Multivariate Analysis Of Outcome Research Articles

Assessment of rehabilitation following subarachnoid haemorrhage in China: findings from the Chinese Stroke Center Alliance

BackgroundRehabilitation improves functional recovery in subarachnoid hemorrhage (SAH) patients, and assessing patients for rehabilitation is the first step in this process. However, little is known about clinical practice in China regarding the assessment and provision of rehabilitation for patients with SAH.MethodsTo identify patients hospitalized with SAH and to analyze rehabilitation assessment rates, we used data for 11,234 SAH patients admitted to 861 hospitals from the China Stroke Center Alliance from August 2015 to July 2019. We examined factors for rehabilitation assessment and analyzed the relationship between rehabilitation assessment and outcomes in these patients.ResultsAmong 11,234 patients with SAH, 6,513 (58.0%) were assessed for rehabilitation. Assessed patients had an increased length of stay (mean ± SD days: 17.3 ± 12.5 versus 11.6 ± 10.5, P = 49.4), a higher Glasgow Coma Scale (GCS) score on admission (mean ± SD GCS score: 12.3 ± 3.8 versus 11.8 ± 4.4, P = 12.2), and were more likely to be admitted to the stroke unit (19.6% versus 13.8%, P = 15.6). In multivariable analysis, factors associated with an increased likelihood of a rehabilitation assessment (p < 0.05) included a longer length of stay (odds ratio [OR], 1.04; 95% confidence interval (CI), 1.04 to 1.05) and care such as dysphagia screening (OR, 1.88; 95% CI, 1.73 to 2.04), DVT prophylaxis (OR, 1.56; 95% CI, 1.41 to 1.72) and vessel evaluation (OR, 1.80; 95% CI, 1.63 to 1.98). For the multivariate analysis of outcomes, patients undergoing rehabilitation assessment had a longer length of stay (OR, 1.96; 95% CI, 1.81 to 2.12), a higher modified Rankin Scale (mRS) score at discharge (OR, 1.49; 95% CI, 1.36 to 1.64), and higher rates of discharge to a rehabilitation center (OR, 3.23; 95% CI, 1.81-5.75).ConclusionMore than two-fifths of SAH patients were not assessed for rehabilitation. Rates vary considerably among hospital grades, and there is a need to improve adherence to recommended care for SAH patients.

Temporal trends in adverse ischemic events, bleedings, kidney injury and overall mortality for patients with ST-elevation myocardial infarctions and advanced kidney disease

Abstract Background Although the negative effects of advanced chronic kidney disease (CKD) on the pathogenesis and prognosis of coronary artery disease (CAD) has been shown in prior studies, there is few data on the efficacy and safety of modern interventional therapies and medications in patients with advanced CKD. Aim of the present study was to analyse temporal trends in patients with ST-elevation myocardial infarctions (STEMI) and advanced CKD during the last 15 years. Methods All STEMI-Patients admitted to a German heart center between 2006–2019 were analysed. Advanced CKD, estimated with the CKD-EPI-equation, was defined as stage ≥G3b (glomerular filtration rate (GFR) &amp;lt;45 ml/min). Cumulative ischemic events at 1 year were defined as a combination of in-stent-thrombosis, myocardial re-infarction and repeat target-lesion-revascularisation Results Of a total of 9605 patients, 1013 (10.6%) showed a moderately or severely (G3b-G5) reduced renal function with a mean baseline Serum creatinine of 2.2±4.2 mg/dl and a GFR of 32.3±10 ml/min/1.73 m2. CKD-Patients were less likely to be treated with a primary percutaneous coronary interention (PCI): 84.1 vs. 94.1% (p&amp;lt;0.01) and showed higher all-cause-mortality (44.4 vs. 3.6%, p&amp;lt;0.01) and bleeding-rates (9.4 vs 3.7%, p&amp;lt;0.01) compared to non-CKD-patients at 1 year, while cumulative ischemic events did not differ (6.5 vs. 5.1%, p=0.12). Over time however, patients with advanced CKD were also more likely to be treated with primary PCI (2006–10: 75.8 to 2015–19: 90.1%, p&amp;lt;0.01), ticagrelor/prasugrel (1.7 to 59.6%, p&amp;lt;0.01) and drug eluting stents (DES: 1.3 to 90.7%, p&amp;lt;0.01). After adjustment for confounders (multivariate analysis of outcomes adjusted for age, gender, diabetes and cardiogenic shock) patients with advanced CKD showed a decline in ischemic events at 1 year, however offset by an increase in bleedings (table). Neither overall mortality nor rates of acute kidney injury changed over time (table), despite an increase in amount of contrast media used (132±62 ml to 152±73 ml, p&amp;lt;0.01). In patients with advanced CKD both ticagrelor/prasugrel (OR 0.48, 95% CI 0.2–0.98) and DES (OR 0.38, 95% CI 0.2–0.8) were associated with a decrease in ischemic-events. Conclusions This registry data shows, that during the last 15 years STEMI-patients with advanced CKD were more likely to be treated with primary PCI and are in their majority now treated with ticagrelor, prasugrel and modern DES. These changes in therapeutic strategies probably have contributed to the decline in adverse ischemic events, while overall mortality was not affected. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): State of BremenStiftung Bremer Herzen Multivariate outcome analysis over time

