Independent Predictors Of Shorter Time Research Articles

Higher Mutational Burden Is an Independent Predictor of Shorter Time to First Treatment in Untreated Chronic Lymphocytic Leukemia Patients

Background. Recent advancements in next-generation sequencing (NGS) technologies have revolutionized the ability to comprehensively profile chronic lymphocytic leukemia (CLL), unveiling various molecular lesions. Complex mutational landscapes and diverse combinatorial patterns of genetic alterations lead to heterogeneity of clinical course and outcomes. The primary objective of this study was to identify patterns of co-occurrence (CO) and mutual exclusivity (ME) among mutations in CLL and their impact on time to first treatment (TTFT). Methods. The cohort included 795 treatment-naïve (TN) patients (pts) with CLL diagnosed according to iwCLL guidelines. The median follow-up time for the cohort was 3.91 years (range 0 - 42.8). The median time from diagnosis to mutational analysis was 6.6 months (26.50 - 33.27, 95% CI). Mutational screening was performed by a clinical targeted NGS panel, covering all or hotspot exons of 95 genes - the Rapid Heme Panel implemented by BWH (Kluk MJ, et al. J Mol Diagn. 2016;18(4):507-515). Standard protocols were applied to analyze IGHV gene mutational status, chromosomal aberrations by FISH with probes for 11q, 13q, 17p, and trisomy 12, and stimulated karyotype, where complex karyotype (CK) was defined as ≥3 abnormalities. CO and ME patterns were analyzed in pts with a higher mutational burden, determined as ≥2 distinct mutated genes, using Fisher's exact test ( p<.05). Control for false discovery rate was performed using the Benjamini, Krieger and Yekutieli method ( q=20%). TTFT was the time from diagnosis to initial treatment. Results. We detected 1798 mutations in 719 (90.4%) pts. No mutations were detected in 9.6% (n=76) patients, while a single mutated gene was found in 216 (27.2%) pts, 2 mutated genes in 206 (25.9%) pts, and mutations in 3 and ≥4 genes were found in 153 (19.2%) and 144 (18.1%) pts, respectively. The most mutated (≥10%) genes in the cohort were ATM (18.1%), NOTCH1 (17.7%), TP53 (13.2%), SF3B1 (12.3%), TET2 (10.2%), and DNMT3A (10.1%). A higher mutational burden was associated with clinical Rai stages 1-4 [ p=.003]; elevated (>3.5 mg/L) levels of baseline ß-2 microglobulin (B2M) [ p=.036] and established high-risk genomic features: del(17p) [ p<.001], del(11q) [ p=.021], CK [ p=.009], unfavorable ZAP70 [ p=.027] and unmutated IGHV (UM- IGHV) [ p<.001] (incidence of UM- IGHV cases is 48.4% (n=359) in cohort). At the same time, cases with 0-1 mutation were more likely to have del(13q) [ p=.006]. Sex and age >65 years at diagnosis were not associated with mutational burden. Otherwise, lack of any mutations was associated with absence of del(17p) (0% vs 11.1% [ p=.002]), lower rates of B2M >3.5 mg/L (3.9% vs 21.7% [ p<.001]), less frequent UM- IGHV (25.4% vs 50.9% [p<.001]), lower ratio of CK (7.0% vs 17.5% [p=.024] and age >65 years at diagnosis (21.1% vs 35.1% [ p=.014]). After controlling for multiple comparisons, no genes showed significant mutational co-occurrence. UM- IGHV cases were enriched in mutated ATM [ p=.003], NOTCH1 [ p<.00001], SF3B1 [ p=.0012] and XPO1 [ p<.00001]. Mutated NOTCH1 [ p<.00001], as well as KRAS [ p=.0012], occurred along with tri12. In contrast, UM- IGHV did not co-occur with mutations in MYD88 [ p<.00001], as previously reported. Del(13q) did not co-occur with mutated BRAF [ p=.0006] or BCOR [ p=.006]. Mutated TP53 [ p=.008] and SF3B1 [ p=.0013] were absent in tri12 positive cases. Increased mutational burden in ≥2 distinct mutated genes predicted a shorter TTFT than 0 or 1 mutated gene (HR 2.16; 95%CI 1.57 - 2.97; p<.001). Factors including Rai stages 1-4 (HR 2.63; 95%CI 1.88 - 3.7; p<0.001), UM- IGHV (HR 2.4; 95%CI 1.74 - 3.3; p<.001), CK (HR 1.47; 95%CI 1.07 - 2.0; p=.018), mutational burden in ≥2 genes (HR 1.57; 95%CI 1.14 - 2.2; p=.006) and del(17p) /TP53mut (HR 1.79; 95%CI 1.15 - 2.8; p=.01) were independently associated with worsened TTFT ( Figure 1). Neither mutated TP53 without del(17p) (HR 1.47; 95%CI 0.92 - 2.3; p=.104), or wild-type TP53 with del(17p) (HR 1.03; 95%CI 0.51 - 2.1; p=.932) were significant predictors of TTFT. Conclusions: Higher mutational burden is associated with worsened TTFT in CLL pts independently of other genomic events. In this cohort we did not see co-occurrence of specific mutations.

