetron; Aprepitant; Dexamethasone; Highly emetogenic chemotherapy
8.  Stabilization of HIF-2α induces sVEGFR-1 production from tumor-associated macrophages and decreases tumor growth in a murine melanoma model1 
Macrophage secretion of VEGF in response to hypoxia contributes to tumor growth and angiogenesis. In addition to VEGF, hypoxic macrophages stimulated with GM-CSF secrete high levels of a soluble form of the VEGF receptor (sVEGFR-1), which neutralizes VEGF and inhibits its biological activity. Using mice with a monocyte/macrophage-selective deletion of HIF-1α or HIF-2α, we recently demonstrated that the anti-tumor response to GM-CSF was dependent on HIF-2α-driven sVEGFR-1 production by tumor-associated macrophages, while HIF-1α specifically regulated VEGF production. We therefore hypothesized that chemical stabilization of HIF-2α using an inhibitor of prolyl hydroxylase 3 (PHD3; an upstream inhibitor of HIF-2α activation) would increase sVEGFR-1 production from GM-CSF-stimulated macrophages. Treatment of macrophages with the PHD3 inhibitor AKB-6899 stabilized HIF-2α and increased sVEGFR-1 production from GM-CSF-treated macrophages, with no effect on HIF-1α accumulation or VEGF production. Treatment of B16F10 melanoma-bearing mice with GM-CSF and AKB-6899 significantly reduced tumor growth compared to either drug alone. Increased levels of sVEGFR-1 mRNA, but not VEGF mRNA, were detected within the tumors of GM-CSF- and AKB-6899-treated mice, correlating with decreased tumor vascularity. Finally, the anti-tumor and anti-angiogenic effects of AKB-6899 were abrogated when mice were simultaneously treated with a sVEGFR-1 neutralizing antibody. These results demonstrate that AKB-6899 decreases tumor growth and angiogenesis in response to GM-CSF by increasing sVEGFR-1 production from tumor-associated macrophages. Specific activation of HIF-2α can therefore decrease tumor growth and angiogenesis.
PMCID: PMC3436995  PMID: 22869907
9.  Early versus delayed autologous stem cell transplantation in patients receiving novel therapies for Multiple Myeloma 
Leukemia & lymphoma  2012;54(8):1658-1664.
Autologous stem cell transplant (ASCT) is an effective treatment for multiple myeloma (MM). However the timing of ASCT in the era of novel agents (lenalidomide, thalidomide, bortezomib) is unknown. We retrospectively reviewed the outcome of MM patients who received novel agent based induction treatment and received first ASCT within 12 months of diagnosis (early ASCT, N = 102), or at a later date (late ASCT, N = 65). Median time to ASCT was 7.9 months vs. 17.7 months in the early vs. late ASCT. The 3 and 5 yr overall Survival (OS) from diagnosis was 90 and 63% versus 82 and 63% in early and late ASCT respectively (P=0.45). Forty-one and 36 patients in the early and late ASCT have relapsed or progressed with median time to relapse of 28 and 23 mos (p=0.055). On multivariable analysis, factors predictive of increased risk for progression were ISS stage III (p=0.007), and < VGPR post-ASCT (p<0.001). Factor predictive of worst outcomes for OS was being on hemodialysis (p=0.037). No superiority of one agent was seen. In summary, early or late ASCT is a viable option for MM patients receiving induction treatment with novel targeted therapies.
PMCID: PMC3769940  PMID: 23194056
Multiple Myeloma; Transplantation; Bortezomib; Lenalidomide
10.  Effects of Nasal Continuous Positive Airway Pressure and Cannula Use in the Neonatal Intensive Care Unit Setting 
To investigate the effects of nasal continuous positive airway pressure (CPAP) and cannula use in the neonatal intensive care unit.
Cross-sectional study.
Tertiary care children’s hospital.
One hundred patients (200 nasal cavities), younger than 1 year, who received at least 7 days of nasal CPAP (n = 91) or cannula supplementation (n = 9) in the neonatal intensive care unit.
External nasal examination and anterior nasal endoscopy with photographic documentation.
Main Outcome Measures
The incidence and characteristics of internal and external nasal findings of patients with nasal CPAP or cannula use.
