Log-rank Test For Trend Research Articles

Independent Prognostic Value of High-sensitivity C-reactive Protein in Patients with Coronary Artery Ectasia.

Background:Despite its severity, coronary artery ectasia (CAE) is still poorly understood. High-sensitivity C-reactive protein (hs-CRP) has been recognized as a prognostic factor in some cardiovascular diseases but not assessed in CAE. The aim of this observational study was to investigate the prognostic value of hs-CRP in CAE.Methods:Our analysis evaluated the effect of the baseline hs-CRP on cardiovascular events (CVs) (cardiac death and nonfetal myocardial infarction) in consecutively enrolled stable CAE patients. We used the Cox proportional hazards regression models to examine the association between baseline hs-CRP level and follow-up CVs in CAE. The net reclassification improvement and integrated discrimination improvement (IDI) of hs-CRP were also assessed.Results:We obtained the follow-up results of 540 patients over a median follow-up period of 36 (37.41 ± 15.88) months. The multivariable Cox analysis showed that the hs-CRP was a significant predictor of adverse outcomes in CAE (hazard ratio [HR]: 2.99, 95% confidence interval [CI]: 1.31–6.81, P = 0.0091). In Kaplan–Meier analysis, the group with hs-CRP >3 mg/L had a lower cumulative 66-month event-free survival rate (log-rank test for trend, P = 0.0235) and a higher risk of CVs (HR = 2.66, 95% CI: 1.22–5.77, P = 0.0140) than the group with hs-CRP ≤3 mg/L. Hs-CRP added predictive information beyond that given by the baseline model comprising the classical risk factors (P value for IDI = 0.0330).Conclusions:A higher level of hs-CRP was independently associated with cardiac death and nonfatal myocardial infarction in CAE patients. The hs-CRP level may therefore provide prognostic information for the risk stratification of CAE patients.

Monogenic and polygenic determinants of sarcoma risk: an international genetic study

Sarcomas are rare, phenotypically heterogeneous cancers that disproportionately affect the young. Outside rare syndromes, the nature, extent, and clinical significance of their genetic origins are not known. We aimed to investigate the genetic basis for bone and soft-tissue sarcoma seen in routine clinical practice. In this genetic study, we included 1162 patients with sarcoma from four cohorts (the International Sarcoma Kindred Study [ISKS], 966 probands; Project GENESIS, 48 probands; Asan Bio-Resource Center, 138 probands; and kConFab, ten probands), who were older than 15 years at the time of consent and had a histologically confirmed diagnosis of sarcoma, recruited from specialist sarcoma clinics without regard to family history. Detailed clinical, pathological, and pedigree information was collected, and cancer diagnoses in probands and relatives were independently verified. Targeted exon sequencing using blood (n=1114) or saliva (n=48) samples was done on 72 genes (selected due to associations with increased cancer risk) and rare variants were stratified into classes approximating the International Agency for Research on Cancer (IARC) clinical classification for genetic variation. We did a case-control rare variant burden analysis using 6545 Caucasian controls included from three cohorts (ISKS, 235 controls; LifePool, 2010 controls; and National Heart, Lung, and Blood Institute Exome Sequencing Project [ESP], 4300 controls). The median age at cancer diagnosis in 1162 sarcoma probands was 46 years (IQR 29-58), 170 (15%) of 1162 probands had multiple primary cancers, and 155 (17%) of 911 families with informative pedigrees fitted recognisable cancer syndromes. Using a case-control rare variant burden analysis, 638 (55%) of 1162 sarcoma probands bore an excess of pathogenic germline variants (combined odds ratio [OR] 1·43, 95% CI 1·24-1·64, p<0·0001), with 227 known or expected pathogenic variants occurring in 217 individuals. All classes of pathogenic variants (known, expected, or predicted) were associated with earlier age of cancer onset. In addition to TP53, ATM, ATR, and BRCA2, an unexpected excess of functionally pathogenic variants was seen in ERCC2. Probands were more likely than controls to have multiple pathogenic variants compared with the combined control cohort group and the LifePool control cohort (OR 2·22, 95% CI 1·57-3·14, p=1·2 × 10(-6)) and the cumulative burden of multiple variants correlated with earlier age at cancer diagnosis (Mantel-Cox log-rank test for trend, p=0·0032). 66 of 1162 probands carried notifiable variants following expert clinical review (those recognised to be clinically significant to health and about which patients should be advised), whereas 293 (25%) probands carried variants with potential therapeutic significance. About half of patients with sarcoma have putatively pathogenic monogenic and polygenic variation in known and novel cancer genes, with implications for risk management and treatment. Rainbows for Kate Foundation, Johanna Sewell Research Foundation, Australian National Health and Medical Research Council, Cancer Australia, Sarcoma UK, National Cancer Institute, Liddy Shriver Sarcoma Initiative.