Comparative Outcome of Reduced Intensity and Myeloablative Preparative Regimen in HLA Identical Sibling Allogeneic Hematopoietic Stem Cell Transplantation for Patients Older Than 50 Years of Age with Acute Myeloblastic Leukaemia: A Retrospective Survey from the Acute Leukemia Working Party (ALWP) of the European Group for Blood and Marrow Transplantation (EBMT).

Results of reduced intensity preparative regimen (RIC) hematopoietic stem cell transplantation (HSCT) in the HLA identical HSCT setting have not been compared to myeloablative HSCT (MA) in patients with AML over 50 years of age. With this aim, outcomes of 315 RIC were compared with 407 MA HSCT recipients from 182 transplant centers. The majority of RIC was fludarabine-based regimen associated to Busulfan (BU) (53%) or low dose TBI (24%). Multivariate analyses of outcomes were used adjusting for differences between both groups. The median follow-up was 13 months. Cytogenetics, FAB classification, WBC count at diagnosis and status of the disease at transplant were not statistically different between the two groups. However, RIC patients were older (median 57 years versus 54 years), transplanted more recently, and more frequently with peripheral blood allogeneic stem cells as compared to MA recipients. In multivariate analysis, Incidence of grade II-IV acute GvHD (aGvHD) was significantly lower after RIC: 22% compared to 31% after MA HSCT (p=0.003) but not Grade III-IV (8% versus 12%, respectively)(p=0.12). the risk of chronic GVHD was lower following RIC (RR=0.69; 95% CI,=0.51 to 0.94, p=0.02). Transplant-related mortality was significantly decreased(18% versus 32%) (p<10−4; RR=0.48, CI= 0.33 to 0.68), and relapse incidence was significantly higher (41% versus 24%) (p=0.0003; RR=1.78, CI=1.3 to 2.43) after RIC transplantation. Leukaemia-free survival (LFS) was not statistically different between the two groups. These results may set the grounds for prospective trials comparing RIC with other strategies of treatment in elderly AML.

Electroencephalographic Abnormalities are Common in COVID-19 and are Associated with Outcomes.

ObjectiveThe aim was to determine the prevalence and risk factors for electrographic seizures and other electroencephalographic (EEG) patterns in patients with Coronavirus disease 2019 (COVID‐19) undergoing clinically indicated continuous electroencephalogram (cEEG) monitoring and to assess whether EEG findings are associated with outcomes.MethodsWe identified 197 patients with COVID‐19 referred for cEEG at 9 participating centers. Medical records and EEG reports were reviewed retrospectively to determine the incidence of and clinical risk factors for seizures and other epileptiform patterns. Multivariate Cox proportional hazards analysis assessed the relationship between EEG patterns and clinical outcomes.ResultsElectrographic seizures were detected in 19 (9.6%) patients, including nonconvulsive status epilepticus (NCSE) in 11 (5.6%). Epileptiform abnormalities (either ictal or interictal) were present in 96 (48.7%). Preceding clinical seizures during hospitalization were associated with both electrographic seizures (36.4% in those with vs 8.1% in those without prior clinical seizures, odds ratio [OR] 6.51, p = 0.01) and NCSE (27.3% vs 4.3%, OR 8.34, p = 0.01). A pre‐existing intracranial lesion on neuroimaging was associated with NCSE (14.3% vs 3.7%; OR 4.33, p = 0.02). In multivariate analysis of outcomes, electrographic seizures were an independent predictor of in‐hospital mortality (hazard ratio [HR] 4.07 [1.44–11.51], p < 0.01). In competing risks analysis, hospital length of stay increased in the presence of NCSE (30 day proportion discharged with vs without NCSE: HR 0.21 [0.03–0.33] vs 0.43 [0.36–0.49]).InterpretationThis multicenter retrospective cohort study demonstrates that seizures and other epileptiform abnormalities are common in patients with COVID‐19 undergoing clinically indicated cEEG and are associated with adverse clinical outcomes. ANN NEUROL 2021;89:872–883

Failures and Successes in Pediatric Patients with Acute Myeloid Leukemia with First Relapse: A Large International Report on Current Treatment Strategies and Outcome