Nasal complications were seen in 12 of the 91 patients (13.2%) with at least 7 days of nasal CPAP exposure, while no complications were seen in the 9 patients with nasal cannula use alone. The external nasal finding of columellar necrosis, seen in 5 patients (5.5%), occurred as early as 10 days after nasal CPAP use. Incidence of intranasal findings attributed to CPAP use, in the 182 nostrils examined, included ulceration in 6 nasal cavities (3.3%), granulation in 3 nasal cavities (1.6%), and vestibular stenosis in 4 nasal cavities (2.2%). Intranasal complications were seen as early as 8 to 9 days after nasal CPAP administration. Nasal complications from CPAP were associated with lower Apgar scores at 1 (P = .02) and 5 (P = .06) minutes.
External or internal complications of nasal CPAP can be relatively frequent (13.2%) and can occur early, and patients with lower Apgar scores may be at higher risk. Close surveillance for potential complications should be considered during nasal CPAP use.
PMCID: PMC3740519  PMID: 20231649
11.  Pulmonary Rehabilitation for Bronchiolitis Obliterans Syndrome after Hematopoietic Stem Cell Transplantation 
Bronchiolitis obliterans syndrome (BOS) is a progressive, insidious lung disease affecting allogeneic hematopoietic stem cell transplant (HSCT) recipients. Unfortunately, there is no standardized approach for treatment of BOS in post HSCT patients. Pulmonary rehabilitation is a standard treatment in emphysema, an irreversible obstructive lung disease secondary to tobacco abuse. The National Emphysema Treatment Trial (NETT) demonstrated improved exercise tolerance, decrease dyspnea, and increase of quality of life in patients with severe emphysema after pulmonary rehabilitation. We hypothesized that pulmonary rehabilitation may benefit patients with BOS. Patients with BOS were identified retrospectively from January 2005 to the present. Patients who enrolled in pulmonary rehabilitation were included in the study. We obtained summaries via chart review of each patient’s progress after pulmonary rehabilitation enrollment from their respective rehabilitation centers. Six minute walk distances, spirometry, and pulmonary symptoms were compared before and after the completion of pulmonary rehabilitation. We identified 11 patients with BOS documented from their pulmonologist’s clinical notes that were enrolled into pulmonary rehabilitation. Ten of the 11 patients completed pulmonary rehabilitation. All patients had improvement in their 6 minute walk distances after the completion of pulmonary rehabilitation with an average improvement in distance of 307 feet (p value = 0.005). Six of the 10 patients completed a Short Form-36 questionnaires prior to and after rehab. There was a significant improvement in the physical functioning score (p value =0.029). Pulmonary rehabilitation appears to improve 6 minute walk distance, subjective symptoms of dyspnea and exercise tolerance in patients with BOS. This may be an important adjunctive therapy for a debilitating disease with limited treatment options.
PMCID: PMC3378799  PMID: 22300617
12.  Abundant Intracellular IgG in Enterocytes and Endoderm Lacking FcRn 
PLoS ONE  2013;8(7):e70863.
FcRn, a non-classical MHCI molecule, transports IgG from mother to young and regulates the rate of IgG degradation throughout life. Brambell proposed a mechanism that unified these two functions, saying that IgG was pinocytosed nonspecifically by the cell into an FcRn-expressing endosome, where, at low pH, it bound to FcRn and was exocytosed. This theory was immediately challenged by claims that FcRn specificity for ligand could be conferred at the cell surface in neonatal jejunum. Assessing Brambell's hypothesis we found abundant nonspecifically endocytosed IgG present in the cytoplasm of FcRn−/− enterocytes. Further, IgG was present in the intercellular clefts and the cores of FcRn+/+ but not FcRn−/− jejunum. FcRn specificity for ligand could be determined within the cell.
PMCID: PMC3726603  PMID: 23923029
13.  Prolonged myelosuppression with clofarabine in the treatment of patients with relapsed or refractory, aggressive non-Hodgkin lymphoma 
Leukemia & lymphoma  2009;50(3):349-356.