Time for Resolution of COVID-19 Vaccine-Related Axillary Lymphadenopathy and Associated Factors.

BACKGROUND. The variable clinical course of subclinical lymphadenopathy detected on breast imaging after COVID-19 vaccination creates management challenges and has led to evolving practice recommendations. OBJECTIVE. The purpose of this study was to assess the duration of axillary lymphadenopathy ipsilateral to COVID-19 vaccination detected by breast imaging and to assess factors associated with the time until resolution. METHODS. This retrospective single-center study included 111 patients (mean age, 52 ± 12 years) with unilateral axillary lymphadenopathy ipsilateral to mRNA COVID-19 vaccine administration performed within the prior 8 weeks that was detected on breast ultrasound performed between January 1, 2021, and October 1, 2021, and who underwent follow-up ultrasound examinations at 4- to 12-week intervals until resolution of the lymphadenopathy. Patient information was extracted from medical records. Cortical thickness of the largest axillary lymph node on ultrasound was retrospectively measured and was considered enlarged when greater than 3 mm. Multivariable linear regression analysis was used to identify independent predictors of time until resolution. RESULTS. The mean cortical thickness at the initial ultrasound examination was 4.7 ± 1.2 mm. The lymphadenopathy resolved a mean of 97 ± 44 days after the initial ultrasound examination, 127 ± 43 days after the first vaccine dose, and 2.4 ± 0.6 follow-up ultrasound examinations. A significant independent predictor of shorter time to resolution was Pfizer-BioNTech (rather than Moderna) vaccination (β = -18.0 [95% CI, -34.3 to -1.7]; p = .03]. Significant independent predictors of longer time to resolution were receipt of the second dose after the initial ultrasound examination (β = 19.2 [95% CI, 3.1-35.2]; p = .02) and greater cortical thickness at the initial ultrasound examination (β = 8.0 [95% CI, 1.5-14.5]; p = .02). Patient age, history of breast cancer, and axillary symptoms were not significantly associated with time to resolution (all p > .05). CONCLUSION. Axillary lymphadenopathy detected with breast ultrasound after COVID-19 mRNA vaccination lasts longer than reported in initial vaccine clinical trials. CLINICAL IMPACT. The prolonged time to resolution supports not delaying screening mammography because of recent COVID-19 vaccination. It also supports the professional society recommendation of a follow-up interval of at least 12 weeks when vaccine-related lymphadenopathy is suspected.

