Forward Stepwise Multivariate Analysis Research Articles

Predictors of length of stay following maxillofacial abscess surgery: A 10-year retrospective cohort

The aim of this study was to identify predictors of length of stay (LOS) after surgical therapy of maxillofacial abscess. Patients diagnosed with a maxillofacial abscess who underwent extraoral incision and drainage under general anesthesia between January 1st, 2012 and January 1st, 2022 were retrospectively reviewed Univariable and multivariable linear regressions were performed to identify the association between pre- and perioperative variables and the LOS. In total, 228 patients were included. In the forward stepwise multivariable analysis, all factors with a p-value <0.2 in the univariable model were included. Ultimately, six independent predictors of increased LOS were identified: female (coef. 0.14, 95% CI 0.03–0.25), immunosuppression (coef. 0.37, 95%CI 0.13–0.61), penicillin allergy (coef. 0.25, 95% CI 0.04–0.46), C-reactive protein (coef. 0.0008, 95% CI 0.0001–0.0014), multiple spaces involvement (coef. 0.36, 95% CI 0.13–0.59), and time to operation (coef. 0.005, 95% CI 0.002–0.008). In conclusion, our study provides new insights into predicting LOS for patients admitted with maxillofacial abscesses. The identification of these markers not only enhances the ability to forecast LOS, but also lays the groundwork for optimizing resource planning and potentially integrating them into a primary prevention algorithm.

Exploring published and novel pre-treatment CT and PET radiomics to stratify risk of progression among early-stage non-small cell lung cancer patients treated with stereotactic radiation

PurposeDisease progression after definitive stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) occurs in 20–40% of patients. Here, we explored published and novel pre-treatment CT and PET radiomics features to identify patients at risk of progression. Materials/MethodsPublished CT and PET features were identified and explored along with 15 other CT and PET features in 408 consecutively treated early-stage NSCLC patients having CT and PET < 3 months pre-SBRT (training/set-aside validation subsets: n = 286/122). Features were associated with progression-free survival (PFS) using bootstrapped Cox regression (Bonferroni-corrected univariate predictor: p ≤ 0.002) and only non-strongly correlated predictors were retained (|Rs|<0.70) in forward-stepwise multivariate analysis. ResultsTumor diameter and SUVmax were the two most frequently reported features associated with progression/survival (in 6/20 and 10/20 identified studies). These two features and 12 of the 15 additional features (CT: 6; PET: 6) were candidate PFS predictors. A re-fitted model including diameter and SUVmax presented with the best performance (c-index: 0.78; log-rank p-value < 0.0001). A model built with the two best additional features (CTspiculation1 and SUVentropy) had a c-index of 0.75 (log-rank p-value < 0.0001). ConclusionsA re-fitted pre-treatment model using the two most frequently published features – tumor diameter and SUVmax – successfully stratified early-stage NSCLC patients by PFS after receiving SBRT.

A Pooled Analysis of Preoperative Inflammatory Biomarkers to Predict 90-Day Outcomes in Patients with an Aneurysmal Subarachnoid Hemorrhage: A Single-Center Retrospective Study.

An inflammatory response after an aneurysmal subarachnoid hemorrhage (aSAH) has always been in the spotlight. However, few studies have compared the prognostic impact of inflammatory biomarkers. Moreover, why these inflammatory biomarkers contribute to a poor prognosis is also unclear. We retrospectively reviewed aSAH patients admitted to our institution between January 2015 and December 2020. The 90-day unfavorable functional outcome was defined as a modified Rankin scale (mRS) of ≥ 3. Independent inflammatory biomarker-related risk factors associated with 90-day unfavorable outcomes were derived from a forward stepwise multivariate analysis. Receiver operating characteristic curve analysis was conducted to identify the best cut-off value of inflammatory biomarkers. Then, patients were divided into two groups according to each biomarker's cut-off value. To eliminate the imbalances in baseline characteristics, propensity score matching (PSM) was carried out to assess the impact of each biomarker on in-hospital complications. A total of 543 patients were enrolled in this study and 96 (17.7%) patients had unfavorable 90-day outcomes. A multivariate analysis showed that the white blood cell (WBC) count, the systemic inflammation response index, the neutrophil count, the neutrophil-to-albumin ratio, the monocyte count, and the monocyte-to-lymphocyte ratio were independently associated with 90-day unfavorable outcomes. The WBC count showed the best predictive ability (area under the curve (AUC) = 0.710, 95% CI = 0.652-0.769, p < 0.001). After PSM, almost all abnormal levels of inflammatory biomarkers were associated with a higher incidence of pneumonia during hospitalization. The WBC count had the strongest association with poor outcomes. Similar to nearly all other inflammatory biomarkers, the cause of poor prognosis may be the higher incidence of in-hospital pneumonia.