Acute Kidney Injury as a Complication of Cardiac Transplantation: Incidence, Risk Factors, and Impact on 1-year Mortality and Renal Function.

Although chronic deterioration in renal function is frequently seen after cardiac transplantation, which is partly explained by the use of calcineurin inhibitors, data on the consequences of acute kidney injury (AKI) after cardiac transplantation are scarce. In the current study, the incidence of AKI and its impact on mortality and renal function was evaluated. Five hundred thirty-one cardiac transplant recipients (age ≥18 years) were evaluated for the postoperative incidence of AKI defined by the Kidney Disease Improving Global Outcome criteria. Secondary outcomes were renal function and mortality during the first postoperative year. Overall, 405 (76%) recipients met the AKI criteria of which 211 (40%) had AKI stage I, 119 (22%) stage II, 75 (14%) stage III, and 25 patients (5%) required renal replacement therapy (RRT). One-year mortality rates in patients without AKI, stages I, II, and III were 4.8%, 7.6%, 11.8%, and 14.7%, respectively (log-rank test for trend, P = 0.008). In patients that required RRT 1-year mortality was 28.2% (log-rank test P = 0.001). In multivariable analysis only AKI requiring RRT was an independent predictor of 1-year mortality (hazard ratio, 2.75; P = 0.03). Improvement in renal function, compared with baseline values, occurred in 27% of recipients 1 month after transplantation. This was less likely to occur after previous AKI (P ≤ 0.04). The AKI stages I to III were independently proportionally associated with a worse renal function 1 year after transplantation (P ≤ 0.01). Acute kidney injury is highly frequent after cardiac transplantation, and the stage of AKI is associated with increased mortality and impaired renal function in the first postoperative year.

Trends in Long-Term Outcomes Among Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis With Renal Disease.

It is still not clear how advances in the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have impacted long-term outcomes. We undertook this study to examine changes over 25 years in long-term clinical outcomes, including the impact of renal function at diagnosis (a potential marker of time to disease detection) and the duration of cyclophosphamide use in AAV patients with renal involvement. We included ANCA-positive patients with biopsy-proven AAV diagnosed between 1985 and 2009 who were followed up in the Glomerular Disease Collaborative Network inception cohort. Outcomes included the composite outcome of end-stage renal disease (ESRD) or death as well as relapse. Cox proportional hazards or competing risks regression models were adjusted for potential baseline confounders. Data from 554 patients were included in the analysis. There was a decreasing 5-year risk of ESRD or death over time (P < 0.001 by log rank test for trend). After adjustment for baseline characteristics, the risk of relapse was similar across the time periods (P = 0.45 by test for trend). Serum creatinine level at baseline was the only significant predictor of an increased risk of ESRD or death (hazard ratio 1.11 per 1 mg/dl of serum creatinine [95% confidence interval 1.04-1.18], P = 0.002). In patients with renal disease secondary to AAV, over 25 years the risk of ESRD or death has decreased but the risk of relapse has not changed. A higher serum creatinine level at diagnosis is associated with a higher risk of ESRD or death, suggesting that earlier disease detection is potentially an important measure to improve outcomes in AAV.

Residual Memory Impairment in Remitted Depression May Be a Predictive Factor for Recurrence

Memory impairment in remitted depression is reported to be related to the number of previous depressive episodes. A recent report hypothesized that each depressive episode increases the risk of memory impairment during remission, which further increases the risk of recurrence. We investigated whether the risk for recurrence increased as a function of memory impairment at remission. One hundred ten participants with DSM-IV-TR major depressive disorder (MDD) after remission (defined as a score ≤ 7 on the Hamilton Depression Rating Scale) were recruited between April 2004 and March 2012 and were followed up prospectively. All patients were divided into 2 groups: those who had memory impairment and those who had no memory impairment after remission. (Memory impairment was determined with the Wechsler Memory Scale-Revised.) The time to recurrence of depression (a score ≥ 4 on the Clinical Global Impressions-Severity of Illness scale) was compared between the groups prospectively. Kaplan-Meier survival curves, log-rank test for trend for survivor functions, and Cox proportional hazard ratio (HR) estimates for a multivariate model were conducted to examine the risk of recurrence by presence of memory impairment after remission. One hundred nine participants completed this study. In the follow-up period, recurrence occurred in 25 (55.6%) of the 45 patients with memory impairment and 21 (32.8%) of the 64 patients with no memory impairment. In the Kaplan-Meier survival estimates for time to incidence of recurrence in patients with and without memory impairment, the cumulative probability of developing a recurrence for patients with memory impairment was higher than for patients with no memory impairment (log-rank test: χ(2)1 = 4.63, P = .03). Survival analysis was also performed using Cox proportional hazards regression in a multivariate model. The presence of memory impairment remained significantly associated with incidence of recurrence (HR = 2.55; 95% CI, 1.30-4.99; P = .006). The presence of residual memory impairment in patients with remitted MDD may increase the risk of recurrence.