We evaluated the safety and efficacy of the purine nucleoside analogue, clofarabine, in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Six patients with DLBCL (n = 5) or MCL (n = 1) and a median age of 68 years were treated with 40 mg/m2 clofarabine IV over 2 h for 5 days, repeated every 28 days, for 1–2 cycles. The overall response rate was 50% (complete response = 1, complete response unconfirmed = 1, partial response = 1). Median progression-free survival was 3.5 months (range 1.5–10 months) and the median overall survival was 7.8 months (range 3–31 months). Grade 3–4 neutropenia and thrombocytopenia was universal, with a median of 34 (range 19–55) and 77 (range 0–275) days required for neutrophil and platelet recovery. Grade 3 non-hematologic toxicities included transaminitis, febrile neutropenia, non-neutropenic infections and orthostatic hypotension. Further accrual to the study was terminated due to prolonged Grade 3–4 myelosuppression and orthostatic hypotension in five of six patients. Clofarabine exhibits evidence of single agent activity in relapsed or refractory DLBCL. However, further study with novel administration schedules that maintain this efficacy and limit toxicity is warranted.
PMCID: PMC3695225  PMID: 19263294
Clofarabine; diffuse large B cell lymphoma; mantle cell lymphoma; nucleoside analogues; myelosuppression
14.  β-Blockers and Survival among Danish Patients with Malignant Melanoma: A Population-Based Cohort Study 
To study whether use of β-blockers increases survival in patients with malignant melanoma because experimental data suggest that catecholamine hormones may be involved in stimulating the aggressiveness of malignant melanoma.
A total of 4,179 patients diagnosed with malignant melanoma in Denmark with a median follow-up of 4.9 years and identified in the Danish Cancer Registry participated. Data on β-blocker use, comorbidity, and survival were obtained from medical and administrative databases. Cox proportional hazards models were used to estimate HRs for all-cause mortality with 95% CIs with adjustment for prognostic factors.
A total of 372 (8.9%) patients with malignant melanoma were treated with β-blockers within 90 days of melanoma diagnosis. The median β-blocker duration for exposure within 90 days of melanoma diagnosis, more than 90 days, and no prior exposure was 7.6, 1.4, and 0 years, respectively. The patients receiving β-blockers were older, had more comorbidities, and more cardiovascular and psychotropic drug user than the patients receiving no β-blockers prior to melanoma diagnosis. After adjustment for age and comorbidity index, the HR for melanoma death was 0.87 (95% CI: 0.64–1.20) and for all-cause mortality was 0.81 (95% CI: 0.67–0.97).
Increased survival time of patients with melanoma receiving β-blockers suggests that this class of drugs may hold promise in treatment strategy for these patients.
The observations described here suggest that catecholamines may retard melanoma progression and that β-blockers may have unrecognized potential as a therapeutic intervention for melanoma.
PMCID: PMC3652234  PMID: 21933972
15.  Use of ß-blockers and mortality following ovarian cancer diagnosis: a population-based cohort study 
BMC Cancer  2013;13:85.
Experimental data suggest that catecholamine hormones are involved in stimulating the aggressiveness of ovarian cancer, but few population-based studies have examined this association. We therefore conducted a population-based cohort study to examine whether ß-blockers affect mortality following ovarian cancer diagnosis.
We used the Danish Cancer Registry to identify all patients diagnosed with ovarian cancer in northern Denmark between 1999 and 2010 (n=6,626). Data on medication use, comorbidity, and survival were obtained from medical databases. According to the last redeemed prescription before diagnosis, ß-blocker use was categorized as current (within ≤90 days), previous (>90 days) or never. We used Cox proportional hazards regression to calculate hazard ratios (HRs) for all-cause mortality with 95% confidence intervals (CIs) adjusting for confounding factors.
Among the ovarian cancer patients, 373 (5.6%) were current, 87 (1.3%) previous, and 6,166 (93.1%) were nonusers of ß-blockers. Median duration of use was 19.0 months among current users and 43.0 months among previous users. Median follow-up was 2.55 years (IQR: 0.81-9.23). Nonusers and current users of ß-blockers had similar comorbidity burden whereas previous users had moderate comorbidity more frequently. Compared with nonusers, the adjusted HR was 1.17 (95% CI: 1.02–1.34) for current users and 1.18 (95% CI: 0.90–1.55) for previous users. Secondary analyses stratifying by cancer stage and duration of ß-blocker use supported the overall results.
We found no evidence that ß-blocker use was associated with decreased mortality following ovarian cancer diagnosis.
PMCID: PMC3598679  PMID: 23433478
16.  Higher Busulfan Dose Intensity Does Not Improve Outcomes of Patients Undergoing Allogeneic Hematopoietic Cell Transplantation Following Fludarabine, Busulfan-based Reduced Toxicity Conditioning 
Hematological oncology  2011;29(4):202-210.