Association between resuscitation in the critical care resuscitation unit and in-hospital mortality

IntroductionPatients who present in shock have high expected mortality and early resuscitation is crucial to improve their outcomes. The Critical Care Resuscitation Unit (CCRU) is a specialized unit at the University of Maryland Medical Center (UMMC) that prioritizes early resuscitation of critically ill patients. We hypothesized that lactate clearance and reduction of Sequential Organ Failure Assessment (SOFA) score during CCRU stay would be associated with lower in-hospital mortality. MethodsWe performed a retrospective analysis of adult patients who were admitted to the CCRU between 01/01/2018–12/31/2018 and had a diagnosis of severe shock, determined by serum lactate ≥4 mmol/L. We excluded patients who died during CCRU stay. We used multivariable logistic regression to evaluate the association between lactate clearance and reduction in SOFA scores during CCRU stay and in-hospital mortality. ResultsOut of 1740 patients admitted to the CCRU in 2018, 172 (10%) had serum lactate ≥4 mmol/L. Twenty-two (13%) patients died during their CCRU stay. Our primary analysis included 129 patients with lactate clearance data and 136 patients with SOFA data. Average patients' age was 54 years, and median length of stay in the CCRU was 6 h 55 min. The average lactate and SOFA score on admission were 7.4 (3.8) mmol/L and 8.3 (4.7), respectively. Average lactate clearance was 1.9 (3.1) and average SOFA score reduction was 0.2 (2.9). In multivariable logistic regressions evaluating SOFA score and lactate separately, SOFA score reduction during CCRU stay was associated with lower in-hospital mortality (OR 0.83, 95% CI: 0.70–0.97) but lactate clearance was not (OR 0.90, 95% CI 0.78–1.03). In forward stepwise multivariable analysis containing both SOFA score and lactate values, SOFA score clearance during CCRU stay was still associated with decreased in-hospital mortality (OR 0.84, 95% CI 0.72–0.98). ConclusionsCare in the CCRU is more effective at reducing lactate than SOFA scores in patients with severe shock. However, SOFA score reduction in the resuscitation phase during the CCRU stay was associated with decreased odds of in-hospital mortality in this group of patients. Further studies are necessary to confirm our observations.

A Pre-Treatment PET And CT-Derived Model for Progression-Free Survival in Early Stage Non-Small Cell Lung Cancer

The maximum value of the standardized uptake value (SUV) and tumor diameter have been associated with progression after stereotactic body radiotherapy (SBRT) for early stage non-small cell lung cancer (NSCLC). In this work, we explored whether other tumor parameters based on pre-SBRT PETs and CTs predict progression-free survival (PFS) in this patient population. 412 patients treated between 2006 and 2017 were included. Patients had to have PETs and CTs available within three months prior to SBRT start. The median prescription dose was 50Gy in 5 fractions. The planning-CT gross tumor volumes (GTVs) were propagated onto the pre-treatment PETs and CTs using b-spline deformable image registration. PET intensity features (90th percentile, entropy, maximum, mean, peak, robust mean absolute deviation, SD, valley) and CT shape features (compactness, diameter, elliptic axes, elongation, flatness, number of lobules/peaks/spicules, sphericity, surface area, surface to volume ratio, volume) were extracted. Data were split into training and hold-out validation subsets (n = 283, 123; 70%, 30%). In the training subset, the imaging features and six patient characteristics (age, gender, histology, performance status, prior surgery, tumor location) were tested for association with PFS using Cox Proportional Hazards regression with re-sampling (bootstrapping with 1000 samples). Significance was denoted at p≤0.0019 (corrected for 26 tests). A bootstrapped forward-stepwise multivariate analysis was undertaken including only non-strongly correlated predictors (Spearman’s rank, |Rs|<0.70). The most frequently selected model was explored in the validation subset in which model performance was assessed using the c-index and the prediction-stratified high and low risk tertiles (HR, LR) of the observed PFS were compared. Nineteen of the 20 identified candidate predictors were either PET or CT features (p-value range: 3E-9, 1.2E-3). The intra-imaging modality correlation between features was strong (median |Rs|: PET: 0.93; CT: 0.76) and only four features were passed on to multivariate analysis: PET entropy, CT number of peaks, CT major axis, and gender. The most frequently selected model included PET entropy and CT number of peaks; the c-index in the validation subset was 0.77 and the prediction-stratified survival indicated a clear separation between the observed HR and LR: e.g. a PFS of 60% was observed at 12 months in HR vs. 22 months in LR. This PET and CT-based model identified the SUV distribution randomness (entropy) and spiculated tumor pattern on CTs as the most important features in predicting PFS in early stage NSCLC. The associated performance on the hold-out validation subset was good and its use has the potential to further improve the prediction of response to SBRT for this patient population. This model will be used to identify high-risk patients based on the predicted PFS in an upcoming phase II study on adjuvant immunotherapy.

Dose to the cardio-pulmonary system and treatment-induced electrocardiogram abnormalities in locally advanced non-small cell lung cancer