Cognitive-motor dissociation and time to functional recovery in patients with acute brain injury in the USA: a prospective observational cohort study

Recovery trajectories of clinically unresponsive patients with acute brain injury are largely uncertain. Brain activation in the absence of a behavioural response to spoken motor commands can be detected by EEG, also known as cognitive-motor dissociation. We aimed to explore the role of cognitive-motor dissociation in predicting time to recovery in patients with acute brain injury. In this observational cohort study, we prospectively studied two independent cohorts of clinically unresponsive patients (aged ≥18 years) with acute brain injury. Machine learning was applied to EEG recordings to diagnose cognitive-motor dissociation by detecting brain activation in response to verbal commands. Survival statistics and shift analyses were applied to the data to identify an association between cognitive-motor dissociation and time to and magnitude of recovery. The prediction accuracy of the model that was built using the derivation cohort was assessed using the validation cohort. Functional outcomes of all patients were assessed with the Glasgow Outcome Scale-Extended (GOS-E) at hospital discharge and at 3, 6, and 12 months after injury. Patients who underwent withdrawal of life-sustaining therapies were censored, and death was treated as a competing risk. Between July 1, 2014, and Sept 30, 2021, we screened 598 patients with acute brain injury and included 193 (32%) patients, of whom 100 were in the derivation cohort and 93 were in the validation cohort. At 12 months, 28 (15%) of 193 unresponsive patients had a GOS-E score of 4 or above. Cognitive-motor dissociation was seen in 27 (14%) patients and was an independent predictor of shorter time to good recovery (hazard ratio 5·6 [95% CI 2·5-12·5]), as was underlying traumatic brain injury or subdural haematoma (4·4 [1·4-14·0]), a Glasgow Coma Scale score on admission of greater than or equal to 8 (2·2 [1·0-4·7]), and younger age (1·0 [1·0-1·1]). Among patients discharged home or to a rehabilitation setting, those diagnosed with cognitive-motor dissociation consistently had higher scores on GOS-E indicating better functional recovery compared with those without cognitive-motor dissociation, which was seen as early as 3 months after the injury (odds ratio 4·5 [95% CI 2·0-33·6]). Recovery trajectories of clinically unresponsive patients diagnosed with cognitive-motor dissociation early after brain injury are distinctly different from those without cognitive-motor dissociation. A diagnosis of cognitive-motor dissociation could inform the counselling of families of clinically unresponsive patients, and it could help clinicians to identify patients who will benefit from rehabilitation. US National Institutes of Health.

Quantitative assessment of lung involvement on chest CT at admission: Impact on hypoxia and outcome in COVID-19 patients

BackgroundThe aim of this study was to quantify COVID-19 pneumonia features using CT performed at time of admission to emergency department in order to predict patients' hypoxia during the hospitalization and outcome. MethodsConsecutive chest CT performed in the emergency department between March 1st and April 7th 2020 for COVID-19 pneumonia were analyzed. The three features of pneumonia (GGO, semi-consolidation and consolidation) and the percentage of well-aerated lung were quantified using a HU threshold based software. ROC curves identified the optimal cut-off values of CT parameters to predict hypoxia worsening and hospital discharge. Multiple Cox proportional hazards regression was used to analyze the capability of CT quantitative features, demographic and clinical variables to predict the time to hospital discharge. ResultsSeventy-seven patients (median age 56-years-old, 51 men) with COVID-19 pneumonia at CT were enrolled. The quantitative features of COVID-19 pneumonia were not associated to age, sex and time-from-symptoms onset, whereas higher number of comorbidities was correlated to lower well-aerated parenchyma ratio (rho = −0.234, p = 0.04) and increased semi-consolidation ratio (rho = −0.303, p = 0.008).Well-aerated lung (≤57%), semi-consolidation (≥17%) and consolidation (≥9%) predicted worst hypoxemia during hospitalization, with moderate areas under curves (AUC 0.76, 0.75, 0.77, respectively). Multiple Cox regression identified younger age (p < 0.01), female sex (p < 0.001), longer time-from-symptoms onset (p = 0.049), semi-consolidation ≤17% (p < 0.01) and consolidation ≤13% (p = 0.03) as independent predictors of shorter time to hospital discharge. ConclusionQuantification of pneumonia features on admitting chest CT predicted hypoxia worsening during hospitalization and time to hospital discharge in COVID-19 patients.

Machine Learning to Predict Cardiac Death Within 1 Hour After Terminal Extubation.