Abstract P5-08-30: Androgen receptor in early breast cancer: Distribution and prognostic value

Abstract Purpose: Androgen receptor (AR) status in breast cancer has received renewed interest over the last years especially in triple-negative disease (TNBC), but the prognostic value is still under debate. The aim of this study was to assess the distribution and prognostic value of AR in early breast cancer patients with or without adjuvant endocrine treatment. Patients and methods: AR was assessed on tissue microarray with the AR 441 antibody (Thermo Scientific) on a cohort consisting of 471 patients derived from two clinical studies: (1) 208 premenopausal node-negative patients of which 87% had received no adjuvant medical treatment and (2) 263 estrogen receptor (ER)+ and ER-, node-positive and –negative patients treated with 2 years of adjuvant tamoxifen. Nuclear AR was divided in 5 groups: 0-1%, 2-10%, 11-50%, 51-75%, and 76-100% positive cells, scored as 0-4. Cox proportional hazards regression, stratified by study, was used to model the impact of the prognostic factors on distant disease-free survival (DDFS), both using trend tests and a cut-off for positivity set at &amp;gt;10%, and log-rank tests to compare survival in different strata. Due to non-proportional hazards, the analysis was restricted to the first 5 years after diagnosis, a time period during which 95 patients developed distant recurrences. Results: 76% of all patients were AR+, and 89%, 48%, and 23% of the ER+, ER-, and TNBC, respectively. Positive associations were observed between AR, ER and progesterone receptor status (PgR), negative associations with Ki67, and histological grade, but no associations with tumour size, age or Human Epidermal Growth Factor Receptor 2 (HER2). In univariable analysis, when divided into 5 groups, AR was a prognostic factor for DDFS with a Hazard Ratio (HR) of 0.86 per step in fraction score (95% Confidence Interval (CI): 0.76-0.98, p=0.018), as was HER2, age, size, grade, node-status, PgR, and ER status. In the Kaplan-Meier curves for each study, a similar but weaker trend was found (log-rank test for trend p=0.14 and 0.057 for cohort 1 and 2, respectively). With a cut-off at 10%, a similar HR was found (HR=0.67, 95% CI:0.43-1.05, p=0.078). In multivariable analysis, adjusted for grade, tumour size, HER2, ER, node-status, and age, AR did not retain independent prognostic value (HR 1.04 95% CI:0.88-1.23, p=0.66). In the TNBC patients there were no significant differences in DDFS in the AR+ vs AR-patients, possibly due to few events and a small population (n=20/75). Conclusion: This study demonstrates that AR is a weak prognostic factor for recurrence in a cohort consisting of node-negative premenopausal patients without endocrine treatment and patients who have received adjuvant endocrine treatment. There was however no independent value in multivariable analyses. It is noteworthy that there were 23% AR positive TNBC patients, for whom there is currently no available targeted treatment. There are several ongoing studies with AR-targeted treatment in the metastatic setting, which if proven effective, may be transferred to studies in the adjuvant setting with the goal of improving long-term prognosis for TNBC. Taken together, AR may be clinically helpful for prognostic considerations and for selection of adjuvant treatment. Citation Format: Werner-Hartman L, Folkesson E, Nodin B, Malmström P, Fernö M, Nimeus E, Klintman M. Androgen receptor in early breast cancer: Distribution and prognostic value. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-30.

Frailty in Geriatric Glioblastoma Patients: A Predictor of Operative Morbidity and Outcome

Frailty is an emerging means of assessing overall health status and guiding management for geriatric patients. Frailty is associated with outcomes for many surgical indications in this age group. While half of all glioblastoma patients are 65 years old or older, frailty has not been examined in relation to surgery for glioblastoma. We performed a retrospective study of patients age 65 years and older with pathologically confirmed glioblastoma at Columbia Presbyterian Hospital from 2000 to 2012; 319 patients were identified, 243 of whom underwent craniotomy for lobar lesions. Frailty was quantified using the Canadian Study of Health and Aging Modified Frailty Index. Postoperative complications were classified according the Glioma Outcomes Project system. Systemic, regional, neurologic, and overall complications were examined in relation to age, Karnofsky performance status, frailty, comorbid disease burden, cardiovascular risk, and tumor sidedness. Frailer patients were less likely to undergo surgical resection (P= 0.0002; odds ratio [OR], 0.15; 95% confidence interval [CI], 0.05-0.40) as opposed to biopsy, had longer hospital stays (log-rank test for trend, P= 0.0061), an increased overall risk of complications (P= 0.0123; OR, 1.40; 95% CI, 1.08-1.83), and decreased overall survival (Log rank test for trend, P= 0.0028). Frailer patients with glioblastoma receive less aggressive intervention, have longer hospital stays, and experience more complications. Frailty may be an underused metric for the preoperative risk assessment of geriatric glioblastoma patients.