IntroductionHigh dose radiotherapy (RT) has been associated with unexpectedly short survival times for locally advanced Non-Small Cell Lung Cancer (LA-NSCLC) patients. Here we tested the hypothesis that cardiac substructure dose is associated with electrocardiography (ECG) assessed abnormalities after RT for LA-NSCLC. Materials and methodsPre- and post-RT ECGs were analyzed for 155 LA-NSCLC patients treated to a median of 64 Gy in 1.8–2.0 Gy fractions using intensity-modulated RT plus chemotherapy (concurrent/sequential: 64%/36%) between 2004 and 2014. ECG abnormalities were classified as new Arrhythmic, Ischemic/Pericardial, or Non-specific (AΔECG, I/PΔECG, or NSΔECG) events. Abnormalities were modeled as time to ECG events considering death a competing risk, and the variables considered for analysis were fractionation-corrected dose-volume metrics (α/β = 3 Gy) of ten cardio-pulmonary structures (aorta, heart, heart chambers, inferior and superior vena cava, lung, pulmonary artery) and 15 disease, patient and treatment characteristics. Each abnormality was modelled using bootstrapping and a candidate predictor was suggested by a median multiple testing-adjusted p-value ≤0.05 across the 1000 generated samples. Forward-stepwise multivariate analysis was conducted in case of more than one candidate. ResultsAt a median of eight months post-RT, the rate of AΔECG, I/PΔECG, and NSΔECG was 66%, 35%, and 67%. Both AΔECG and I/PΔECG were associated with worse performance status (p = 0.007, 0.03), while a higher superior vena cava minimum dose was associated with NSΔECG (p = 0.002). ConclusionThis study suggests that higher radiation doses to the cardio-pulmonary system lead to non-specific ECG abnormalities. Reducing dose to this system, along with effective tumor control, is likely to decrease radiation-induced cardiac toxicity.

Waist circumference is the anthropometric variable more related to clinical severity in women with knee osteoarthritis with synovial effussion

Purpose: Different anthropometric variables such as obesity with its different ways of measure (body fat index, waist circumference, waist/hip ratio) as well as the metabolic syndrome and his individual components have been related to knee osteoarthritis (OA). However, no specific studies analyzing the influence of these factors on clinical severity have been carried out in patients with synovial effusion. Objective: to assess the relationship between different anthropometric measures, the metabolic syndrome and its individual components with clinical severity as measured by the Lequesne algofunctional questionnaire in women with knee OA and significant synovial effusion. Methods: Transversal study including consecutively women aged 50 to 80 years with symptomatic knee OA, Kellgren–Lawrence I-IV with significant synovial effusion. Demographic data and history of hypertension (HT), dyslipidemia, obesity or diabetes mellitus (DM) were collected. Blood samples were taken to determine basal glycemia, total, HDL- and LDL-cholesterol, insulinemia and glycated hemoglobin. Anthropometric variables assessed included weight, height, body mass index (BMI), waist circumference, hip circumference and percentage of body fat as measured by bioelectrical impedance analysis). Patients were evaluated for the presence of metabolic syndrome by strict NCEP-ATP-III criteria. All patients underwent joint aspiration to confirm non-inflammatory synovial fluid without microcrystals. To evaluate knee OA clinical severity patients completed the Lequesne algofunctional index. Univariant and multivariant analyses were performed to evaluate which variables had a greater influence on the Lequesne index. Results: One hundred and fifteen women were analysed, average age 68.8 ± 11.1 years, average knee OA symptoms duration 50 ± 23 months. Percentage of HT was 54.58%, DM 10.4%, obesity 57.4% and dyslipidemia 47.8%, all above the expected by age and gender (40%, 10%, 40% and 30%, respectively). Metabolic syndrome was present in 40.9% of patients, also above 30% expected. In the univariant analysis all the anthropometric variables showed a significant association with the Lequesne index (body fat index, BMI, weight, waist circumference, hip circumference and waist/hip ratio, p =0.008, p =0.002, p =0.007, p < 0.001, p =0.006 and p =0.01 respectively). Neither the metabolic syndrome nor any of its individual components achieved statistical significance. After performing a forward stepwise multivariate analysis including OA symptom duration, age and Kellgren-Lawrence, waist circumference emerged as the only significant variable (p < 0.001). The relationship between BMI and Lequesne index was confirmed but when the waist circumference was included in the model only the waist circumference remained significant. Conclusions: In this study waist circumference was the anthropometric variable more related to clinical severity measured by the Lequesne index in women with knee OA and synovial effusion.

Factors associated with changes in mobility and living arrangements in a comprehensive geriatric outpatient assessment after hip fracture

Purpose: To examine factors associated with changes in mobility and living arrangements in a comprehensive geriatric outpatient assessment after hip fracture. Method: Population-based prospective data on 887 consecutive hip fracture patients aged 65 years and older. The domains of the geriatric assessment were the independent and changes in mobility level and living arrangements 4 months postoperatively the outcome variables. Results: Of the survivors, 499 (73%) attended the assessment. The mobility level had declined in 39% of the attendees and 38% of them had moved to more supported living arrangements 4 months after the hip fracture. In the age-adjusted univariate logistic regression analyses, almost all the domains of the comprehensive geriatric assessment were significantly associated with both outcomes. In the forward stepwise multivariate analysis, disability in activities of daily living, poor performance in Timed Up and Go and comorbidity as measured by the American Society of Anesthesiologists scores remained significantly associated with the outcomes. Conclusions: While comorbidity and disability in activities of daily living and mobility are the major indicators of poor outcomes of mobility and living arrangements after hip fracture, all the domains in the comprehensive geriatric assessment deserve attention during hip fracture care and rehabilitation.Implications for RehabilitationIn almost half of the patients the mobility level and living arrangements had deteriorated 4 months after the hip fracture, suggesting an urgent need for more effective postoperative rehabilitation.Almost all the domains of the comprehensive geriatric assessment were associated with poor outcomes and require equal attention during the acute and postacute phases of hip fracture care and in the course of rehabilitation.A geriatric outpatient assessment a few months after the hip fracture provides a check-point for the outcomes and an opportunity to target interventions at different domains of the comprehensive assessment.