Accurate prediction of time to death after withdrawal of life-sustaining therapies may improve counseling for families and help identify candidates for organ donation after cardiac death. The study objectives were to: 1) train a long short-term memory model to predict cardiac death within 1 hour after terminal extubation, 2) calculate the positive predictive value of the model and the number needed to alert among potential organ donors, and 3) examine associations between time to cardiac death and the patient's characteristics and physiologic variables using Cox regression. Retrospective cohort study. PICU and cardiothoracic ICU in a tertiary-care academic children's hospital. Patients 0-21 years old who died after terminal extubation from 2011 to 2018 (n = 237). None. The median time to death for the cohort was 0.3 hours after terminal extubation (interquartile range, 0.16-1.6 hr); 70% of patients died within 1 hour. The long short-term memory model had an area under the receiver operating characteristic curve of 0.85 and a positive predictive value of 0.81 at a sensitivity of 94% when predicting death within 1 hour of terminal extubation. About 39% of patients who died within 1 hour met organ procurement and transplantation network criteria for liver and kidney donors. The long short-term memory identified 93% of potential organ donors with a number needed to alert of 1.08, meaning that 13 of 14 prepared operating rooms would have yielded a viable organ. A Cox proportional hazard model identified independent predictors of shorter time to death including low Glasgow Coma Score, high Pao2-to-Fio2 ratio, low-pulse oximetry, and low serum bicarbonate. Our long short-term memory model accurately predicted whether a child will die within 1 hour of terminal extubation and may improve counseling for families. Our model can identify potential candidates for donation after cardiac death while minimizing unnecessarily prepared operating rooms.

Impact of Molecular Drug Susceptibility Testing on the Time to Multidrug-resistant Tuberculosis Treatment Initiation.

BackgroundThe purpose of this study was to evaluate the current status and trends in the coverage of molecular drug susceptibility testing (mDST), and the impact of mDST on the time to multidrug-resistant tuberculosis (MDR-TB) treatment initiation in Korea.MethodsWe included confirmed rifampin-resistant (RR)/MDR-TB patients who submitted application forms for novel drug uses to the National TB Expert Review Committee from September 1, 2016 to November 30, 2019. We retrospectively reviewed their medical records.ResultsOf the 621 MDR/RR-TB patients, mDST was performed in 442 (71.2%); Xpert MTB/RIF (Xpert) alone in 109 (17.6%), MTBDRplus line probe assay (LPA) alone in 199 (32.0%), and both Xpert and LPA in 134 (21.6%) patients. The coverage rate of mDST has gradually increased to 70% in 2015, 50.7% in 2016, 67.9% in 2017, 75.2% in 2018, and 79.4% in 2019 (P for trend < 0.001). Median time to MDR-TB treatment initiation was 35 days (interquartile range25–75 0–72), which has gradually decreased during the study period (P < 0.001). Independent predictors of shorter time to MDR-TB treatment initiation were retreatment case (adjusted hazard ratio [aHR], 1.30; 95% confidence interval [CI], 1.10–1.54), Xpert testing (aHR, 2.42; 95% CI, 2.03–2.88), and LPA testing (aHR, 1.83; 95% CI, 1.55–2.16). Transfer to another healthcare facility was inversely related to shorter time to treatment initiation (aHR, 0.74; 95% CI, 0.63–0.88).ConclusionmDST coverage is gradually increasing and contributes to reducing the time to MDR-TB treatment initiation. Further efforts are needed to achieve universal access to mDST and to properly integrate mDST into routine clinical practice.

Time to Death after Terminal Withdrawal of Mechanical Ventilation: Specific Respiratory and Physiologic Parameters May Inform Physician Predictions