THE RISK OF CORONARY ARTERY DISEASE DEVELOPMENT IN PATIENTS WITH ANKYLOSING SPONDYLITIS (BECHTEREW’S DISEASE) AND PSORIATIC ARTHRITIS: A 10-YEAR PROSPECTIVE FOLLOW-UP STUDY

Objective: assessment of coronary artery disease (CAD) incidence among patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) without manifestation of cardiovascular diseases. Materials and methods. We analyzed the data of 10-year prospective follow-up of the patient with AS (n = 278), psoriatic arthritis (n = 85) and healthy controls (n = 150) without any cardiovascular diseases. All groups were comparable in regard to cardiovascular risk factors. During these 10 years all new cases of CAD (verified by cardiologist) in the study population were tracked. Results. New cases of CAD were fixed in 64 out of 278 patietns with AS and in 16 out of 150 controls (p = 0.0017). Using log-rank MantelCox test and logrank test for trend we demonstrated statistically significant differences in CAD incidence between patients without spondyloarthritis (SpA) and patients with AS and PsA (p 0.05). Conclusion. The risk of exertional stenocardia in patients with AS was not higher than that in individuals without SpA. However, patients with AS have higher risk of myocardial infarction than those without SpA. PsA patients have increased risk of CAD development comparing to healthy controls and individuals with AS.

PTU-092 Crohn’s disease: strictureplasty and risks for further surgery

Introduction Surgery plays an important role in the treatment of Crohn’s disease. Strictureplasty in particular is a practical and attractive treatment for Crohn’s disease, conserving bowel length. Only a few large surgical series have been published in the literature. We describe our own experience and factors that determine risk of reoperation or death over a ten year period. Method All the Crohn’s disease strictureplasties for a specialist IBD surgeon at St George’s Hospital from 1st January 2005 to 31st December 2014 were identified. Information was collected for weight, height, gender, smoking status as well as their medical and surgical management. Patients whose records were incomplete were contacted for further information. Results There were a total of 53 cases of strictureplasty, with just under 3,400 months of follow-up. 22 had concurrent bowel resection. 32 were male. Mean age of diagnosis was 24 years and 10 months. Mean time from diagnosis to first ever surgery was 6 years and 3 months. Mean number of prior surgeries was 1. Total number of further surgery in the follow-up period was 11, with mean time to reoperation 42 months. No patients died during in the follow-up period. 86.54% were non smokers. At the time of surgery 30.25% had a low BMI, 60.45% had a normal BMI and 9.3% had a high BMI. 72.55% were receiving treatment with the immunomodulators: azathioprine, 6-mercaptopurine or methotrexate. Kaplan Meier survival analysis was used to compare those that had strictureplasties and those that had strictureplasty and concurrent bowel resection, with further surgery or death up to 31st December 2014 as the endpoint. Log rank test for trend did not find that there was any significant difference between the two groups and probability of further surgery. Cox regression analysis was used to assess for risk for further surgery: age of diagnosis, number of previous surgeries, time from diagnosis to first ever surgery, treatment with immunomodulators, concurrent bowel resection, sex, BMI and smoking status. Significant risk for further surgery was found in those that had ever smoked (hazard ratio 4.775, p = 0.003) and those patients with a low BMI who had concurrent bowel resection as well as strictureplasty (hazard ratio 6.31, p = 0.002). Importantly previous surgery and age of diagnosis were not a risk factor for recurrent surgery (hazard ratios 1.016 and 1.198 respectively). Conclusion We review a decade of strictureplasties in the management of Crohn’s disease and have identified significant risks for further surgery of smoking and low BMI as well as concurrent bowel resection. We show that strictureplasty remains a viable and attractive management for stricturing Crohn’s disease with no deaths resulting from the surgery and a low number of reoperations. Disclosure of interest None Declared.

Risk factors for cardiovascular events among Asian patients without pre-existing cardiovascular disease on the renal transplant wait list.