Social deprivation as a risk factor for late presentation of proliferative diabetic retinopathy.

PurposeThe aim of this study was to determine whether social deprivation is a risk factor for late presentation of patients with proliferative diabetic retinopathy and whether it affects their access to urgent laser treatment.MethodsUsing a 2:1 case: control design, 102 patients referred to a UK teaching hospital as part of the UK Diabetic Retinopathy National Screening Programme were identified for the period between 1 June 2010 to 1 June 2013. Social deprivation was scored using the Index of Multiple Deprivation 2010. Additional variables considered included age, duration of disease, ethnicity, and HbA1c at time of referral.ResultsThe cases comprised 34 patients referred with proliferative (grade R3) retinopathy with a control group of 68 patients with lower retinopathy grades; two control patients were excluded due to incomplete data. On univariate analysis, R3 retinopathy was associated with higher social deprivation (P<0.001, Mann–Whitney U-test), and with higher HbA1c (11.5% vs 8.4%; P<0.001, Mann–Whitney U-test). Forward stepwise multivariable analysis showed that the association of R3 retinopathy with deprivation was significant even after adjusting for HbA1c (P=0.016). On univariate analysis South Asian ethnicity was also identified as being a risk factor for presentation with R3 retinopathy, but this was no longer significant when HbA1c was adjusted for in a forward stepwise logistic regression analysis.ConclusionIn our cohort social deprivation appears to be associated with late presentation of proliferative diabetic retinopathy. Our study supports the need to target these groups to reduce preventable blindness and to identify strategies which overcome barriers to care.

Pre-Transplant Consolidation and Cost Effectiveness of RIC Allogeneic SCT in Patients of AML-CR1 in India

▪Management of acute myeloid leukemia (AML) in India remains a challenge. A major constraint is the cost of therapy. In a predominantly self paying system the majority of patients will not have the resources to manage a subsequent relapse. Hence, the choice of consolidation therapy has to be carefully considered to balance cost and efficacy. An allogeneic SCT (alloSCT) with a reduced intensity conditioning regimen (RIC) in first remission (CR1) is an attractive option to fulfill these requirements of relatively low cost without compromising efficacy. The need for consolidation chemotherapy prior to offering a RIC alloSCT for AML CR1 remains controversial. To evaluate these aspects we undertook a retrospective analysis of patients with AML CR1 who received a RIC alloSCT from multiple centers in India. Conventional criteria were used for definition of conditioning regimens to be considered RIC (CIBMTR).Data from 8 centers in India was collected between 2005 and 2013. A total of 138 patients fulfilled the criteria of AML CR1 having received an alloSCT with a RIC regimen. The median age was 34 years (range: 2 – 63) and 60% were males. The median time from diagnosis of AML to transplant was 99 days (range: 41 – 504). 123 (89%) were HLA matched related donors, 3 (2.1%) were MUD transplants and the rest were HLA mismatched related donors. The majority by cytogenetics (n=115) were intermediate risk (76%) followed by high risk (23%). 70 (51%) received chemotherapy consolidation prior to transplant, 61 (44%) did not and data was not available in 7 (5%). 68% of those that received consolidation received intermediate or low dose cytosine based regimens. 129 (94%) were CMV serology positive pre-transplant. Fludarabine with melphalan (140mg/m2) (128{93%}) was the most commonly used regimen and cyclosporine with short course low dose methotrexate (126{91%}) the most commonly used GVHD prophylaxis regime. All patients received a PBSC graft with a median CD34 cell dose of 9.1x106/kg (range: 1.3 – 43). With the exception of one, all patients engrafted. The median time to ANC >500/mm3 was 13 days (range: 7 – 22) and platelet count of >20,000/mm3 was 15 days (range: 0-33). Of those that engrafted, 97% achieved complete chimerism at one month post transplant (data not available in 4). Post transplant CMV reactivation was seen in 32% and a fungal infection (possible, probable or definitive) in 13%. Acute GVHD Grade 2-4 was seen in 29% and of patients evaluated 62% had chronic GVHD, the majority of these being limited (61%). The 100 day treatment related mortality (TRM) was 7.5% and the one year TRM was 25.6%. At a median follow up of 24 months the 5 year EFS and OS was 64.0±5.07 (Figure 1A) and 71.1±4.0 respectively. The 5 year cumulative incidence of relapse was 21.8% (Figure 1A). The baseline characteristics as mentioned above were not significantly different between the group that received consolidation and the group that did not. The use of consolidation therapy prior to alloSCT did not have a significant impact on EFS or OS (Figure 1B).On univariate analysis the factors that adversely impacted EFS were mismatched non sibling family donor (RR 8.1; P-value 0.001), CMV reactivation (RR 2.6; P-value 0.001), fungal infection post transplant (RR 6.8; P-value 0.000) and acute GVHD (RR 2.1; P-value 0.02). On a forward stepwise multivariate analysis adjusting for these and other conventional risk factors only CMV reactivation (RR 2.0; 95% CI 1.03-3.87; P-value 0.042) and fungal infection (RR 7.1; 95%CI 3.154-16.12; P-value 0.000) retained their adverse impact. There was no correlation between CMV reactivation and relapse of disease post transplant.The mean costs of induction chemotherapy for these patients was US$ 9239±3596 (n=74), for consolidation chemotherapy it was 5007±3490 (n=21) and for alloSCT it was 18138±13826 (n=118; costing up to 1 year post transplant). Induction chemotherapy followed by HLA matched RIC alloSCT is likely to be a cost effective and affordable treatment option for young adults with AML in CR1in an Indian context. With an average gross net income in India of US$3500/year (http://indiabudget.nic.in) the limitation still remains the cost of treatment and number of centers that can offer this therapy. [Display omitted] DisclosuresSrivastava:Octapharma: Consultancy, Other. Off Label Use: Bortezomib in the treatment of acute promyelocytic leukemia.

