Not Available Research Articles

Mutational analysis of key genes in patients from the Kazakh population with early onset of breast cancer.

e13038 Background: Breast cancer (BC) represents the most common malignancy and has the highest mortality among women, both in the world and in Kazakhstan. Approximately 20-30% of cases of hereditary BC are caused by presence of BRCA1/2 genes defects. Also, there are additional genes which can increase the risk of BC and they are still under study.The aim of this study was to identify new, detectable and objective markers of key cancer genes by next-generation sequencing (NGS) of young BC patients. Methods: Blood was collected from 129 BC patients (average age 34.87±5.587). DNAs were extracted using GeneJET Genomic DNA Purification Kit. NGS was done on the MiSeq platform using TruSightCancer Kit. NGS data were analyzed by the MiSeq Reporter v. 2.4 software. Variant annotation and interpretation was done by Variant Studio 3.0 software. Results: We perform the NGS and did the detailed bioinformatics analysis of sequences of 16 key genes of BC (BRCA1/BRCA2, BRIP1, ATM, CDH1, CHEK2, NBN, NF1, PALB2, STK11, TP53, RAD51C, RAD51D, BARD1, MUTYH and FANCC). At all 3016 variants were detected, 1080 (35.8%) out of which were missense; 1494 (49.5%) synonymous; 17 (0.6%) frameshifts; 2 (0.06%) inframe deletions, 8 (0.3%) stop gained; 4 (0.1%) splice variant, 411 (13.6%) intron or non-coding variants. We identified 24 pathogenic and likely pathogenic mutations in 31 patients (24% of all patient cohort), 3 mutations are novel. All mutations were in heterozygous state and were rare or had frequency data not available (NA) in 1000G, ESP6500and ExAC databases. Analysis of mutation type revealed 17 frameshift mutations, 2 missense mutations, 8 stop gained mutations, 4 mutations involving uncorrected splicing. Out of the 31 pathogenic and likely pathogenic variants, were detected 14 in BRCA1, 9 in BRCA2, 4 in TP53 genes, 3 in PALB2 and 1 in NBN. (BRCA2: c.6468_6469delTC, c.7567_7568delCT, c.9976A > T, c.8174G > A, c.2442delC, c.2808_2811delACAA, c.9253delA, c.9409dupA and c.6058G > T; BRCA1: c.2498delT, c.5224C > T, c.3020C > G, c.3352C > T, c.5530+1G > A, c.5341-2delA and BRCA1-c.5329dupC in 6 cases; NBN: c.657_661delACAAA; PALB2: c.172_175delTTGT, c.1034T > G and c.18_22delGAAGC; TP53- c.156dupA, c.1024C > T, c.844C > T and c.584T > C). The most frequent genes were BRCA1 (45%) and BRCA2 (29%). Conclusions: The study focused on identifying mutation profile of early onset BC using NGS. Clinically significant variants was detected which are promising biomarkers for the successful diagnosis and therapy of BC at women in reproductive age.

Efficacy and tolerability of initial low-dose lenvatinib to treat differentiated thyroid cancer.

Some patients with differentiated thyroid cancer (DTC) may require an initial low dose (LD) of lenvatinib. However, few studies have investigated the efficacy of LD lenvatinib. We compared the efficacy and tolerability of lenvatinib at an initial LD to those of the standard initial dose of 24 mg in patients with DTC.In this cross-sectional study, records of patients with DTC treated with lenvatinib were retrospectively reviewed. Patients were divided into 2 groups based on the initial dose of lenvatinib: a full-dose (FD) group that received an initial dose of 24 mg/d and a LD group that received an initial dose of less than 24 mg/d. Categorical variables were compared with the Fisher exact test and continuous variables with Student t test. A progression-free survival (PFS) curve was constructed with the Kaplan–Meier method. A probability (P) value of < .05 was considered statistically significant.Thirty-six patients with DTC were treated with lenvatinib (30 in the FD group and 6 in the LD group). The response rates were 43% and 33% in the FD and LD groups, respectively. The median PFS duration was 696 [95% confidence interval (CI): 318–not available (NA)] days in the FD group. The median PFS of the LD group was not reached (95% CI: 124–NA) (P = .293). Treatment interruptions were required in 25 (83%) patients in the FD group and 4 (67%) in the LD group (P = .573). Dose reductions were required in 28 (93%) patients in the FD group and 4 (67%) in the LD group (P = .121). There were no significant differences in the incidences of common adverse events between the 2 groups.The LD group also required dose reduction and interruption frequently. Since these findings are only the short-term results of a limited number of cases, a large number of cases and long-term observations are needed to determine whether an initial LD is effective for patients with DTC in poor general condition.