BACKGROUND: Children with high risk acute myeloid leukemia (AML) still experience consistently high rates of relapse. Survival after first relapse increased from 21% between 1987 and 1997 up to 39% in recent studies. However, since 2009, there have been no publications on subsequent large pediatric AML relapse trials. As the indications for HSCT during first-line treatment have been extended since then, the current survival of these patients at relapse remains unclear. Herein, we report outcome results from the BFM and COG study group, which represents the largest available dataset analyzed for post-relapse survival. PATIENTS AND METHODS: Pediatric patients with first relapse of AML (no Down syndrome, secondary leukemia or FAB M3) have been analyzed from two large study groups with patients from the United States, Canada, Australia, New Zealand, Germany, Austria, Czech Republic and Switzerland. Out of 1222 patients in the BFM cohort (AML-BFM study 2004, registry 2012 and study 2012), 350 experienced at least one relapse and 197 of those had a first relapse after closure of the last I-BFM relapse trial (04/2009 through 2017). Within the Children's Oncology Group (COG) Phase 3 trials (AAML0531 and AAML1031, n=2119) 852 pediatric patients suffered a relapse. Five-year probability of overall survival (pOS) and event-free survival (pEFS) were calculated according to Kaplan-Meier. EFS was calculated for the BFM cohort as time from relapse to the next event (second relapse, death, failure to achieve a second remission or secondary malignancy) or until last follow-up, while OS reflects the time from relapse until death or last follow-up. The Cox proportional hazards model was used for multivariate analysis of outcomes. Living patients were censored at last follow-up with a median follow-up after relapse of 4·2 years (BFM) and 4·8 years (COG). Data have been frozen at 03/27/2020 (BFM) and 03/31/2020 (COG). RESULTS: In the 197 patients with relapse after closure of the last BFM relapse trial (04/2009 through 2017) the pOS at 5 years was 42±4% (BFM). The 5-year pOS in patients relapsing after COG trials 2006-2018 was 35±2% (n=852). Patients experiencing a relapse between 2014 to 2017 had a pOS of 49±6% (BFM, n=78) and 40±3% (COG, n=333). Risk classification at initial diagnosis and a short time from diagnosis to relapse predicted a diminished survival probability in both cohorts (see Table 1). However, the absence of full hematopoietic regeneration of the bone marrow after re-induction did not predict survival: Within the BFM dataset, a subgroup analysis in all patients receiving DNX-FLA (n=156) have been performed. Initial characteristics are comparable to the total cohort. Among these patients 147 were evaluable for response (7 excluded due to early death before evaluation, 2 for insufficient data). Eighty-nine (57%) achieved a CR (n=69) or CRp (n=20) and 52 (33%) no response. Overall survival was superior for patients with a CR/CRp (54±6% (CR/CRp) vs. 32±7% (No CR/CRp); p=0·0064), but long-term survival was still possible even with a poor re-induction response. Patients with a CRp had a comparable survival to those with a CR after a second re-induction (pOS 60±11% (CRp) vs. pOS 52±7% (CR); p=0·57). Patients with &amp;gt;5% leukemic blasts (n=32) had the lowest survival (pOS 27±9%). The 5-year pEFS for this cohort was 29±4% (pEFS 50±6% (CR) vs. pEFS 50±11% (CRp)). The analysis of post-relapse treatment showed that the vast majority of patients who survive had a HSCT following relapse. By landmark analysis, survival was significantly higher in patients with subsequent HSCT compared to that of non-transplanted patients (BFM: pOS 53±4%, n=154 vs. pOS 5±5%, n=21; p(Mantel-Byar)=0·0002). CONCLUSION: This is the largest report to date on post relapse survival in children with AML. Our analysis confirmed previously described risk factors for poor survival while also highlighting new findings contrary to established standards. Strikingly, the absence of full hematopoietic regeneration of the bone marrow after re-induction did not predict survival at first relapse, thereby questioning the current value of the established International Working Group Criteria published by Cheson et al for response-evaluation in pediatric AML. As the international pediatric AML community embarks on collaborative efforts to evaluate new therapies in children with relapsed AML, a comprehensive review of post relapse survival is critical. Disclosures Bourquin: Servier: Other: Travel Support. Reinhardt:Novartis: Membership on an entity's Board of Directors or advisory committees; CLS Behring: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding.

The Prognostic Significance of Lymph Node Status and Lymph Node Ratio (LNR) on Survival of Right Colon Cancer Patients: a Tertiary Center Experience.