Unchecking the box: beta blocker associated harm in carotid endarterectomy

METHODS: The vascular procedure specific American College of Surgeons National Surgical Quality Improvement Program database for 2011-2012 was queried for carotid endarterectomy (CEA). Univariate statistics were performed to identify factors associated with MI and pre-procedural beta-blockers. A propensity score was created for beta-blocker use, accounting for selection bias. A forward stepwise multivariable analysis was undertaken for the primary endpoint using factors meeting criteria of p<0.01.

Vascular surgeons have better outcomes than non-vascular surgeons in key index open vascular procedures

METHODS: The vascular procedure specific American College of Surgeons National Surgical Quality Improvement Program database for 2011-2012 was queried for carotid endarterectomy (CEA). Univariate statistics were performed to identify factors associated with MI and pre-procedural beta-blockers. A propensity score was created for beta-blocker use, accounting for selection bias. A forward stepwise multivariable analysis was undertaken for the primary endpoint using factors meeting criteria of p<0.01.

The association between brain injury, perioperative anesthetic exposure, and 12‐month neurodevelopmental outcomes after neonatal cardiac surgery: a retrospective cohort study

Adverse neurodevelopmental outcomes are observed in up to 50% of infants after complex cardiac surgery. We sought to determine the association of perioperative anesthetic exposure with neurodevelopmental outcomes at age 12months in neonates undergoing complex cardiac surgery and to determine the effect of brain injury determined by magnetic resonance imaging (MRI). Retrospective cohort study of neonates undergoing complex cardiac surgery who had preoperative and 7-day postoperative brain MRI and 12-month neurodevelopmental testing with Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Doses of volatile anesthetics (VAA), benzodiazepines, and opioids were determined during the first 12months of life. From a database of 97 infants, 59 met inclusion criteria. Mean±sd composite standard scores were as follows: cognitive=102.1±13.3, language=87.8±12.5, and motor=89.6±14.1. After forward stepwise multivariable analysis, new postoperative MRI injury (P=0.039) and higher VAA exposure (P=0.028) were associated with lower cognitive scores. ICU length of stay (independent of brain injury) was associated with lower performance on all categories of the Bayley-III (P<0.02). After adjustment for multiple relevant covariates, we demonstrated an association between VAA exposure, brain injury, ICU length of stay, and lower neurodevelopmental outcome scores at 12months of age. These findings support the need for further studies to identify potential modifiable factors in the perioperative care of neonates with CHD to improve neurodevelopmental outcomes.

Clinical Profile and Outcomes of Patients with β Thalassemia Major and Hepatitis C Virus Infection Undergoing an Allogeneic Stem Cell Transplant

AbstractAbstract 4160There is limited data on the prevalence, clinical profile and outcome of patients with β thalassemia major (TM) who is HCV sero-positive (HCV+) prior to an allogeneic stem cell transplant (SCT). From October, 1991 to June, 2012, 370 SCT were done for TM at our center. The median age was 7.5 years (range: 2–24) and there were 232 (62.87%) males. 209 (56.5%) belonged to Lucarelli Class III. There were 44 (11.9%) cases who were HCV+, 6 (1.6%) who were HBsAg positive and 350 (94.6%) who were CMV sero-positive at the time of pre-transplant screening.HCV+ cases were significantly older and had a significantly larger liver size. There were significantly more number of HCV+ cases who were Lucarelli Class III and the median liver enzyme and ferritin levels were higher in the HCV+ group. Table 1 summarizes these and other major differences between those who were HCV positive at diagnosis and the remaining patients. The number of graft rejections was significantly higher in the HCV+ group while the TRM was comparable between the two groups. This translated into a significantly inferior event free survival (P=0.016) though the overall survival was not significantly different (P=0.140)(Table 1). It is well recognized that patients with TM are at a high risk of developing sinusoidal obstruction syndrome (SOS) post SCT. In this series, 165 (4.6%) patients developed SOS. HCV+ cases did not have a significantly higher incidence of SOS compared to those that were HCV negative. In only 3 (6.8%) of HCV+ cases was SOS the major cause of death while SOS was a major contributory factor for death in 17 (5.2%) of the remaining cases. Among the 15 (34%) of HCV+ cases that died, the major contributory cause of death was infection (40%), graft failure (20%) and SOS (20%). On a univariate cox regression analysis, HCV+ had an adverse impact on EFS (RR=1.710; 95%CI 1.066–1.744; P=0.026). However, on a forward stepwise multivariate analysis after adjusting for conventional risk factors HCV+ status did not confer an independent adverse risk factor. Of the 29 patients who are surviving, at a median follow up of 25 months, none have had progression to chronic liver disease. 20 (69%) had a normal liver function test at last follow up while only 3 have had HCV directed therapy post transplant.From August, 2009 at our center we have been using a treosulfan based conditioning regimen for our Class III patients. Among the HCV+ cases 10 were conditioned with this regimen. This regimen was well tolerated with 100% engraftment. Two patients died, one due to sepsis and the other to GVHD. In comparison, in the historical control of HCV+ cases conditioned with a conventional busulfan based regimen where there were graft rejections in 9 (26.4%) and 13 (38.2%) deaths, the major contributory cause for death being infections (46%), SOS (23%) and graft failure (23%).In conclusion HCV+ status is a surrogate risk factor for other adverse risk factors such as older age, increased liver size and inadequate medical therapy prior to SCT. After adjusting for such risk factors HCV+ cases with TM undergoing an allogeneic SCT transplant have comparable outcomes to HCV negative cases. Use of a treosulfan based regimen is well tolerated in the HCV+ group and could potentially improve the outcome in this high risk group. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Pharmacokinetics of Cyclophosphamide Metabolites Influence Outcome in Patients with β-Thalassemia Major Undergoing Allogeneic HSCT