Treatment of clinical T4 stage superior sulcus non-small cell lung cancer: a propensity-matched analysis of the surveillance, epidemiology, and end results database.

Purpose/Objective(s): Treatments for superior sulcus non-small cell lung cancer (SS-NSCLC) have evolved, but adequate treatments of T4 disease have not been found. The aim of our study was to evaluate the prognostic factors and optimal treatment strategy for patients with T4 SS-NSCLC. Materials/Methods: We utilized the Surveillance, Epidemiology, and End Results (SEER) database (1973–2015) to identify patients diagnosed with T4 stage SS-NSCLC (according to the 7th edition American Joint Committee on Cancer (AJCC) staging system) from 2004 to 2015; those with M1 disease were excluded. Propensity score matching (PSM) with Kaplan–Meier and Cox proportional hazards’ models was performed to estimate prognosis. Results: A total of 384 patients were included. The majority was male (59.4%) at stage IIIB (56.6%), with N2 accounting for 45.3%. A total of 47 patients underwent cancer-directed surgery, while radiotherapy alone was received by 60.2% of patients. Median overall survival (OS) and lung cancer-specific survival (LCSS) were 12 and 17 months, respectively, and the 5-year OS and LCSS rates were 15.8 and 25.4%, respectively. In the matched population, the median survival outcomes were better following surgery (OS: 25 compared with 9.0 months, P<0.001; LCSS: not available (NA) compared with 11.0 months, P<0.001). Multivariate Cox analysis showed that ages ≥ 66 years (hazard ratio (HR) = 1.639, P=0.001), unmarried status (HR = 1.356, P=0.034), and tumor size ≥ 6.0 cm (HR = 1.694, P<0.001) were associated with inferior OS. Cancer-directed surgery (HR = 0.537, P=0.009) and radiotherapy (HR = 0.644, P=0.006) were independent prognostic factors for patients with T4 SS-NSCLC. Conversely, in the subgroup analysis, favorable impacts of radiotherapy were observed for nonsurgical patients (OS: HR = 0.58, P<0.001; LCSS: HR = 0.55, P<0.001). Conclusion: Our study showed that T4 stage SS-NSCLC patients had a poor prognosis. Surgical resection remains the best option for those with resectable disease. For nonsurgical T4 SS-NSCLC patients, radiotherapy should be actively considered.

Medical card data imputation and patient psychological and behavioral profile construction

Missing data is a typical problem for many hands-on tasks and researches, which has required human intervention and contributed to an increase in errors during algorithms application that demand for a large number of metrics. Solving this particular problem is essential for medicine and healthcare, because it allows more easily diagnosing certain types of diseases, improving medical service quality, etc. The main approach for medical data imputation is to automate this process at all stages, beginning from finding the NA (Not Available) or missing Data, to the completion of the analysis and insertion of lost information entity. The proposed methods of mathematical computing and modeling, statistical functions, data flow diagrams during the imputation, and the use of computer programming tools should be implemented in the medical field to improve and address the missing data issue. The evaluation of key characteristics (algorithm’s error, number of imputed data, datasets dimensionality) helped to determine the factors for obtaining the most accurate result with the help of various algorithms and functions. The study is useful for the medical industry in general, since it will eliminate the missing data values in patient medical records by applying statistical methods and artificial intelligence, which will significantly shorten the automation of large datasets processing and facilitate their descriptive and exploratory analysis during further data discovery to identify certain patterns and features.

Sustained prognostic impact of circulating tumor cell status and kinetics upon further progression of metastatic breast cancer.