We evaluated the impact of busulfan dose-intensity in patients undergoing reduced toxicity/intensity conditioning allogeneic transplantation in a multicenter retrospective study of 112 consecutive patients. Seventy-five patients were conditioned with busulfan (0.8 mg/kg/dose IV × 8 doses), fludarabine (30mg/m2/day, days −7 to −3), and 6mg/kg of ATG (RIC group), while 37 patients received a more-intense conditioning with busulfan (130mg/m2/day IV, days −6 to −3), fludarabine (40mg/m2/day, days −6 to −3), and 6mg/kg of ATG (RTC group). At baseline both groups were matched for median age, unrelated donor allografts, and HLA-mismatched allografts. More patients in RIC group had high-risk disease, and higher median co-morbidity index. There were no graft rejections. Median time to neutrophil (17 vs. 15 days; p=0.003) and platelet engraftment (16 vs. 11 days; p<0.001) was significantly longer in the RIC group. RTC group had significantly more bacterial (62.2% vs. 32%; p=0.004) and fungal infections (13.5% vs. 1.3% p=0.01). For RIC and RTC groups rates of grade II-IV acute GVHD (34% vs. 40%; p-value=0.54), and chronic GVHD (45% vs. 57%; p-value=0.30) were not significantly different. In similar order at 1-year the cumulative-incidence of non-relapse mortality (NRM) (12% vs. 21%; p-value=0.21) and relapse rates (38% vs. 39%; p=0.96) were not significantly different. Patients in RIC and RTC groups had similar 1-year overall survival (61% vs. 50% p=0.11) and progression free survival (50% vs. 36% p-value=0.39). Our data suggest that merits of higher busulfan dose-intensity in the context of fludarabine/busulfan-based RTC may be offset by higher early morbidity.
PMCID: PMC3557914  PMID: 21360728
Fludarabine; busulfan; thymoglobulin; busulfan dose; allogeneic stem cell transplantation; graft-versus-host disease
17.  Serum free light chains in myeloma patients with an intact M-protein by immunofixation: potential roles for response assessment and prognosis during induction therapy with novel agents 
Hematological oncology  2011;30(3):156-162.
The ascertainment of serum free light chain levels (sFLC) has been shown to be valuable in screening for the presence of plasma cell dyscrasia as well as for baseline prognosis in newly diagnosed patients. For patients with amyloidosis and those with oligo- or non-secretory multiple myeloma (MM), serial measurement of sFLC has also been shown to be valuable in monitoring disease status. However, in patients with a measureable, intact monoclonal protein by immunofixation (M protein), the serial measurement of sFLC remains undefined and is currently not recommended in professional guidelines. Herein, we provide data comparing sFLC to M protein as biomarkers of response in newly-diagnosed patients with MM undergoing induction therapy with the novel agents thalidomide, lenalidomide and/or bortezomib. We show that while M protein appears to outperform sFLC comparatively over the course of induction therapy, the addition of FLC to M-protein further informs the characterization of residual disease status post-induction. Moreover, sFLC at the time of stem cell mobilization appears to hold prognostic power for survival endpoints following HDC/SCT. These findings suggest potentially novel roles for sFLC in patients with MM with an intact M-protein receiving novel agent-based induction strategies followed by HDC/SCT.
PMCID: PMC3557798  PMID: 22028144
Multiple myeloma; biomarker; serum free light chains
18.  Transcription Factor ets-2 Plays an Important Role in the Pathogenesis of Pulmonary Fibrosis 
Ets-2 is a ubiquitous transcription factor activated after phosphorylation at threonine-72. Previous studies highlighted the importance of phosphorylated ets-2 in lung inflammation and extracellular matrix remodeling, two pathways involved in pulmonary fibrosis. We hypothesized that phosphorylated ets-2 played an important role in pulmonary fibrosis, and we sought to determine the role of ets-2 in its pathogenesis. We challenged ets-2 (A72/A72) transgenic mice (harboring a mutated form of ets-2 at phosphorylation site threonine-72) and ets-2 (wild-type/wild-type [WT/WT]) control mice with sequential intraperitoneal injections of bleomycin, followed by quantitative measurements of lung fibrosis and inflammation and primary cell in vitro assays. Concentrations of phosphorylated ets-2 were detected via the single and dual immunohistochemical staining of murine lungs and lung sections from patients with idiopathic pulmonary fibrosis. Ets-2 (A72/A72) mice were protected from bleomycin-induced pulmonary fibrosis, compared with ets-2 (WT/WT) mice. This protection was characterized by decreased lung pathological abnormalities and the fibrotic gene expression of Type I collagen, Type III collagen, α–smooth muscle actin, and connective tissue growth factor. Immunohistochemical staining of lung sections from bleomycin-treated ets-2 (WT/WT) mice and from patients with idiopathic pulmonary fibrosis demonstrated increased staining of phosphorylated ets-2 that colocalized with Type I collagen expression and to fibroblastic foci. Lastly, primary lung fibroblasts from ets-2 (A72/A72) mice exhibited decreased expression of Type I collagen in response to stimulation with TGF-β, compared with fibroblasts from ets-2 (WT/WT) mice. These data indicate the importance of phosphorylated ets-2 in the pathogenesis of pulmonary fibrosis through the expression of Type I collagen and (myo)fibroblast activation.