Colon cancer is a major health problem and is one of the most frequent cancers all over the world. In Egypt, the incidence of colon cancer is relatively low, but its mortality rate is high. Lymphatic spread of colon cancer is one of the most important factors affecting the prognosis of patients. Recently, the lymph node ratio (LNR) has been evaluated as a prognostic parameter for survival. This study aimed at evaluation of nodal status of resected specimens and LNR, as well as its impact on the disease-free survival (DFS) and overall survival (OS) after curative resection of right colon cancer. The institutional registry of the Oncology Center Mansoura University (OCMU) was revised for node-positive right colon cancer cases that were operated in the period between January 2010 and January 2015. Fifty-three patients met the inclusion criteria and were followed up till January 2020. A total of 766 lymph nodes were excised from the patients. Thirty-two patients (60.4%) had a LN yield of ≥12 LNs with a mean LNR of 0.257 ± 0.27. Multivariate analysis of outcomes showed that LNR was significantly correlated with both DFS (p = 0.015) and OS (p = 0.024). Moreover, the number of resected LNs was also associated with statistically significant relationship with the DFS and OS. Our study confirms the validity of LNR as a prognostic tool that correlates with the survival of patients. Moreover, LNR cutoff values may help predict those of high chance of tumor recurrence. MS/20.03.1087 (Institutional IRB), date of registration: March 10, 2020, "retrospectively registered".

Early childhood adversity in adult patients with metastatic lung cancer: Cross-sectional analysis of symptom burden and inflammation

ObjectivePsychological and physical symptoms commonly occur in patients with metastatic lung cancer and are associated with reduced quality of life and decreased survival. Previous work has associated these symptoms with inflammation. The experience of Early Childhood Adversity (ECA) is linked to chronic inflammation and may identify adult cancer patients who are at-risk for psychological and physical symptoms. We thus hypothesized that ECA in lung cancer patients would be associated with increased psychological symptoms (distress, anxiety, and depression) and physical symptoms and that this relationship would be explained by inflammation. MethodsPatients with metastatic lung cancer (n = 92) were evaluated for ECA using the Risky Families Questionnaire. Concomitant assessments were made of distress (Distress Thermometer and Problem List [DT&PL]), anxiety (Generalized Anxiety Disorder-7), depression (Patient Hospital Questionniare-9), physical symptoms (DT&PL), and inflammation (C-reactive protein [CRP]). Multivariate models were created to explain associations of ECA with depression, anxiety, distress, number of physical problems, and inflammation. ResultsECA was associated with distress (r = 0.24, p = .03), anxiety (r = 0.30, p = .004), depression (r = 0.35, p = .001), greater physical problems (r = 0.25, p = .03), younger age (r = -0.29, p = .006), and elevated CRP (r = 0.22, p = .04). Multivariate analyses of outcomes found that depression severity was independently explained by both ECA and inflammation (β = 0.37, p = .001) but not distress or anxiety, while controlling for age and sex. Number of physical problems were also associated with ECA (β = 0.35, p = .004) but not inflammation. The association between ECA and physical problems was not significant after controlling for depression. ConclusionECA is associated with increased depression and physical symptoms independent of inflammation. Moreover, depression appears to mediate the impact of ECA on physical symptoms. ECA may identify patients at risk for psychological and physical symptoms.

Effect of Peanut Ball and Position Changes in Women Laboring With an Epidural

ObjectiveTo examine the effect of a nurse-driven intervention using a peanut ball (PB) with position changes on length of labor and incidence of cesarean birth among women who receive epidural anesthesia. DesignQuasiexperimental comparison group design. Setting/Local ProblemA 407-bed, nonprofit, Magnet-designated, Baby-Friendly Hospital Initiative–designated hospital with 8 labor and delivery suites and an average of 100 births per month. ParticipantsA total of 343 participants were included, with 164 women in the PB group. Intervention/MeasurementsThe PB was placed after epidural administration; women were repositioned a minimum of every 1 to 2 hours, and the PB was removed at second stage of labor; duration was recorded. ResultsOverall, women in the PB group were 50% less likely to have cesarean birth. For women with cervical dilation of 4 cm or less, rates of vaginal birth were 61% with use of the peanut ball. A multivariate analysis of outcomes was used. A multiple linear regression model showed, after adjusting for other variables, that PB placement alone did not shorten labor length (p = .4684). However, a stratified analysis indicated that for women with cervical dilation of 4 cm or less, length of the first stage of labor was affected by parity (p = .0042) and frequency of position change (p < .001). For women with cervical dilation greater than 4 cm, length of the first stage of labor was influenced by frequency of position changes (p = .0130) and effacement (p = .0050). Length of the second state of labor was affected by the frequency of position change (p = .0416). ConclusionThe PB may be an effective intervention to reduce the incidence of cesarean birth. Changing position frequently was associated with reduced length of first and second stages of labor.

Joint regression analysis of mixed-type outcome data via efficient scores

Joint analysis of multivariate outcomes composed of mixed data types (continuous, count, binary, survival, etc.) induces special complexity in model specification and analysis. When the scientific question of interest involves a joint effect of covariate(s) of interest on the set of outcome variables, specifying a full probability model may be infeasible, undesirably complex, or computationally intractable. A flexible method to estimate and conduct inference on such joint effects is presented which accounts for correlation among the outcomes without needing to explicitly specify their joint distribution. Simulation studies and an analysis of health care data illustrate the approach and its operating characteristics vis-à-vis other methods.