Introduction:For suitable end-stage renal failure (ESRF) patients, renal transplantation gives better long term survival and quality of life as compared to dialysis. Prior to entry into the renal transplant wait list, potential candidates are screened for the presence of cardiovascular disease. However, the waiting time on the transplant list is long, and interval screening for cardiac fitness for surgery is not well defined. We aim to study the risk factors for the development of a cardiovascular event (CVE) and the time interval from recruitment to onset of a CVE that resulted in their removal from the transplant wait list.Methods:A retrospective study of all patients registered under the cadaveric renal transplant waiting list in Singapore General Hospital (SGH) from 16th April 1987 to 31st October 2010. We identified patients who developed a CVE among this cohort. We compared the demographics and clinical characteristics of patients who experienced a CVE versus those who did not. Univariable and multivariable cox regression were performed to investigate the significant variables for the development of a CVE. The time to development of CVE was estimated using Kaplan Meier estimation and log-rank test was used to compare the time to CVE between those with diabetes mellitus and those without.Results:1265 patients were enrolled in this study. 273 patients dropped out of the wait list due to medical reasons or death, of which 38.8% were due to CVE. The mean and median time duration from recruitment into the waiting list to development of a CVE was 14.42 (95% CI 13.72 to 15.11) and 15.69 (95% CI 13.86 to 17.51) years respectively. For patients with diabetes mellitus, this was 8.22 (95% CI 6.30 to 10.14) and 8.16 (95% CI 4.95 to 11.36) years respectively. Factors associated with an increased risk of developing a CVE included male gender (adjusted HR 2.21, 95% CI 1.43 to 3.41, p<0.001), presence of diabetes mellitus (adjusted HR 5.13, 95% CI 2.85 to 9.24, p<0.001) and patients who were either not working or working part-time as compared to their full-time counterparts (adjusted HR 1.76, 95% CI 1.14 to 2.72, p=0.010). In addition, hazard ratio for CVE significantly increased with advancing age quartile (p<0.001 by log rank test for trend).Conclusion:A significant proportion of patients exited from the renal transplant wait list due to a CVE. Being male, age 37 years old or more, presence of diabetes mellitus and non-working or part-time workers as compared to full-time workers were found to increase the risk of developing a CVE during the wait period for transplantation. The presence of diabetes mellitus significantly shortened the time to development of a CVE.

Su1924 Evaluating the Relationship Between Clinicopathological Variables and Mortality in Patients With Esophagogastric Adenocarcinomas

Introduction Gastric (GC) and oesophageal adenocarcinoma’s (OA) are a major global health problem. This study analysed the relationship between demographic, clinical and pathological variables on and all-cause mortality in a cohort of GC and OA patients. Method Data was captured from 227 patients for age, sex, highest histological grade in tissue, tumour type, tumour location, TNM stage, HER2 status, R0 resection, nodal status, presence of linitis plastica, inflammation, atrophic gastritis (for GC) or Barrett’s epithelium (BE) (for EC). All patients’ received standard treatment through a multidisciplinary team and tissue specimens were examined by expert pathologists. Mortality was the primary outcome and was measured from date of diagnosis to date of death from any cause to calculate median survival (MS) of assessed variables. Kaplan-Meir curves were then compared between related variables (log-rank test, Mantel-Cox) and (log-rank test for trend). Results Using Mantel-Cox analysis, MS (months=m) was significantly worse in GC vs EA (12.5 m, n = 126; 23.8 m; n = 51; p = 0.027); diffuse vs intestinal type tumours (17.4 m, n = 69; 27.9 m, n = 97; p = 0.008); poorly vs moderately differentiated tumours (20.78 m, n = 51; 32.68 m, n = 125; p = 0.08); metastatic vs localised cancers (6.5 m, n = 28; 26.4 m, n = 64; p= Conclusion Survival was worse in tumours of gastric origin, diffuse grade, poor differentiation, higher TNM stage, and for OA, in those arising from Barrett’s epithelium. Older age was a worse prognostic indicator. This data helps understand the prognostic implications of GC and OA histology when counselling patients. Disclosure of interest None Declared.

The Treatment Related Mortality Score Predicts Early Adverse Events during Intensive Induction Chemotherapy for Acute Myeloid Leukemia (AML)

Background: Despite improvements in supportive care, treatment of AML remains associated with complications. We have developed a multivariate model – the Treatment-Related Mortality (TRM) score – which includes age, performance status, and 6 other covariates to predict 28-day mortality with c-statistic = 0.82 (1.0 = perfect prediction, 0.5 = no prediction) (Walter et al. J Clin Oncol 2011). We investigated associations between TRM score and complications developing during AML treatment.Patients and Methods: 179 adults (median age 53 [range: 18-77] years) with newly diagnosed AML treated at our institution from 2002-2012 with 7 + 3 or similar therapy were included. Documented infections, ICU transfer, and death until the earlier of day 28 or administration of additional chemotherapy were recorded. Patients were categorized by quartiles of TRM score. All outcomes were treated as time-to-event endpoints. The survival probabilities in the absence of infection or ICU transfer were estimated using the Kaplan-Meier method; the 10 patients in the ICU at the start of chemotherapy were excluded from analysis of ICU transfer as an adverse event. Outcomes between TRM scores by quartile were assessed using log-rank test for trend; scores above and below the median were compared using Cox regression. Multivariate models were adjusted for gender, cytogenetic risk, baseline absolute neutrophil count, and year of treatment.Results: The median TRM score was 4.6 (quartiles 2.3 and 10.5). Documented infections occurred in 72 patients (40%), ICU transfer in 14 (8%), and death in 4 (2%) within 28 days of induction. Patients with higher ranges of TRM scores were more likely to develop infections (Ptrend=0.006; Fig 1a) and require ICU transfer (Ptrend=0.003; Fig 1b). In particular, TRM scores above the median were associated with increased risk of infection (P=0.02; Fig 1c) and ICU transfer P=0.0004; Fig 1d). After multivariable adjustment, the risk of documented infection was 1.72 (95% CI: 1.06-2.81)-fold higher for patients with TRM >4.5. Consistent with our recent analysis, baseline grade 4 neutropenia was also independently associated with infection (HR 2.2 [95% CI: 1.38-3.52]) (Buckley et al. Am J Hematol 2014). There was only one ICU transfer, and there were no deaths among the 92 patients with TRM score less than the median. Although supportive care measures have improved in recent years, a high TRM score was still associated with ICU transfer in the subset of patients treated from 2007-2012 (P=0.001).Conclusions: The TRM score is associated not only with death, but also with other early adverse events. A cut-point of 4.5, which will need to be confirmed in an independent study cohort, may separate low- from high-risk patients in terms of susceptibility to infection and likelihood of requiring an ICU transfer. The TRM score may thus improve assessment of the risks of intensive induction chemotherapy and help allocate health care resources. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