PMCID: PMC3262682  PMID: 21562315
ets-2; Type I collagen; pulmonary fibrosis; bleomycin; fibroblast
19.  Ex vivo stimulation of whole blood as a means to determine glucocorticoid sensitivity 
Glucocorticoids are commonly prescribed to treat a number of diseases including the majority of inflammatory diseases. Despite considerable interpersonal variability in response to glucocorticoids, an insensitivity rate of about 30%, and the risk of adverse side effects of glucocorticoid therapy, currently no assay is performed to determine sensitivity.
Patients and methods
Here we propose a whole blood ex vivo stimulation assay to interrogate known glucocorticoid receptor (GR) up- and downregulated genes to indicate glucocorticoid sensitivity. We have chosen to employ real-time PCR in order to provide a relatively fast and inexpensive assay.
We show that the GR-regulated genes, GILZ and FKBP51, are upregulated in whole blood by treatment with dexamethasone and that LPS-induction of cytokines (IL-6 and TNFα) are repressed by dexamethasone in a dose responsive manner. There is considerable interpersonal variability in the maximum induction of these genes but little variation in the EC50 and IC50 concentrations. The regulation of the GR-induced genes differs throughout the day whereas the suppression of LPS-induced cytokines is not as sensitive to time of day.
In all, this assay would provide a method to determine glucocorticoid receptor responsiveness in whole blood.
PMCID: PMC3430009  PMID: 22952414
glucocorticoid responsiveness; gene regulation; nuclear receptor; GILZ; FKBP51; cytokines
20.  HIF-2α regulates GM-CSF-derived sVEGFR-1 production from macrophages and inhibits tumor growth and angiogenesis1 
Macrophage secretion of VEGF in response to the hypoxic tumor microenvironment contributes to tumor growth, angiogenesis, and metastasis. We have recently demonstrated that macrophages stimulated with GM-CSF at low O2 secrete high levels of a soluble form of the VEGF receptor (sVEGFR-1), which neutralizes VEGF and inhibits its biological activity. Using siRNA targeting to deplete HIF-1α or HIF-2α in murine macrophages, we found that macrophage production of sVEGFR-1 in response to low O2 was dependent on HIF-2α, while HIF-1α specifically regulated VEGF production. In our current report, we evaluated the growth of B16F10 malignant melanoma in mice with a monocyte/macrophage-selective deletion of HIF-1α or HIF-2α (HIF-1αflox/flox-or HIF-2αflox/+/LysMcre mice). GM-CSF treatment increased intra-tumoral VEGF and sVEGFR-1 in control mice, an effect that was associated with a decrease in microvessel density. GM-CSF treatment of HIF-1αflox/flox/LysMcre mice induced sVEGFR-1 but not VEGF, resulting in an overall greater reduction in tumor growth and angiogenesis compared to control mice. In addition, real-time PCR for melanoma-specific genes revealed a significantly reduced presence of lung micrometastases in HIF-1αflox/flox/LysMcre mice treated with GM-CSF. Conversely, GM-CSF treatment induced VEGF but not sVEGFR-1 in HIF-2αflox/+/LysMcre mice, and correspondingly, GM-CSF did not decrease tumor growth, angiogenesis, or lung metastasis in these mice. This study reveals opposing roles for the HIFs in the regulation of angiogenesis by tumor-associated macrophages, and suggests that administration of GM-CSF might be an effective means of inducing sVEGFR-1 and inhibiting tumor growth and angiogenesis in patients with melanoma.