Abstract 1941Busulfan in combination with cyclophosphamide (Cy) is the commonly used conditioning regimen for hematopoietic stem cell transplantation (HSCT) for various hematological diseases. Cy, a prodrug, undergoes hepatic biotransformation to 4-hydroxy cyclophosphamide (4-HCy) and subsequently to its active metabolite, phosphoramide mustard (PM) and carboxyethyl PM (CEPM), a nontoxic oxidation product of HCY/aldophosphamide. Though toxic complications like hemorrhagic cystitis (HC) and hepatic sinusoidal obstruction syndrome (SOS) have been associated with metabolites of Cy such as acrolein and CEPM, respectively, there is no data correlating pharmacokinetics (PK) of Cy, HCy or CEPM with toxicity and outcome of HSCT for ß thalassemia major. Aim of the present study was to evaluate Cy, 4-HCy and CEPM PK and the influence of these PK parameters on clinical outcome in patients with ß thalassemia major undergoing HSCT. Between January 2001 to June 2009, out of the 168 HSCT for thalassemia major conditioned with Bu/Cy regimen (including 8 second transplants), 90 patients for whom PK samples were collected were included in this study. Cy was administered at 50 mg/kg/day for 4 days (days −5 to −2) following 4 days of busulfan (days −9 to −6). Peripheral blood samples were collected during Cy infusion at various time interval and plasma samples were stored for Cy, HCy and CEPM PK analysis. Levels of Cy and 4-HCy were measured by high performance liquid chromatography, and CEPM, by a modified LCMSMS method. The population PK estimates were determined using non-linear mixed effects modeling analysis performed with Monolix (version 3.1, www.monolix.org). Specifically, a compartmental model which included two compartments each for Cy, HCy and CEPM was used to describe the data. Clinical outcome endpoints including graft rejection, event free survival (EFS), overall survival (OS), transplant related mortality (TRM), SOS, and HC were evaluated using standard criteria. The influence of Cy and metabolite PK on clinical outcome endpoints were compared using logistic regression analysis.Age range of the patients was 2 to 24 years. Four patients belonged to Lucarelli risk class I, 49 class II and 37 class III. Based on risk stratification that we have defined using liver size and age (high risk: age >7 years and liver size >5cm; and the rest as low risk; Mathews et al, 2007), 39 were in low risk, 40 intermediate and 11 were high risk. Overall incidence of OS, EFS, rejection, TRM, SOS, HC in this cohort was 77, 70, 14, 10, 18 and 31% respectively. It should be noted that this does not completely represent the outcome of HSCT in thalassemia during this period, as only patients with available Cy PK analysis were included for analysis. The high risk patients had significantly reduced OS (RR 2.59; p=0.04), EFS (RR 2.23; p=0.058), increased risk of TRM (RR: 3.56; p=0.03) and HC (RR: 3.19; p=0.036) compared to others, while this was not significantly different with respect to Lucarelli class except for increased incidence of HC in Lucarelli class III patients (RR: 2.6; p=0.04).Upon univariate analysis, there was significantly increased Cy AUC (1887 ng*h/ml; range: 679–8546; vs. 1544, range: 662–4434; p= 0.028) in patients who developed HC compared to those who did not. There was significantly decreased HCy AUC (median 5.172 ug*L/h, range: 0.795–6.457; vs. 6.224; 2.536–12.003 p=0.007) in patients who died compared to those who are alive; similar but more significant association was seen with EFS as well. There was decreased CEPM Cl/F in those who rejected the grafts (0.013 vs. 0.028 L/h/Kg; p=0.016), while it was significantly increased in patients who developed SOS (median 0.029; vs. 0.013, range: L/h/Kg; p=0.05). Upon forward stepwise multivariate analysis including all the Cy and metabolite PK parameters, only HCy AUC significantly influenced EFS and OS in these patients. We show here for the first time that Cy and metabolite PK influences HSCT outcome in a uniform cohort of patients with thalassemia major. However, due to the complex metabolic pattern of Cy, and the association of metabolite PK instead of the levels of the parent compound with outcome, the possibility of targeted dose adjustment of Cy to improve HSCT outcome may be more challenging than targeted dose adjustment of other drugs used in HSCT. Disclosures:No relevant conflicts of interest to declare.