Density ratio model for multivariate outcomes

The Density Ratio Model is a semi-parametric regression model which allows analysis of data from any exponential family without making a parametric distribution assumption. For univariate outcomes several authors have shown desirable properties of this model including robustness to mis-specification and efficiency of the estimators within a suitable class. In this paper we consider analysis of multivariate outcomes with this model, where each marginal distribution is from an exponential family. We show that the model successfully analyzes data from mixed outcome types (continuous, integer, binary), providing valid tests of the joint effects of covariates. Furthermore, for continuous outcomes we provide a bootstrap technique which correctly estimates the underlying marginal regression parameters and provides appropriate coverage probabilities without specifying the covariance structure. The methods are demonstrated via simulation studies and analysis of healthcare data.

Plasmacytoma of the Skull Base: A Meta-Analysis.

Objective Extramedullary plasmacytomas are rare tumors. In the current study we aim to characterize its clinical course at the skull base and define the most appropriate therapeutic protocol. Methods We conducted a meta-analysis of articles in the English language that included data on the treatment and outcome of plasmacytoma of the base of skull. Results The study cohort consisted of 47 patients. The tumor originated from the clivus and sphenoclival region in 28 patients (59.5%), the nasopharynx in 10 patients (21.2%), the petrous apex in 5 patients (10.6%), and the orbital roof in 4 patients (8.5%). The chief complaints at presentation included recurrent epistaxis and cranial nerve palsy, according to the site of tumor. Twenty-two patients (46.8%) had surgical treatment; 25 (53.2%) received radiation therapy. Adjuvant therapy was administered in 11 cases (50%) with concurrent multiple myeloma. The 2-year and 5-year overall survival rates were 78% and 59%, respectively. Clear margin resection was achieved in a similar proportion of patients who underwent endoscopic surgery and open surgery (p = 0.83). A multivariate analysis of outcome showed a similar survival rate of patients treated surgically or with radiotherapy. Conclusions The mainstay of treatment for plasmacytoma is based on radiation therapy, but when total resection is feasible, endoscopic resection is a valid option.

Bayesian mixed-effects location and scale models for multivariate longitudinal outcomes: an application to ecological momentary assessment data.

In the statistical literature, the methods to understand the relationship of explanatory variables on each individual outcome variable are well developed and widely applied. However, in most health-related studies given the technological advancement and sophisticated methods of obtaining and storing data, a need to perform joint analysis of multivariate outcomes while explaining the impact of predictors simultaneously and accounting for all the correlations is in high demand. In this manuscript, we propose a generalized approach within a Bayesian framework that models the changes in the variation in terms of explanatory variables and captures the correlations between the multivariate continuous outcomes by the inclusion of random effects at both the location and scale levels. We describe the use of a spherical transformation for the correlations between the random location and scale effects in order to apply separation strategy for prior elicitation while ensuring positive semi-definiteness of the covariance matrix. We present the details of our approach using an example from an ecological momentary assessment study on adolescents.

In house registry of acute coronary syndrome - A multivariate analysis of outcome and management

In house registry of acute coronary syndrome - A multivariate analysis of outcome and management

The Impact of Income on Clinical Outcomes in FIGO Stages I to II Endometrioid Adenocarcinoma of the Uterus

To determine the influence of income on clinical outcomes in patients with surgical stages I to II endometrioid adenocarcinoma of the uterus. We retrospectively analyzed the records of 660 women initially treated from 1985 to 2009. On the basis of income data obtained from the 2000 US census, patients were separated into various income groups (halves, tertiles, and quartiles) based on median household income, with most focus on the half income groups. Income groups were similar regarding treatments received and characteristics, with the exception of more African American (AA), unmarried patients, and a predilection for higher grade in the lower half income group (LHIG). Compared with the upper half income group (UHIG), the LHIG had lower disease-specific survival (DSS) (5 y: 93.9% vs. 97.0% and 10 y: 90.1% vs. 95.9%; P=0.023) and a trend toward lower overall survival (OS) (5 y: 83.4% vs. 86.5% and 10 y: 62.6% vs. 68.5%; P=0.067). In patients with higher-risk features, differences in outcomes between LHIG and UHIG were more pronounced; 10-year OS of 43.4% versus 60.2% (P=0.004) and 10-year DSS of 75.0% versus 93.0% (P=0.007), respectively. Regarding race, AA patients in the LHIG had lower OS than AA in the UHIG. On univariate analysis, income group and race were significant predictors for DSS, but on multivariate analysis, they were not statistically significant. Despite similar treatments and characteristics, a small decrease in DSS and a trend toward reduced OS was observed in LHIG patients, but income group was not statistically significant on multivariate analysis of outcome. These differences were more significant in patients with high-risk features.

Comparison of in vivo skin and in vitro blood lymphocyte models for the prediction of late normal tissue responses in breast radiotherapy (RT) patients.