KIR B haplotype donors confer a reduced risk for relapse after haploidentical transplantation in children with ALL

AbstractWe analyzed the influence of donor killer-cell immunoglobulin-like receptor (KIR) gene haplotypes on the risk for relapse and the probability of event-free survival (EFS) in children with acute lymphoblastic leukemia who received human leukocyte antigen–haploidentical transplantation of ex vivo T-cell-depleted peripheral blood stem cells. The KIR gene haplotype was evaluated in 85 donors, and the KIR B content score was determined in the 63 KIR haplotype B donors. Patients transplanted from a KIR haplotype B donor had a significantly better EFS than those transplanted from a KIR haplotype A donor (50.6% vs 29.5%, respectively; P = .033). Moreover, a high donor KIR B-content score was associated with a significantly reduced risk for relapse (Log-rank test for trend, P = .026). These data indicate that KIR genotyping should be included in the donor selection algorithm for haploidentical transplantation in children with acute lymphoblastic leukemia with the aim of choosing, whenever possible, a KIR haplotype B donor with a high KIR B-content score.

Psychomotor agitation in major depressive disorder is a predictive factor of mood-switching

BackgroundThe relationship between psychomotor agitation in unipolar depression and mood-switching from depression to manic, hypomanic and mixed states has been controversial. We investigated the future risk of initial mood-switching as a function of psychomotor agitation in unipolar depression. MethodsWe identified 189 participants diagnosed with major depressive disorder (MDD). We divided all patients with MDD into two categories (1) agitated patients (n=74), and (2) non-agitated patients (n=115). These groups were prospectively followed and compared by time to mood-switching. Kaplan–Meier survival curves, log-rank test for trend for survivor functions, and Cox proportional hazard ratio estimates for a multivariate model were conducted to examine the risk of mood-switching by psychomotor agitation. ResultsDuring follow-up, mood-switching occurred in 20.3% of the agitated patients and 7.0% of the non-agitated patients. In the Kaplan–Meier survival estimates for time to incidence of mood-switching with agitated or non-agitated patients, the cumulative probability of developing mood-switching for agitated patients was higher than those for non-agitated patients (log-rank test: χ2=7.148, df=1, p=0.008). Survival analysis was also performed using Cox proportional hazards regression within a multivariate model. The agitation remained significantly associated with incidence of mood-switching (HR=2.98, 95% CI: 1.18–7.51). LimitationsWe did not make a clear distinction between antidepressant-induced mood-switching and spontaneous switching. ConclusionsThe main finding demonstrated that MDD patients with agitation were nearly threefold as likely to experience mood-switching, suggesting that psychomotor agitation in MDD may be related to an indicator of bipolarity.

PWE-117 Have Perianal Surgery Rates Decreased With The Rise In Thiopurine Use In Crohn’s Disease?

IntroductionAlthough thiopurines (TPs) have proven efficacy in the maintenance of remission in Crohn’s disease (CD) and may reduce the need for intestinal surgery, their impact on perianal disease is not...

The construction of risk prediction models using GWAS data and its application to a type 2 diabetes prospective cohort.