Lower osteocalcin and osteopontin contents of the femoral head in hip fracture patients than osteoarthritis patients

In patients with femoral neck fracture, clinical factors, bone metabolism markers (in serum, urine, and bone), bone mineral density, radiographic parameters, and bone histomorphometric parameters were investigated to detect determinants of fragility fracture. The osteocalcin/deoxypyridinoline ratio and osteopontin/calcium ratio of cortical bone were selected as significant predictors. Measurement of bone mineral density is widely used to assess bone strength, but this also depends on other bone components and on bone structure. The objective of this study was to investigate risk factors for fracture related to bone quality, the patient's history, and the patient's lifestyle. Twenty-one patients with femoral neck fracture and 18 patients with osteoarthritis were enrolled. Blood and urine samples were collected on admission to hospital, and bone samples were obtained from femoral necks resected during surgery. Multivariate logistic regression analysis was performed using osteoarthritis and femoral neck fracture as combined variables to assess the influence of alcohol or coffee intake, eating natto (fermented soybeans), osteocalcin and calcium concentrations, the osteocalcin/deoxypyridinoline ratio and osteopontin/calcium ratios of cortical bone and cancellous bone, various bone histomorphometric parameters, the bone mineral density of the lumbar spine and the intact contralateral femoral neck, and various radiographic parameters of the spine By forward stepwise multivariate analysis, the osteocalcin/deoxypyridinoline and osteopontin/calcium ratios of cortical bone were selected as significant factors for fracture (the odds ratios were 0.493 and <0.001, respectively; both P<0.001). A decrease of osteopontin and osteocalcin in bone is important for promoting vulnerability to hip fracture.

Total and high–molecular weight adiponectin in women with the polycystic ovary syndrome

Adiponectin, an adipokine with antidiabetic properties, forms multimers; and the high–molecular weight (HMW) form most closely correlates with insulin sensitivity ( S i). Therefore, we hypothesize that HMW adiponectin levels are decreased in women with polycystic ovary syndrome (PCOS), a condition characterized by insulin resistance, compared with healthy controls and that HMW adiponectin correlates with testosterone and S i. A cross-sectional study involving 13 women with PCOS and 13 age- and body mass index–matched healthy controls was performed. Waist-to-hip ratios (WHRs), glucose, insulin, sex hormone–binding globulin, total testosterone, and total and HMW adiponectin levels were measured after an overnight fast. Free testosterone was calculated from sex hormone–binding globulin and total testosterone, and S i was determined using a frequently sampled intravenous glucose tolerance test. The study's primary outcomes were differences in total and HMW adiponectin between women with PCOS and healthy control women. Total adiponectin ( P < .01), HMW adiponectin ( P < .01), and the ratio of HMW to total adiponectin ( P = .03) were lower in women with PCOS compared with healthy women. Total and HMW adiponectin levels correlated inversely with WHR ( P < .01) and free testosterone ( P < .01) and positively with S i ( P < .001). Using forward stepwise multivariate analysis, HMW adiponectin and WHR, but not PCOS status, were independent predictors of S i. Women with PCOS have lower total and HMW adiponectin levels compared with healthy women. High–molecular weight adiponectin also comprises a smaller proportion of total circulating adiponectin in women with PCOS. Alterations in HMW adiponectin levels in women with PCOS may contribute to the insulin resistance intrinsic to the syndrome.

Polymorphism in the IFN-γ Gene Is Associated with Severe Acute Graft Versus Host Disease in β Thalassemia Major Patients Undergoing Matched Related Hematopoietic Stem Cell Transplantation (HSCT).

Acute graft versus host disease (aGVHD) is a major cause for morbidity and mortality following allogeneic HSCT (alloHSCT). Polymorphisms in Th2 cytokine genes such as IL-10 have been shown to modulate GVHD. Th1 cytokines, IFN-γ, TNF-α and IL-1β have been implicated in the pathogenesis of aGVHD in mouse models but there is limited data in human HSCT. We have evaluated the prevalence of the following functional polymorphisms in Th1 cytokines (IFN-γ +874, TNF-α −308, IL-1β −511 and +3953), Th2 cytokines (IL-10, IL-6), TGF-β and IL-1Ra in patients with β thalassemia major undergoing matched related alloHSCT and correlated them with the incidence of aGVHD. A total of 129 patients were evaluated. Patients who expired before day 15 (n=9) and for whom appropriate DNA samples were not available (n=18) were excluded. Of the 102 patients who were assessable, 72 (72%) patients received conditioning with Bu (16mg/kg) / Cy (200mg/kg) with anti-thymocyte globulin (ATG) while 30 (28%) patients received Bu (600mg/m2) / Cy (200mg/kg) without ATG. All patients received unmanipulated bone marrow and standard cyclosporine / short-course methotrexate towards prophylaxis against GVHD. Patients who died after HSCT without achieving ANC >500/mm3 were not assessed for aGVHD (n=6). Of the remaining 96 patients, 54 (53%) had aGVHD, 13 (24%) of which were grade III–IV. Apart from the immunogenetic markers mentioned above, the impact of other risk factors for aGVHD such as recipient and donor age, sex mismatch, conditioning regimen, cell dose, ABO compatibility and thalassaemia risk class were also analyzed. Of these, recipient age >10 years and female to male sex-mismatched transplants were found to increase the risk of developing severe aGVHD (grade III–IV). Among the cytokine polymorphisms evaluated, donor IFN-γ (dIFN-γ) +874 T/T genotype, associated with higher levels, was found to significantly increase the risk of developing severe aGVHD (RR= 4.9; p= 0.013; 95% CI 1.39–17.08). These results were also found to be consistent on forward stepwise multivariate analysis. No correlation was found between severe aGVHD and TNF-α, IFN-γ, IL 10 polymorphisms of recipients and IL-1Ra polymorphisms of donor. IFN-γ may facilitate antigen presentation and effector cell recruitment as elucidated in various experimental studies. Therefore, it is possible that dIFN-γ +874 T/T genotype might contribute to increased incidence of severe aGVHD since the effector T cells mediating aGVHD are of donor origin after transplant. Our data shows for the first time that development of severe aGVHD in patients with β thalassemia major undergoing matched related alloHSCT is affected by immunogenetic factors other than HLA.Risk factorsRelative risk [95% CI] *P-value *Relative risk [95% CI] ♠P-value ♠Recipient age >103.1 [1.05–9.34]0.0404.3 [1.36–13.33]0.012< 101.01.0Sex mismatched Transplant - Yes4.7 [1.05–21.32]0.043NSNo1.0Female to Male Transplant Yes3.5 [1.15–10.74]0.0285.3 [1.59–17.49]0.006No1.01.0IFN- γ +874 TT3.3 [1.00–10.59]0.0504.9 [1.39–17.08]0.013TA+AA1.01.0* - Univariate analysis, ♠- Multivariate analysis