11116 Background: Critical opinions for the lack of success of DNA double-strand break (DSB) repair as a predictive marker of normal tissue radiosensitivity include the argument that in vitro cellular responses correlate poorly with in vivo responses due to the modifying influence of tissue environment. In this study, we test the hypothesis that a DNA damage assay based on in vivo irradiated skin tissues better predicts clinical responses in human skin, as opposed to the same assay performed in ex vivo irradiated lymphocytes. Methods: DSB levels (24 h post-4 Gy) were quantified using γH2AX/53BP1 immunostaining in irradiated skin tissues and G0 lymphocytes of 35 breast RT patients. Patients were selected on the basis of late RT effects in their breast and individuals with marked or minimal effects were classified as cases and controls, respectively. Risk factors of late effects established from multivariate analyses of outcomes of two breast RT trials were also considered in patient selection. They were 1) total RT dose, 2) RT dosimetry, 3) tumour bed boost, 4) breast size, 5) surgical cavity, and 6) axillary treatment. Results: Clinical parameters were balanced in both patient groups. Residual foci levels in skin epidermis and dermis were comparable between cases (n = 20) and controls (n = 15). Mean foci per cell were 3.29 in cases, 2.80 in controls for dermal fibroblasts (p = 0.07); 3.28 in cases, 2.60 in controls for endothelial cells (p = 0.08); 2.87 in cases, 2.41 in controls for superficial keratinocytes (p = 0.45); 2.32 in cases, 2.35 in controls for basal keratinocytes (p = 0.27). Residual foci levels in lymphocytes were however significantly higher among cases (foci per cell = 12.1) compared to controls (foci per cell = 10.3, p = 0.01). Of the different cell types, only residual foci levels of dermal fibroblasts and lymphocytes correlated with clinical severity (R = 0.722, p &lt; 0.001; 0.593, p = 0.01, respectively). Interestingly, foci levels were not correlated between skin cells and lymphocytes of the same patients. Conclusions: DSB repair of ex vivo irradiated lymphocytes appears to be a better predictive marker of late effects to breast RT than DSB repair of in vivo irradiated skin.

Outcomes Continue to Be Favorable for De Novo Philadelphia Chromosome Negative B-Lymphoblastic Leukemia (ALL) After Therapy with Hyper-CVAD (with or without Rituximab) Regimen

AbstractAbstract ▪3572▪This icon denotes a clinically relevant abstractThe hyper-CVAD regimen [Kantarjian, JCO 18: 547, 2000; Kantarjian, Cancer 101: 2788, 2004] includes intensive cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternating with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone) interrupted by early and late intensifications. The regimen was modified in 1999 to include use of laminar air flow rooms during the induction phase for patients (pts) aged 60 years or older. Therapeutic modifications included rituximab 375 mg/m2 (Days 1 & 11 of hyper-CVAD, Days 1 & 8 of MTX-cytarabine for 8 total doses) for CD20 expression > 20% to counteract increased propensity for relapse [Thomas D, Blood 113: 6330, 2009], early anthracycline intensification with liposomal daunorubicin-cytarabine from 1999–2000 only [omitted thereafter owing to lack of benefit, Thomas D, Cancer 116: 4580, 2010], augmentation of CNS prophylaxis, and extension of maintenance POMP therapy from 24 to 30 months with additional early and late intensifications [details in Thomas D, JCO 28: 3830, 2010]. Overall, 216 pts with Ph negative B-lymphoblastic leukemia have been treated with the modified hyper-CVAD regimens. Median age was 46 years (range, 16–84). For the CD20 positive B-lymphoblastic subset treated with hyper-CVAD and rituximab 3-yr rates of CR duration (CRD) and survival (OS) were 66% and 57%. In the younger (age < 60 years) CD20-positive subset, rates of CRD and OS were superior compared with standard hyper-CVAD (69% v 38%; P <.001% and 71% v 47%, P =.003). Historical experience in 37 adolescent and young adult (AYA) subset aged 15 – 30 yrs with CD20 positive B-lymphoblastic leukemia (prior to shift to augmented BFM regimen as first line therapy) showed that the addition of rituximab improved 3-yr CRD rates from 26% to 60% (P =.001) and 3-yr OS rates from 47% to 70% (P =.05) compared with standard hyper-CVAD without rituximab. There were no significant differences in outcome for this AYA subset by regimen (standard or modified) for the CD20 negative groups (all 3-yr rates > 70%). Elderly pts aged 60 year or older with CD20 positive B-lymphoblastic leukemia treated with hyper-CVAD and rituximab, in contrast to the Burkitt experience, had outcomes which were similar to the historical experience with standard hyper-CVAD (rates of CRD 59% v 50%, P = NS and OS 23% v 32%, P = NS, respectively), despite high rates of negativity for minimal residual disease (MRD) by multiparameter flow cytometry (MFC) at CR, related mainly to deaths in CR during consolidation. MRD positivity by MFC after induction therapy with hyper-CVAD and rituximab was associated with a higher relapse rate and lower 3-yr CR duration rates compared with MRD negative status at the time of CR. Additional doses of rituximab were added to consolidation (Day 1 of cycles 5 – 8) and maintenance chemotherapy in order to potentially improve outcomes for the MRD positive subset. Upfront dose reductions of cyclophosphamide, doxorubicin, vincristine, dexamethasone and methotrexate have been implemented for all cycles of induction-consolidation phase for older age and/or poor performance status with reduction in rate of deaths in CR noted. Incorporation of pegylated asparginase (one dose of 2000 Units/m2 with capping per cycle, 1000 Units/m2 if older or poor performance status) during the induction-consolidation phase (“augmented hyper-CVAD”) was piloted as first line therapy in 19 pts aged 30 – 59 years of age, then omitted owing to excessive toxicity. Incorporation of rituximab into first line intensive chemotherapy such as the hyper-CVAD regimen appears beneficial for younger pts, prompting investigation of second generation anti-CD20 monoclonal antibodies such as ofatumumab and hyper-CVAD (regardless of CD20 expression owing to data showing upregulation of CD20 expression) for the younger subsets and inotuzumab (with or without rituximab) and “mini-hyper-CVAD” for the elderly group. Multivariate analysis of outcomes by risk groups (age/MRD status/CD20 expression) and the impact of the early/late intensifications during maintenance chemotherapy will be presented. Disclosures:O'Brien:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Ineffective Therapy, Underpowered Studies, or Merely Too Little, Too Late?