Serial longitudinal enumeration of circulating tumor cells (CTCs) has shown its prognostic value on progression-free survival and overall survival (OS) in patients with stage IV breast cancer. This study prospectively evaluated the role of CTCs as a prognostic marker during further progression of metastatic breast cancer (MBC). Among 476 MBC patients recruited between 2010 and 2015, the 103 patients with a known CTC status at baseline (CTCBL) and within 4weeks of tumor progression (CTCPD) were included. Progressive disease (PD) was defined according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Using the CellSearch method, < 5 and ≥ 5 CTCs per 7.5ml blood were determined as negative and positive, respectively. A shift in CTC status from baseline to progression ([Formula: see text] to [Formula: see text] and vice versa) was considered as alternating KineticsBL-PD. Median follow-up was 29.9 [21.2, 40.0] months. CTCPD positivity (37%, n = 38) was associated with a significantly shorter OS than CTCPD negativity (8.0 [5.1, 10.9] vs 22.6 [15.3, 39.8] months; P < 0.001). Alternating KineticsBL-PD was observed in 24% of the patients. This significantly changed the OS prediction of [Formula: see text] patients ([Formula: see text] vs [Formula: see text], 11.4 [9.7, not available (NA)] vs. 7.6 [4.4, 11.5] months; P = 0.044) and [Formula: see text] patients ([Formula: see text] vs. [Formula: see text], 8.4 [4.0, NA] vs. 22.6 [18.9, NA] months, respectively; P < 0.001). Prediction of survival was significantly improved (P = 0.002) by adding CTCPD status to clinicopathological characteristics and CTCBL status. CTC status upon further disease progression is a prognostic factor that could significantly improve well-established models. Thus, it represents a potential additional instrument supporting treatment decision.

Assesing Performance of Moving Average Investment Timing Strategy Over the UK Stock Market

Predicting stock returns, despite being complicated, has always been of interest to investors, financial analysts, academicians and policy makers. The finance theory, broadly, follows two approaches, namely fundamental and technical analyzes, in order to forecast future prices. Fundamental analysis uses variables related to intrinsic properties of the stock to estimate price, or value. In contrast, technical analysis utilizes historical data on prices (or other information) to drive signals about future prices. Despite its practical usage, profitability of technical analysis remains questionable. While prior studies apply technical analysis, especially moving average, on US stocks, this study follows the methodology adopted by Han, Yang and Zhou (2013) to assess the performance of moving average technical analysis on UK stock market. The study uses daily data on UK-DS Market-PRICE INDEX, 1-Month T-Bill rate, and all stocks listed on London Stock Exchange, United Kingdom (UK). Data has been downloaded from Thomson Reuters's DataStream over a period of more than sixteen years from December 31, 1999 to February 29, 2016. Data on risk free rate and market index do not have any missing values. However, stock prices do include missing values; we replace all of them by not available (NA). We apply moving average investment timing strategy to five quantile portfolios sorted by volatility and compare their performance with respective buy-and-hold portfolios. We also asses risk adjusted returns of quantile portfolios using CAPM. For robustness check, we test the strategy for alternative lag lengths, random switching, and breakeven transactions costs. The results suggest that MA strategy substantially outperforms buy-and-hold strategy in UK stock market by producing significantly higher average returns and risk adjusted returns, lower standard deviations, higher Sharpe ratios, and reasonable success ratios. Results are quite robust to most of the lag lengths and quantiles. However, random switching strategy does not produce significant results in this case. We test MA strategy for various lag lengths; the strategy based on 10-day lag length performs the best. This indicates that signals generated from closer history provide better proxy for future trading. Finally, although breakeven transaction costs are considerably larger than actual transaction costs in UK, other variables measuring trading behaviour under MA strategy provide mixed results when seen in relation to volatility. The Uk stock market is weak from the efficiency empirically proved through this study, then the investors should be able to exploit predictable patterns of share returns in order to earn excess returns on a regular basis. There is reasonable degree of predictability in their security returns.

Abstract 3187: Concordance of immunohistochemistry (IHC) assay results with gene expression profiling (GEP) methods for diffuse large-B-cell lymphoma (DLBCL) subtype identification