Discussions about withdrawal of life-sustaining therapies often include family members of critically ill patients. These conversations should address essential components of the dying process, including expected time to death after withdrawal. The study objective was to aid physician communication about the dying process by identifying predictors of time to death after terminal withdrawal of mechanical ventilation. We conducted an observational analysis from a single-center, before-after evaluation of an intervention to improve palliative care. We studied 330 patients who died after terminal withdrawal of mechanical ventilation. Predictors included patient demographics, laboratory, respiratory, and physiologic variables, and medication use. The median time to death for the entire cohort was 0.58 hours (interquartile range (IQR) 0.22-2.25 hours) after withdrawal of mechanical ventilation. Using Cox regression, independent predictors of shorter time to death included higher positive end-expiratory pressure (per 1 cm H2O hazard ratio [HR], 1.07; 95% CI 1.04-1.11); higher static pressure (per 1 cm H2O HR, 1.03; 95% CI 1.01-1.04); extubation prior to death (HR, 1.41; 95% CI 1.06-1.86); and presence of diabetes (HR, 1.75; 95% CI 1.25-2.44). Higher noninvasive mean arterial pressure predicted longer time to death (per 1 mmHg HR, 0.98; 95% CI 0.97-0.99). Comorbid illness and key respiratory and physiologic parameters may inform physician predictions of time to death after withdrawal of mechanical ventilation. An understanding of the predictors of time to death may facilitate discussions with family members of dying patients and improve communication about end-of-life care.

Diagnostic timelines and delays in diagnosing amyotrophic lateral sclerosis (ALS)

The objective of this study was to characterize the diagnostic timelines and their predictors in people with amyotrophic lateral sclerosis (ALS). Patients were identified through ALS billing codes. Time from presenting symptom to first doctor visit, first doctor visit to suspected ALS diagnosis, suspected to confirmed ALS diagnosis, and presenting symptom to confirmed ALS diagnosis (total diagnostic time) were collected. Regression models were used to analyze the predictors of diagnostic delay. Three hundred and four ALS patients were included in the analysis. Median total diagnostic time was 11.5 months. Diagnostic timelines were longer in patients with age > 60 years (p < 0.001), sporadic ALS (p = 0.043), and limb onset (p = 0.010). The presence of fasciculations, slurred speech, and lower extremity weakness when symptoms were first noted were independent predictors of shorter time to ALS diagnosis (p = 0.04, p = 0.02, and p = 0.04, respectively). About half of the patients (52%) received an alternative diagnosis and each patient saw an average of three different physicians before ALS diagnosis was confirmed. In conclusion, diagnostic timelines in ALS are long, and patients see many physicians and receive multiple alternative diagnoses before the diagnosis of ALS is confirmed. Older age, sporadic disease, and limb onset can delay ALS diagnosis.

Predictors of access to care in juvenile systemic lupus erythematosus: evidence from the UK JSLE Cohort Study

The objective of this study was to investigate factors that may influence the interval between symptom onset and JSLE diagnosis. Data from all patients recruited to the UK JSLE Cohort Study between 2006 and 2011 and meeting ACR criteria for lupus were analysed. Variables associated with time between symptom onset and diagnosis were identified using correlation tests. Linear regression was used to identify independent predictors of access to care. Two hundred and fifty-seven children with JSLE were included in the analysis (216 females, 41 males, ratio 5.3:1). The median time from symptom onset to diagnosis was 0.4 years (range 0.0-14.1 years, interquartile range 0.2-1.4). A linear regression model identified being of African or Caribbean origin (P = 0.006), Asian (P = 0.045), referred by a paediatrician (P = 0.047) or having nephritis (P = 0.045) at presentation as independent predictors of shorter time to diagnosis. Being of Caribbean or Asian origin, compared with white, was associated with a 56% and 37% reduction in geometric mean time to diagnosis, respectively. Similarly, being referred to paediatric rheumatology by a paediatrician or having nephritis at presentation was also associated with a 32% and 36% reduction in geometric mean time to diagnosis, respectively. Within this national UK cohort, ethnic origin, initial source of referral and having lupus nephritis at presentation were strong predictors of the interval to establishing a diagnosis of JSLE.

AB0658 Predictors of access to care in JSLE - evidence from the UK JSLE cohort study

BackgroundDelays in access to specialist care for children with paediatric rheumatic disease are likely to be associated with adverse outcomes1,2. Factors influencing access to care for Juvenile-onset Systemic Lupus Erythematosus...