NAC Manchester Asthma and Allergy Study (NACMAAS): risk factors for asthma and allergic disorders in adults.

Asthma and atopic disorders are the most common chronic diseases in the developed countries. Knowledge of the risk factors for these disorders may facilitate the development of preventive strategies aimed at reducing prevalence rates. To investigate the risk factors for asthma and allergic diseases in a large number of adults who are the parents of children in the National Asthma Campaign Manchester Asthma and Allergy Study. All pregnant women and their partners attending "Booking" antenatal clinics were invited to take part in the study. Questionnaire data were collected including the history of asthma and other atopic diseases, pet ownership and smoking habits, and skin prick tests were performed. The prevalence of atopy and the risk factors for asthma and allergic disorders were investigated in all subjects who completed the questionnaire and underwent skin testing. Statistical analysis was carried out using logistic regression. Initially, risk factors were assessed by univariate analysis to see how each potential explanatory variable affected the probability of having allergic disease. Variables were then tested in a forward stepwise multivariate analysis. In 5687 adult subjects there was a very high (48.2%) prevalence of atopy, and 9.7% of subjects had a diagnosis of asthma. In a multivariate regression analysis sensitization to dust mite, cat, dog and mixed grasses were all independently associated with asthma. The odds ratios for current asthma increased with the increasing number of positive skin tests (any two allergens - OR 4.3, 95% CI 3.3-5.5; any three allergens - OR 7.0 95% CI 5.3-9.3; all four allergens - OR 10.4, 95% CI 7.7-14; P < 0.00001). Dog ownership (OR 1.31, 95% CI 1.10-1.57; P = 0.003) and current smoking (OR 1.36, 95% CI 1.15-1.62; P = 0.0004) were significantly and directly associated with "asthma ever". Thirteen per cent of participants reported a history of eczema. In the multivariate analysis the strongest independent associate of eczema was sensitization to dog (OR 1.37, 95% CI 1.14-1.63, P < 0.0001). Apart from dog, the strength of the association between sensitization to common allergens and eczema appeared to be much lower than in the case of asthma. The prevalence of hay fever was high (20.6%), and in the multivariate analysis the association between sensitization to pollen and hay fever was extremely strong (OR 13.6, 95% CI 11.3-16.3; P < 0.0001). The results of the current study emphasize the importance of sensitization to indoor allergens in asthma. However, evidence of a possible direct role of allergen exposure in asthma causation remains unclear.

The greatest dimension of prostate carcinoma is a simple, inexpensive predictor of prostate specific antigen failure in radical prostatectomy specimens

Tumor volume in radical prostatectomies can be determined by several different techniques and appears to predict clinical progression. Greatest tumor dimension and area are easily obtained measures that are both correlated with tumor volume. The authors sought to determine whether greatest tumor dimension and/or area were predictors of prostate specific antigen (PSA) failure in men who underwent radical prostatectomy for adenocarcinoma of the prostate. Fifty-seven men with prostate carcinoma who underwent surgical resection were followed for a median of 27.2 months (range, 1-112 months); 24 (42%) of these men had PSA failure. Preoperative PSA, Gleason grade, pathologic stage, margin status, and greatest tumor dimension and area were determined, and both univariate and multivariate analyses of the outcomes of PSA failure were performed. In the univariate analysis, larger values of greatest tumor dimension and area were strongly associated with increased incidence of PSA failure (P = 0.0001 and 0.0011, respectively). The forward stepwise multivariate analysis indicated that greatest tumor dimension had marginal statistical significance as a risk factor for PSA failure (P = 0.0577; risk ratio, 1.117). However, in this series, men with a greatest tumor dimension of less than 1 cm did not experience failure, whereas all patients with a greatest tumor dimension of more than 2 cm did. Measuring greatest tumor dimension is a simple, inexpensive predictor of PSA failure in men who have undergone radical prostatectomy.