Abstract Introduction: The survival of DLBCL patients who receive immunochemotherapy is correlated with the molecular signature of their tumors. The two most common subtypes which are defined by cell of origin (COO) are the germinal center B cell-like (GCB) and activated B cell-like (ABC) subtypes which have 3-year OS rates of 80% and 45%, respectively when treated with R-CHOP. Several methods have been developed to categorize DLBCL into these sub-types as the treatment they receive directly affects their outcome. Microarray GEP was first used to classify DLBCL into ABC or GCB, with a minority unclassified (UNC), however this is difficult to implement widely and has been replaced by more recent technologies. The most commonly used IHC-based Hans method profiles patients into GCB and non-GCB. The primary focus of this study was to evaluate concordance between current GEP and IHC methods to designate DLBCL subtypes. Methods: For this study, the IHC assay used was a standardized IHC assay based on the Hans algorithm and for the GEP-based assay; the NanoString Technologies Lymphoma Subtyping Test (LST) was used. Commercially available DLBCL samples (N = 138) were confirmed for tumor content and sent to a central laboratory for evaluation by the IHC assay. RNA was extracted from each sample and sent to NanoString for GEP evaluations. To compare methods homogeneously, calls for each method were converted to either “GCB” or “non-GCB”. All “ABC” and “UNC” subtype calls from the NanoString platform was converted to “non-GCB” and any “did not pass” (DNP) calls were converted to not available (NA). All NA values were excluded from the tables and concordance calculations. Results: The Positive Percent Agreement [95% CI] in calling non-GCB between IHC and LST was 87% [78% - 96%] (47/54). Overall concordance between IHC and LST was 80% [73% - 87%] (N = 125, 12 LST samples DNP, 1 IHC sample DNP). The Negative Percent Agreement between IHC and LST (i.e., in calling the GCB sub-type) was 75% [65% - 85%] using the LST result as a non-reference standard (53/71). Conclusions: Given that the success of targeted therapy for the treatment of DLBCL is contingent on the correct identification of sub-type of DLBCL, it is important to adopt a method that accurately and consistently identifies the sub-type in the majority of patients. Given the good concordance between the GEP and IHC methods, DLBCL can be stratified into COO sub-types using either platform. The results show that an optimized Hans IHC assay standardized in a central laboratory offers a robust, relatively inexpensive and accessible platform for cell of origin sub-typing in DLBCL and, with clinical validation, may offer an excellent tool for the selection of optimal therapy. Citation Format: Michael Schaffer, Shalini Chaturvedi, Sandy Frans, Regina Aquino, Jaehong Park, Brett Hall, Sriram Balasubramanian. Concordance of immunohistochemistry (IHC) assay results with gene expression profiling (GEP) methods for diffuse large-B-cell lymphoma (DLBCL) subtype identification. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3187.

Emergency physicians’ and nurses’ perception of quality of elderly care in the Emergency Department. Results of a national survey

The present study has been carried out to evaluate the current status of clinical, educational, social, ethical, and resource issues related to the care of the elderly among emergency physicians (EPs) and emergency nurses (ENs) in Italy. A questionnaire was designed by our scientific society, the Academy of Emergency Medicine and Care (AcEMC), and disseminated directly or by e-mail to a large number of EPs and ENs in several Emergency Departments (EDs) throughout Italy, as well as in a Swiss center. Of the questionnaires, 524 were filled out and returned. Responders were in the majority females [273 vs 239; 12 not available (NA)], and nurses [259 vs 207 physicians vs 54 auxiliary; 4 NA]. Responses to five questions appeared to be normally distributed, whereas other questions elicited interesting responses. In this study focusing for the first time on the EPs’ and ENs’ perception of a broad spectrum of issues related to the elderly emergency care, the Italian community of EPs and ENs seems to be rather comfortable with geriatric emergency medicine, but largely unsatisfied with healthcare out-of-hospital services. The lack of elderly-specific diagnostic and therapeutic post-discharge pathways is broadly appreciated, and the concept of medical futility is not explicitly included in the vast majority of Italian hospital protocols.

A170: Neoplasms in Pediatric Patients with Rheumatic Diseases Exposed to Biologics—A Quarternary Centre's Experience