Association between B-cell receptor responsiveness and disease progression in B-cell chronic lymphocytic leukemia: results from single cell network profiling studies

While many prognostic markers in B-cell chronic lymphocytic leukemia provide insight into the biology of the disease, few have been demonstrated to be useful in the daily management of patients. B-cell receptor signaling is a driving event in the progression of B-cell chronic lymphocytic leukemia and markers of B-cell receptor responsiveness have been shown to be of prognostic value. Single cell network profiling, a multiparametric flow cytometry-based assay, allows functional signaling analysis at the level of the single cell. B-cell receptor signaling proteins (i.e. p-SYK, p-NF-κB p65, p-ERK, p-p38, p-JNK) were functionally characterized by single cell network profiling in samples from patients with B-cell chronic lymphocytic leukemia in an exploratory study (n=27) after stimulation with anti-IgM. Significant associations of single cell network profiling data with clinical outcome (i.e. time to first treatment), as assessed by Cox regression models, were then confirmed in patients' samples in two other sequential independent studies, i.e. test study 1 (n=30), and test study 2 (n=37). In the exploratory study, higher responsiveness of the B-cell receptor signaling proteins to anti-IgM was associated with poor clinical outcomes. Patients' clustering based on signaling response was at least as powerful in discriminating different disease courses as traditional prognostic markers. In an unselected subgroup of patients with Binet stage A disease (n=21), increased anti-IgM-modulated p-ERK signaling was shown to be a significant, independent predictor of shorter time to first treatment. This result was independently confirmed in two test cohorts from distinct populations of patients. In conclusion, these findings support the utility of the single cell network profiling assay in elucidating signaling perturbations with the potential for the development of a clinically useful prognostic test in patients with early stage B-cell chronic lymphocytic leukemia. These data support the clinical relevance of B-cell receptor signaling in B-cell chronic lymphocytic leukemia, and suggest a key role of ERK activation in the physiopathology of this leukemia.

Predictors of entering 24‐h care for people with Alzheimer's disease: results from the LASER‐AD study

Many studies have investigated predictors of people with dementia entering 24-h care but this is the first to consider a comprehensive range of carer and care recipient (CR) characteristics derived from a systematic review, in a longitudinal cohort study followed up for several years. We interviewed 224 people with Alzheimer's disease (AD) and their carers, recruited to be representative in terms of their severity, sex and living situation as part of the LASER-AD study; and determined whether they entered 24-h care in the subsequent 4.5 years. We tested a comprehensive range of characteristics derived from a systematic review, and used Cox proportional hazard regression to determine whether they independently predicted entering 24-h care. The main independent predictors of shorter time to enter 24-h care were the patient being: more cognitively or functionally impaired (hazard ratio (HR) = 1.09; 95% CI = 1.06-1.12) and (HR = 1.04 95% CI = 1.03-1.05), having a paid versus a family carer (HR = 2.22; 95% CI = 1.39-3.57), the carer being less educated (HR = 1.43; 95% CI = 1.12-1.83) and spending less hours caring (HR = 1.01; 95% CI = 1.00-1.01). As having a family carer who spent more time caring (taking into account illness severity) delayed entry to 24-h care, future research should investigate how to enable carers to provide this. Other interventions to improve patients' impairment may not only have benefits for patients' health but also allow them to remain longer at home. This financial benefit could more than offset the treatment cost.

De Novo Deletion 17p13.1 Chronic Lymphocytic Leukemia Shows Significant Clinical Heterogeneity: The MD Anderson/Mayo Clinic Experience.