It is estimated that 2% to 3% of pregnant women carry the anti-SSA/Ro antibody, which can be found in various autoimmune disorders, including Sjogren syndrome (SS), systemic lupus erythematosus, rheumatoid arthritis, and mixed connective tissue disorder.1,2 In addition, many women are asymptomatic carriers, with less than one third of anti-SSA/Ro–positive women diagnosed with a rheumatological disorder preceding the discovery of advanced heart block in the fetus.3,4 Prospective studies have demonstrated that, in the absence of a previously affected pregnancy, the fetuses of these women bear up to a 3% risk of developing cardiac manifestations of neonatal lupus (NL), including cardiac conduction abnormalities, structural cardiac defects, and isolated cardiomyopathies.5–7 In women with a previously affected pregnancy, the recurrence rate of congenital heart block can reach as high as 17%.8,9 Articles see p 1919 and p 1927 The cardiac conduction manifestations of NL are thought to result from a pathological response to the transplacental acquisition of anti-SSA/Ro whereby an immune-mediated inflammatory pathway triggers injury and eventually fibrosis of the atrioventricular (AV) node.10 In addition, anti-SSA/Ro antibodies appear to inhibit activation of the cardiac L-type calcium channels, which are essential to normal AV node conduction.11 The role of anti-SSB/La antibodies is less clearly defined. Although anti-SSB/La alone has not been associated with conduction abnormalities, some evidence suggests that it may potentiate the effects of anti-SSA/Ro–mediated injury.12 Antibody-exposed infants without cardiac involvement at birth have little risk of later developing AV block; however, complete AV block can evolve in fetuses with second-degree AV block in utero or neonates born with first- or second-degree AV block.9 Jaeggi and colleagues3 reported that the timing of initial presentation of complete AV block correlated with mortality. Among the 29 cases diagnosed …

Representativeness of PBRN Physician Practice Patterns and Related Beliefs: The Case of the AAFP National Research Network

We wanted to compare survey responses from members of a national practice-based research network (PBRN) with those of a larger sample of family physicians to assess the generalizability of findings from the PBRN to the larger physician population. The American Academy of Family Physicians National Research Network (AAFP NRN) conducted 3 separate national surveys among random samples of AAFP active members and physician members of the AAFP NRN. The surveys assessed self-reported clinical behaviors and beliefs related to hepatitis C, hyperlipidemia, and pharyngitis. Bivariate comparisons were conducted to detect statistical differences between the AAFP and AAFP NRN respondents on both demographic and clinically relevant survey items. Multivariate analyses of outcomes were found to be statistically significant at the bivariate level. Response rates to the surveys ranged from 53% to 59% for AAFP members and 60% to 72% for AAFP NRN members. The most consistent differences (P <.05) in demographic comparisons were for percentage of time spent in patient care, practice location, practice type, and census region. Bivariate comparisons found the groups differed on 8 (12%) of 66 clinically relevant survey items, with the Bonferroni correction for multiple comparisons reducing these items to 4 (6%). These comparisons were followed by multivariate analyses of outcomes that were found statistically significant at bivariate level. The AAFP NRN and AAFP membership differed on several demographic characteristics, but network members were overall more representative than not of the AAFP active membership in their self-reported clinical behaviors and related beliefs.