Recent genome-wide association studies (GWAS) have identified several novel single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2D). Various models using clinical and/or genetic risk factors have been developed for T2D risk prediction. However, analysis considering algorithms for genetic risk factor detection and regression methods for model construction in combination with interactions of risk factors has not been investigated. Here, using genotype data of 7,360 Japanese individuals, we investigated risk prediction models, considering the algorithms, regression methods and interactions. The best model identified was based on a Bayes factor approach and the lasso method. Using nine SNPs and clinical factors, this method achieved an area under a receiver operating characteristic curve (AUC) of 0.8057 on an independent test set. With the addition of a pair of interaction factors, the model was further improved (p-value 0.0011, AUC 0.8085). Application of our model to prospective cohort data showed significantly better outcome in disease-free survival, according to the log-rank trend test comparing Kaplan-Meier survival curves (). While the major contribution was from clinical factors rather than the genetic factors, consideration of genetic risk factors contributed to an observable, though small, increase in predictive ability. This is the first report to apply risk prediction models constructed from GWAS data to a T2D prospective cohort. Our study shows our model to be effective in prospective prediction and has the potential to contribute to practical clinical use in T2D.

Abstract P1-08-12: G protein-coupled estrogen receptor in the plasma membrane is prognostic in early breast cancer

Abstract Background: G protein-coupled estrogen receptor (GPER), also known as GPR30, is a novel putative estrogen receptor. Although contradictory results have been presented e.g. regarding the subcellular localization and function of the receptor, previous studies have shown a prognostic value in breast cancer and proposed treatment predictive information for tamoxifen (Tam). This study aimed at clarifying the prognostic and treatment predictive value for Tam of GPER, in different subcellular localizations, by using samples from a randomized clinical trial - the ideal population for assessing treatment prediction. Material and Methods: GPER levels were assessed semi-quantitatively by immunohistochemistry in tissue microarrays from 742 postmenopausal breast cancer patients with no lymph node metastasis and tumor size ≤ 30mm. Patients were originally included in the STO-3 trial 1976-1990. After surgery, they were randomized to Tam treatment (40mg for 2 years or no systemic treatment), regardless of classical estrogen receptor α (ER) status. GPER staining was evaluated in carcinoma both as intensity in 5 levels regardless of subcellular localization, and in the plasma membrane in 3 levels. Due to statistical considerations regarding group size, the final analysis was made with intensity in 3 levels and plasma membrane as positive or negative. The Kaplan-Meier method and logrank test (for trend when applicable) were used for survival analysis and Cox regression analysis for obtaining hazard ratios (HR), interaction testing and multivariate modeling. Distant disease-free survival (DDFS) was used as endpoint. Results: Analyzing all patients, we found no association between DDFS and GPER intensity. However, positive plasma membrane staining showed a strong correlation with poor prognosis (HR 1.8 p = 0.002). This was only observed in the ER+ subgroup (ER+ patients HR 2.1, p&amp;lt;0.001, ER- patients HR 1.1 p = 0.79). The prognostic value, in untreated patients only, was analyzed with similar results (plasma membrane staining positive vs. negative: all untreated patients HR 1.8 p = 0.008, ER+ patients HR 2.1 p = 0.003, ER- patients HR 1.1 p = 0.83). No obvious difference in tamoxifen response was observed across plasma membrane or intensity groups, and tests for interaction were not significant. A multivariate model including GPER in plasma membrane, ER, histological grade, HER2, tamoxifen and tumor size showed that GPER was an independent prognostic factor (HR 1.6 p = 0.01). Finally we created a group with ER+, progesterone receptor (PR) + patients treated with Tam, as this group today is treated with Tam and thought to have a good response. GPER in the plasma membrane significantly separated this group into an excellent prognosis group and a poor prognosis group (HR 3.3, p = 0.01). The excellent prognosis group, which constitutes more than half of ER+ patients, had a 20 year DDFS of 91% (95% CI 84-95). Conclusion: We found no treatment predictive value of GPER for Tam. However, GPER expressed in the plasma membrane was a strong independent prognostic factor for a poor prognosis in ER+ breast cancer. Used in ER+, PR+, tamoxifen treated patients, it can distinguish patients with an excellent prognosis from patients with a poor outcome that may benefit from additional treatment. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-12.

Accordion complication grading predicts short-term outcome after right colectomy

BackgroundThe Accordion severity grading system is a novel system to score the severity of postoperative complications in a standardized fashion. This study aims to demonstrate the validity of the Accordion system in colorectal surgery by correlating severity grades with short-term outcomes after right colectomy for colon cancer. MethodsThis is a retrospective cohort review of patients who underwent right colectomy for cancer between January 1, 2002, and January 31, 2007, at a single tertiary care referral center. Complications were categorized according to the Accordion severity grading system: grades 1 (mild), 2 (moderate), 3–5 (severe), and 6 (death). Outcome measures were hospital stay, 30-d readmission rate and 1-y survival. Correlation between Accordion grades and outcome measures is reflected by Spearman rho (ρ). One-year survival was obtained per Kaplan-Meier method and compared by logrank test for trend. Significance was set at P ≤ 0.05. ResultsOverall, 235 patients underwent right colectomy for cancer of which 122 (51.9%) had complications. In total, 52 (43%) had an Accordion grade 1 complication; 44 (36%) grade 2; four (3%) grade 3; 11 (9%) grade 4; seven (6%) grade 5; and four (3%) grade 6. There was significant correlation between Accordion grades and hospital stay (ρ = 0.495, P < 0.001) and 30-d readmission rate (ρ = 0.335, P < 0.001). There was a significant downward trend in 1-y survival as complication severity by Accordion grade increased (P = 0.02). ConclusionsThe Accordion grading system is a useful tool to estimate short-term outcomes after right colectomy for cancer. High-grade Accordion complications are associated with longer hospital stay and increased risk of readmission and mortality.