[Display omitted] In order to characterize the clinical course of patients (pts) with deletion 17p13.1 (17p-) CLL, we identified 100 consecutive treatment-naïve pts with 17p- from the MD Anderson Cancer Center (MDACC, n=61) and Mayo Clinic (n=39) clinical databases. The diagnosis of 17p- was established by FISH with a median time from initial diagnosis to FISH documenting 17p- of 9 months. Median age was 64 yrs (60 for MDACC pts & 70 for Mayo pts) and Rai stage was 0, 1–2 and 3–4 in 34%, 49% and 17% pts respectively. 17p- was the sole FISH abnormality in 29%. Unmutated IgVH and ZAP-70 positivity were present in 30/62 and 54/84 patients respectively. <<<TIME TO FIRST THERAPY>>> 69 asymptomatic pts were followed until they developed progressive disease requiring therapy as defined by the NCIWG 96 criteria. The 2 year actuarial risk of progression to initiation of therapy was 43% (46% for MDACC pts & 36% for Mayo pts). Only 2 of 10 pts with stable disease >2 years progressed on prolonged follow-up of up to 54 months. Two pts with baseline 17p- in 10% and 13% of nuclei lost their 17p- clone after 23 and 41 months. Independent predictors of shorter time to treatment were Rai stage > 0 (hazard ratio 7.2) and unmutated IgVH (HR 5.3). Pts with 0, 1 or 2 of these factors had a 2 year progression rate of 0%, 48% and >75% respectively (p<0.01). Other prognostic parameters such as ZAP-70 and CD38 did not have independent prognostic utility. <<<RESPONSE TO THERAPY>>> 41 pts from MDACC were assessable for response to first therapy. Overall (OR) and complete response (CR) rates were: rituximab without chemotherapy (n=6), OR 67% CR 17%; purine analogue + rituximab combinations (n=20), OR 75% CR 30%; purine analogue, rituximab + alemtuzumab combinations (n=13), OR 85% CR 54%. The pt who achieved CR after rituximab was negative for minimal residual disease assessed by flow cytometry and consensus primer IgH PCR, and has remained in remission at 29 months. At 2 years, 75% of complete responders remained relapse free. <<<SURVIVAL FROM 17P- DIAGNOSIS>>> Two year survival was 78%. Independent predictors of inferior survival were age 60+ (HR 3.4), B-symptoms (HR 3.7) and 17p- in nuclei 70+% (HR 6.0). Considering age 60+ and 17p- in nuclei 70+% in a prognostic model, 2 year survival was 100%, 82% and 55% for pts with 0, 1 and 2 risk factors respectively. Other prognostic parameters such as ZAP-70, IgVH mutation status and CD38 did not have independent prognostic utility. <<<CONCLUSIONS>>> Pts with de novo 17p- CLL exhibit marked clinical heterogeneity, with some pts experiencing an indolent course with prolonged survival. Survival and time to treatment among patients with 17p- can be predicted using clinical and biological characteristics.

Recurrent arch obstruction after repair of isolated coarctation of the aorta in neonates and young infants: Is low weight a risk factor?

Background: Repair of aortic coarctation is often delayed in small infants because of the belief that such patients are at risk of recurrent arch obstruction and that growth will decrease this risk. To determine whether low weight was a risk factor for recurrent arch obstruction, we reviewed our experience with coarctation repair via left thoracotomy in infants less than 3 months of age. Methods: From 1990 to 1999, 103 patients less than 3 months of age underwent repair of aortic coarctation through a left thoracotomy. Median age was 18 days (1-90 days), with 45 patients less than 2 weeks. Median weight was 3.3 kg (1.0-6.4 kg) and 14 patients were less than 2 kg. The method of repair was resection and end-to-end anastomosis in 64 patients, subclavian flap angioplasty in 34, and patch augmentation of the arch in 5. Demographic, echocardiographic, and operative variables were analyzed for correlation with recurrent arch obstruction. Results: One early and 1 late death occurred, both in patients who had complications but no evidence of recoarctation. At median follow-up of 24 months, reinterventions for recurrent arch obstruction were performed in 15 patients. The median time to reintervention was 5 months and was less than 1 year in 12 patients. Kaplan-Meier freedom from arch reintervention was 88% at 1 year (95% confidence intervals: 82%-94%) and 82% at 5 years (95% confidence intervals: 72%-92%). Factors associated with shorter duration to arch reintervention by univariable Cox regression included younger age (continuous, P =.01; ||2 weeks, P =.005), smaller transverse arch (absolute diameter, P ||.001; indexed to weight, P =.03; indexed to ascending aortic diameter, P =.02), and smaller ascending aorta (absolute diameter, P =.02). Smaller absolute transverse arch diameter and younger age were the only independent predictors of shorter time to arch reintervention by multivariable Cox regression analysis. Weight and type of repair did not correlate with risk of recoarctation. Conclusions: Low weight is not a risk factor for recurrent obstruction after repair of coarctation of the aorta in infants less than 3 months of age. Rather, risk of recoarctation is more a function of the anatomy of the arch. Thus, it is not indicated to delay repair in low weight infants with the goal of achieving growth.J Thorac Cardiovasc Surg 2001;122:883-90