Laparoscopic bile duct injuries: timing of surgical repair does not influence success rate. A multivariate analysis of factors influencing surgical outcomes

BackgroundMany factors contribute to the success of biliary reconstructions following laparoscopic bile duct injury. We previously reported that control of intra-abdominal infection, complete preoperative cholangiography, surgical technique and surgical experience affected the results. There is no consensus, however, on whether the timing of the operation is important. MethodsWe examined factors influencing the success of the first repair of 307 major bile duct injuries following laparoscopic cholecystectomy. Factors were assessed for cases initially repaired either by the primary surgeon or a biliary specialist. Bivariate and multivariate analyses were used to determine the significance of comparisons. ResultsA total of 137 injuries were initially repaired by a biliary surgeon and 163 injuries were initially repaired by the primary surgeon; seven were managed non-surgically. Repairs by primary surgeons were performed earlier than those by biliary surgeons (11 vs. 59 days; P < 0.0001). Bivariate analysis of the entire cohort suggested that later repairs might have been more successful than earlier ones (17 vs. 50 days; P= 0.003). Multivariate analysis, however, showed that the timing of the repair was unimportant (P= 0.572). Instead, success correlated with: eradication of intra-abdominal infection (P= 0.0001); complete preoperative cholangiography (P= 0.002); use of correct surgical technique (P= 0.0001), and repair by a biliary surgeon (P= 0.0001). Separate multivariate analyses of outcomes for primary and biliary surgeons revealed that timing was unrelated to success in either case. ConclusionsThe success of biliary reconstruction for iatrogenic bile duct injuries depended on complete eradication of abdominal infection, complete cholangiography, use of correct surgical technique, and repair by an experienced biliary surgeon. If these objectives were achieved, the repair could be performed at any point with the expectation of an excellent outcome. We see no reason to delay the repair for some arbitrary period.

Comparison of Outcomes with HTK and UW Solutions in Renal Transplantation

To the Editor: We appreciate the comments of Drs. Opelz and Döhler regarding our submission to the American Journal of Transplantation (1Comparison of Histidine-Tryptophan-Ketoglutarate and University of Wisconsin preservation in renal transplantation.Am J Transplant. 2008; 8: 567-573Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). The authors correctly point out that our series, which encompassed 634 deceased donor and 950 living donor transplants, was not sufficiently powered to detect a difference in UW versus HTK performance in organs cold-preserved for more than 24 h. Our study did show, to a statistically significant degree, apparent equipoise in patient and graft survival between the whole of the UW and HTK groups. Separate multivariate analyses of outcomes validated the data set by showing contributions of donor and recipient factors consistent with previous reports from the literature (2De Boer J De Meester J Smits JMA et al.Eurotransplant randomized multicenter kidney graft preservation study comparing HTK with UW and Euro-Collins.Transplant Int. 1999; 12: 447-453Crossref PubMed Scopus (102) Google Scholar,3Agarwal A Murdock P Fridell JA Comparison of histidine-tryptophan-ketoglutarate solution and University of Wisconsin solution in prolonged cold preservation of kidney allografts.Transplantation. 2006; 81: 480-482Crossref PubMed Scopus (57) Google Scholar). Finally, our study assessed correlation between storage solution type and delayed graft function, and HTK use was actually seen by Cox multivariable analysis to be associated with decreased risk of delayed graft function. The results of the Collaborative Transplant Study, to which Drs. Opelz and Döhler allude, did show a detrimental effect of preservation with HTK over UW in prolonged ischemia times (4Opelz G Döhler B Multicenter analysis of kidney preservation.Transplantation. 2007; 83: 247-253Crossref PubMed Scopus (166) Google Scholar). This excellent work reports on 16 years of registry data. As in our own experience, the authors noted shifts in preservative fluid type and the proportion of organs stored for longer than 24 h over the course of the collection period. While this registry data can be used to calculate a hazard ratio to control for the era effect in our own study, the applicability of such a factor derived from an aggregate of heterogeneous data to a single center’s practices is not certain. Nonetheless, Drs. Opelz and Döhler correctly comment on an important weakness of our report, the potential confounding effects of secular trends on our results. We clearly discussed this in the original manuscript. In summary, final proof of the superiority of HTK over UW or vice versa as a renal preservative remains elusive. In the absence of any new randomized trial of sufficient power and granularity to assess all factors and outcomes of renal transplantation using the two solutions, large reports such as the Collaborative Transplant Study and smaller series such as our own provide complementary information on renal preservation. Our experience shows little, if any, difference between the fluids within the scope of our usual ischemia times, and as HTK has cost and ease of use benefits (5Englesbe MJ Heidt D Sung R Pietroski R Does using HTK solution for cold perfusion of cadaveric kidneys save money.Transplantation. 2006; 82: 580-581Crossref PubMed Scopus (7) Google Scholar), it remains our standard choice for cold preservation of renal allografts.