Adverse Events During Intensive Induction Chemotherapy For Acute Myeloid Leukemia (AML) Or High-Grade Myelodysplastic Syndromes (MDS)

BackgroundIntensive chemotherapy for adults with newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) is associated with a considerable risk of morbidity and mortality, commonly due to infections and bleeding. Little information is available on pre-treatment risk factors that predispose to these complications. Here, we investigated the relationship between baseline peripheral blood counts and (a) subsequent adverse events and (b) duration of neutropenia following administration of induction chemotherapy at our institution over the last decade for newly diagnosed AML/MDS undergoing curative-intent induction chemotherapy. Patients and MethodsWe retrospectively analyzed 205 consecutive adults receiving 7 + 3-like treatment regimens. Daily blood counts were recorded from initiation of chemotherapy until the day of neutrophil recovery (defined as an absolute neutrophil count [ANC] greater than or equal to 500 cells/µL). Adverse events (fever, infection, bacteremia, transfer to the intensive care unit, and death) were recorded until day 35 or administration of additional chemotherapy, whichever came first. Cytogenetic risk was classified based on revised MRC/NCRI criteria. Associations between baseline patient characteristics and adverse events were assessed using Kaplan-Meier survival curves with a log-rank test (for two groups) or log-rank test for trend (for three or more groups); patients requiring salvage therapy for persistent disease were censored on the day such therapy was initiated. Cox proportional hazards models were used to estimate the hazard ratio (HR) for the associations between age, gender, disease type, cytogenetic risk and adverse outcomes in univariate and multivariate analyses. ResultsThe median age of our study cohort was 53 (range: 18 to 81) years. Sixty-six percent of the patients had de novo AML. Cytogenetic risk was favorable in 14%, intermediate in 60%, and adverse in 24%. Among all patients, the complete remission (CR) rate was 75%, while 2% died before response could be assessed (range: day 13 to 28) and 23% were refractory. When analyzed as a continuous variable, the baseline neutrophil count was statistically significantly associated with fever (HR=0.97 [95% confidence interval: 0.95-0.999] for each increase of 1000 cells/µL, P=0.04) and infection (HR=0.92 [0.87-0.98], P=0.01), but not bacteremia (HR=0.95 [0.89-1.01], P=0.10) or requirement for intensive care unit (ICU) care (HR=1.00 [0.93-1.07], P=0.99). For subsequent analyses, we dichotomized the study cohort based on pre-treatment ANC and compared patients with baseline ANC<500/µL (n=75) with those with ANC greater than or equal to 500/µL (n=130). As shown in Figure 1, baseline ANC<500/µL was associated with the development of fever (P=0.022), documented infection (P<0.001), bacteremia (P<0.001), and death (P=0.035) [Figure 1] but not requirement for ICU care (P=0.39). In patients who achieved CR with 1 course of therapy without myeloid growth factor support, baseline ANC<500/µL was associated with delayed neutrophil count recovery (P<0.0001). In addition to low baseline ANC, we also found that low baseline monocyte and lymphocyte counts were associated with increased risk of documented infection or bacteremia. After adjustment for age, gender, disease type, and cytogenetic risk, the risk of documented infection or bacteremia was 2.71 (1.78-4.12)-fold and 2.11 (1.26-3.55)-fold higher in patients with baseline ANC<500/µL. Having demonstrated that baseline ANC<500/µL was associated with both duration of neutropenia and the development of adverse events and death, we wondered whether this patient subset could be suitable for the targeted use of myeloid growth factors. To investigate this, we evaluated whether those with 0% bone marrow blasts at first post-treatment assessment were also more susceptible to adverse events after day 14. Indeed, this was the case for infection (P=0.0140) and bacteremia (P=0.0023). ConclusionOur studies identify pre-treatment ANC<500/µL as a risk factor for both infection-associated adverse events, including death, and longer duration of neutropenia. If validated, these results would provide the rationale for the risk-adapted testing of myeloid growth factor support in patients with AML/MDS with pre-treatment ANC< 500/µL when undergoing curative-intent induction chemotherapy. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Lung clearance index predicts pulmonary exacerbations in young patients with cystic fibrosis

RationaleThe lung clearance index (LCI) is a promising endpoint for use in cystic fibrosis (CF) clinical trials, but correlations with validated clinical endpoints have not yet been established.ObjectiveThis study aimed...