Prognostic value of the proliferative index determined by Ki-67 immunostaining in superficial bladder tumors

The biological behavior of urothelial carcinomas remains unpredictable. The objective of this study was to determine the prognostic value of Ki-67 index in superficial papillary bladder tumors and to correlate it with the S-phase fraction (SPF) measured by flow cytometry. Three hundred nineteen patients with newly diagnosed superficial (pTa, pT1) bladder tumors were included between September 1990 and April 1992. Patients with bladder carcinoma in situ alone were excluded. We observed 255 pTa tumors and 64 pT1 tumors, whereas 111 lesions were classified as grade G1 and 208 as grade G2-G3, Ki-67 immunostaining was performend on paraffin-embedded material using a 3-step immunoperoxidase procedure with the murine monoclonal antibody MiB1. The relation between Ki-67 expression and prognostic variables (stage, grade, tumor size, multifocality, age, and sex) was investigated by the chi-square test. Cox regression was used to describe the association between Ki-67 and tumor recurrence in 308 patients with follow-up while adjusting for potentially confounding prognostic variables. The frequency of high Ki-67 expression (≥10%) increased with stage ( P = .005) and grade ( P = .001), but not with tumor size or multifocality. Two hundred one patients experienced tumor recurrence in a median follow-up of 68 mouths. Stage, grade, tumor size, and multifocality were all independent predictors of recurrence. Ki-67 index greater than 10% was found to be an independent predictor of tumor recurrence among patients with tumors larger than 3 cm in diameter (HR = 2.05, CI = 1.18-3.55), but not those with smaller size tumors. With regards to the DNA index, a significant but weak correlation was observed between Ki-67 expression and the SPF (Spearman's correlation coefficient = 0.23, P = .004). In addition, aneuploid tumors had significantly higher expression of Ki-67 (22.5%) than diploid tumors (10.1%) ( P = .0006). Moreover, patients with DNA aneuploid bladder tumors were more likely to have more than 10% Ki-67-positive cells than those with diploid tumors. In patients with newly diagnosed pTa or pT1 bladder tumors, a Ki-67 index above 10% is an independent predictor of shorter time to recurrence only in those with tumors larger than 3 cm.

Predictors of time to completion of the hepatitis B vaccination series among adolescents

Objectives: To determine adolescents’ completion rates and factors affecting completion time of hepatitis B (HBV) vaccination. Methods: Prior to vaccination, participants from a hospital-based and school-based adolescent clinic completed questionnaires assessing sociodemographic variables, family/friend experience with HBV and the vaccine, likelihood of completing the vaccinations, HBV and vaccine knowledge, risk behaviors, chronic illness, and access to clinic. Vaccination times were recorded. Results: Twenty-six months after initiation of the study, 72% of 896 eligible participants had completed the vaccination series. The independent predictors of shorter time to completion were: higher estimated mean household income [odds ratio (OR) = 1.15, 95% confidence interval (CI) = 1.06–1.25), white race (OR = 1.27, 95% CI = 1.01–1.58), female gender (OR = 1.58, 95% CI = 1.31–1.92], and not having smoked cigarettes (OR for smoking in the past 30 days = 0.74, 95% CI = 0.60–0.92). Site of care, risk factors for acquiring HBV, disease and vaccine knowledge, and self-reported desire to complete the series were not associated with completion time. Conclusions: The primary factors associated with completion of immunization may not be amenable to intervention; mandated strategies for immunization may be more likely to result in protection for adolescents.