PMCID: PMC3150377  PMID: 21765015
21.  Feasibility of stopping paclitaxel premedication after two doses in patients not experiencing a previous infusion hypersensitivity reaction 
Supportive Care in Cancer  2011;20(9):1991-1997.
Paclitaxel-based chemotherapy continues to be an integral component in the treatment of many solid tumors. Prolonged use of paclitaxel may result in repeated doses of premedications and potential unwanted side effects. Infusion hypersensitivity reactions occurring beyond the second dose are infrequent and not well characterized. We hypothesized that patients whose paclitaxel premedications were discontinued after two doses were unlikely to experience infusion hypersensitivity reactions with subsequent paclitaxel doses.
Patients receiving paclitaxel-based chemotherapy who did not experience an infusion hypersensitivity reaction with their first or second dose had their paclitaxel premedications discontinued. The primary endpoint was to estimate the incidence of rescue medication for the treatment of paclitaxel infusion hypersensitivity during doses 3 to 6 for patients whose paclitaxel premedications had been discontinued.
After receiving the first two doses of paclitaxel-based chemotherapy without experiencing an infusion hypersensitivity reaction (any grade), 55 breast cancer patients had their premedications discontinued for all remaining paclitaxel doses. None of these patients required rescue medication to treat an infusion hypersensitivity reaction with subsequent doses.
In patients who have not experienced an infusion hypersensitivity reaction with the first two doses of paclitaxel, discontinuation of paclitaxel premedications may be considered an option without an increased risk of infusion hypersensitivity requiring rescue medication.
PMCID: PMC3411299  PMID: 22089428
Abbreviated; Paclitaxel; Premedication; Prophylaxis; Hypersensitivity
22.  Glucose variability and mortality in patients with sepsis* 
Critical care medicine  2008;36(8):2316-2321.
Treatment and prevention of hyperglycemia has been advocated for subjects with sepsis. Glucose variability, rather than the glucose level, has also been shown to be an important factor associated with in-hospital mortality, in general, critically ill patients. Our objective was to determine the association between glucose variability and hospital mortality in septic patients and the expression of glucose variability that best reflects this risk.
Retrospective, single-center cohort study.
Academic, tertiary care hospital.
Adult subjects hospitalized for >1 day, with a diagnosis of sepsis were included.
Glucose variability was calculated for all subjects as the average and standard deviation of glucose, the mean amplitude of glycemic excursions, and the glycemic lability index. Hospital mortality was the primary outcome variable. Logistic regression was used to determine the odds of hospital death in relation to measures of glucose variability after adjustment for important covariates.
Main results
Of the methods used to measure glucose variability, the glycemic lability index had the best discrimination for mortality (area under the curve = 0.67, p < 0.001). After adjustment for confounders, including the number of organ failures and the occurrence of hypoglycemia, there was a significant interaction between glycemic lability index and average glucose level, and the odds of hospital mortality. Higher glycemic lability index was not independently associated with mortality among subjects with average glucose levels above the median for the cohort. However, subjects with increased glycemic lability index, but lower average glucose values had almost five-fold increased odds of hospital mortality (odds ratio = 4.73, 95% confidence interval = 2.6 – 8.7) compared with those with lower glycemic lability index.
Glucose variability is independently associated with hospital mortality in septic patients. Strategies to reduce glucose variability should be studied to determine whether they improve the outcomes of septic patients.
PMCID: PMC3176449  PMID: 18596625
sepsis; hyperglycemia; insulin therapy; mortality
23.  The Role of Heat Shock Protein 27 in Bronchiolitis Obliterans Syndrome after Lung Transplantation 
Heat shock proteins (Hsps) are a family of evolutionary conserved proteins classified according to their size as small and large Hsps. They have a cytoprotective role and have been shown recently to be immunogenic molecules. In addition, self-reactivity to Hsps has been implicated in various autoimmune diseases and in the development of alloimmunity. The purpose of this study was to examine the relationship of large and small Hsps and anti-Hsp antibodies in recipients of lung transplantation (LTX) who have bronchiolitis obliterans syndrome (BOS).
Anti-Hsp27 and Hsp70 antibodies and Hsp27, Hsp60 and Hsp70 protein expression levels were evaluated in serum and bronchoalveolar lavage samples collected from 8 LTX recipients with established BOS and 8 recipients without BOS (controls). Serum from 8 normal subjects was examined for Hsp levels as a comparison.
Elevated serum Hsp27 levels were observed in recipients with BOS compared to controls or normal subjects, whereas Hsp70 and Hsp60 expression showed no difference. Anti-Hsp27 antibody levels were significantly higher in BAL of recipients with BOS as compared to those without. In contrast, anti-Hsp70 antibodies levels in serum or BAL showed no difference between groups.
These results support the novel concept that Hsp27 but not the classical Hsp60 and Hsp70 may be associated with the development BOS. The expression of anti-Hsp27 antibodies found only in the BAL fluid suggests a local response occurring at the level of the alveoli and terminal airways.
PMCID: PMC2902709  PMID: 20456980
24.  Thrombospondin-1 Contributes to Mortality in Murine Sepsis through Effects on Innate Immunity 
PLoS ONE  2011;6(5):e19654.
Thrombospondin-1 (TSP-1) is involved in many biological processes, including immune and tissue injury response, but its role in sepsis is unknown. Cell surface expression of TSP-1 on platelets is increased in sepsis and could activate the anti-inflammatory cytokine transforming growth factor beta (TGFβ1) affecting outcome. Because of these observations we sought to determine the importance of TSP-1 in sepsis.
Methodology/Principal Findings
We performed studies on TSP-1 null and wild type (WT) C57BL/6J mice to determine the importance of TSP-1 in sepsis. We utilized the cecal ligation puncture (CLP) and intraperitoneal E.coli injection (IP E.coli) models of peritoneal sepsis. Additionally, bone-marrow-derived macrophages (BMMs) were used to determine phagocytic activity. TSP-1−/− animals experienced lower mortality than WT mice after CLP. Tissue and peritoneal lavage TGFβ1 levels were unchanged between animals of each genotype. In addition, there is no difference between the levels of major innate cytokines between the two groups of animals. PLF from WT mice contained a greater bacterial load than TSP-1−/− mice after CLP. The survival advantage for TSP-1−/− animals persisted when IP E.coli injections were performed. TSP-1−/− BMMs had increased phagocytic capacity compared to WT.
TSP-1 deficiency was protective in two murine models of peritoneal sepsis, independent of TGFβ1 activation. Our studies suggest TSP-1 expression is associated with decreased phagocytosis and possibly bacterial clearance, leading to increased peritoneal inflammation and mortality in WT mice. These data support the contention that TSP-1 should be more fully explored in the human condition.
PMCID: PMC3090410  PMID: 21573017
25.  An Assessment of H1N1 Influenza-Associated Acute Respiratory Distress Syndrome Severity after Adjustment for Treatment Characteristics 
PLoS ONE  2011;6(3):e18166.
Pandemic influenza caused significant increases in healthcare utilization across several continents including the use of high-intensity rescue therapies like extracorporeal membrane oxygenation (ECMO) or high-frequency oscillatory ventilation (HFOV). The severity of illness observed with pandemic influenza in 2009 strained healthcare resources. Because lung injury in ARDS can be influenced by daily management and multiple organ failure, we performed a retrospective cohort study to understand the severity of H1N1 associated ARDS after adjustment for treatment. Sixty subjects were identified in our hospital with ARDS from “direct injury” within 24 hours of ICU admission over a three month period. Twenty-three subjects (38.3%) were positive for H1N1 within 72 hours of hospitalization. These cases of H1N1-associated ARDS were compared to non-H1N1 associated ARDS patients. Subjects with H1N1-associated ARDS were younger and more likely to have a higher body mass index (BMI), present more rapidly and have worse oxygenation. Severity of illness (SOFA score) was directly related to worse oxygenation. Management was similar between the two groups on the day of admission and subsequent five days with respect to tidal volumes used, fluid balance and transfusion practices. There was, however, more frequent use of “rescue” therapy like prone ventilation, HFOV or ECMO in H1N1 patients. First morning set tidal volumes and BMI were significantly associated with increased severity of lung injury (Lung injury score, LIS) at presentation and over time while prior prescription of statins was protective. After assessment of the effect of these co-interventions LIS was significantly higher in H1N1 patients. Patients with pandemic influenza-associated ARDS had higher LIS both at presentation and over the course of the first six days of treatment when compared to non-H1N1 associated ARDS controls. The difference in LIS persisted over the duration of observation in patients with H1N1 possibly explaining the increased duration of mechanical ventilation.
PMCID: PMC3064596  PMID: 21464952

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