Background/Purpose:Biologic therapies have revolutionized the management of rheumatic diseases of childhood. However, these medications are associated with adverse effects including the possible development of neoplasms. The aim of our study was to determine the rate as well as risk factors for the development of neoplasms in patients with JIA treated with biologics.Methods:We performed a retrospective review of the rheumatology biologic registry (RBR) at The Hospital for Sick Children (SickKids), Toronto, Canada, one of the largest quarternary pediatric referral centres in North America. Demographic and neoplastic data, clinical course and medication history were extracted from the RBR and clinical charts. Unless specified, data was expressed as median (IQR). The study was approved by the SickKids Ethics Review Board.Results:The cohort consisted of 357 patients with rheumatic diseases who were on one or more biologics between January 1997 and August 2013. Juvenile Idiopathic Arthritis (JIA) was the most common diagnosis [302/357 (84.5%)]. A total of 6/357 (1.68%) patients developed a neoplasm: 4 with JIA, 1 each with idiopathic uveitis and polyarteritis nodosa. (Refer to t87) Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Neoplasm Nasopharyngeal carcinoma 1. Tonsillar lymphoproliferative disorder (LD) in 2006 Clear cell renal carcinoma Hepatosplenic lymphoma Small blue cell sarcoma, undifferentiated Pilomatricoma 2. Renal carcinoma in 2011 Rheumatic Disease (RD) Idiopathic Uveitis Polyarteritis Nodosa Poly JIA (RF negative) Systemic JIA Oligo JIA (extended) Oligo JIA (extended) Age of onset of RD (years) 10.8 1.1 8.2 4.7 1.6 2.0 Sex Male Male Female Female Female Female DMARD(s), Cytotoxic agents MTX (4.7) MTX (1.2); MTX (6.2); MTX (3.6); MTX (7.2); CSA (3.2); (Time (years)) AZA (NA); LFN(0.2); CSA (0.9); LFN (0.2) AZA (4.3); Abbreviations: ‐Methotrexate (MTX), CYC (1.5) CSA (1.5); Tacrolimus (5.0); MTX (6.0); ‐Azathioprine (AZA), AZA (1.2); Etoposide (6 cycles over 34 days); LFN (2.8) ‐Leflunomide (LFN), SSA (0.9) Thalidomide (0.6) Cyclophosphamide (CYC), ‐Cyclosporine (CSA), ‐Sulfasalazine (SSA) ‐Not available (NA) Biologic(s) Infliximab (3.3) Infliximab (7.5) Etanercept (4.8) Etanercept (0.1); Etanercept (5.2) Infliximab (8.2); (Time (years)) Infliximab (1.7); Etanercept (1.5) Anakinra (1.9) Time to neoplasm (years) 5.3 1. 14.1 15.8 11.8 16.7 12.7 2. 18.6 Time from DMARD to neoplasm (years) 4.7 1. 6.8 17.6 11.8 8.4 12.6 2. 11.4 Time from Biologic to neoplasm (years) 3.3 1. 4.8 10.6 8.6 5.3 1.3 2. 9.3 Family history of neoplasm Maternal grandfather: lung cancer; Maternal grandmother: cervical cancer Mother died due to breast cancer. NA NA NA Strong family history of colon cancerAmongst patients with neoplasms, the median (IQR) age at rheumatic disease onset was 3.4 (1.7–7.3) years and the age of diagnosis of the neoplasm was 16.3 (15.3–17.9) years. All cancers were malignant except in patient 6 which was of a benign nature. On average, patients had exposure to 3 DMARDs (range 1–5), with methotrexate as the commonest DMARD used in 5/6 patients prior to diagnosis of the neoplasm. The time from the disease onset to initiation of DMARD was 3.9 (0.4–7.9) years. The time from the DMARD initiation and the diagnosis of a neoplasm was 10.1 (7.2–12.3) years. For methotrexate alone, the duration of use was 5.4 (3.9–6.1) years. All patients diagnosed with a neoplasm, had received both, DMARD(s) and biologic(s). 2 patients were on infliximab alone, 2 on etanercept alone and 2 on multiple biologics of which etanercept and infliximab were both used. The time between onset of a biologic and diagnosis of a neoplasm was 5.0 (3.6–7.7) years. Two patients (2 and 4) also received medications which are associated with the development of the neoplasms (cyclophosphamide or etoposide).Conclusion:Majority of neoplasms were of uncommon morphology and site as well as aggressive in nature. The neoplasms developed late after drug exposure with a median duration to diagnosis of neoplasm of 10.1 years on a DMARD and 5.5 years on a biologics. Whilst DMARDs and biologics are effective for the management of rheumatic diseases, patients with refractory disease requiring ongoing drug therapies should have malignancy/ neoplasm surveillance included as part of routine clinical care. Comparison of patients on biologics with and without neoplasms is in progress.

Virtual chromoendoscopy in small bowel capsule endoscopy: New light or a cast of shadow?

To evaluate whether virtual chromoendoscopy can improve the delineation of small bowel lesions previously detected by conventional white light small bowel capsule endoscopy (SBCE). Retrospective single center study. One hundred lesions selected from forty-nine consecutive conventional white light SBCE (SBCE-WL) examinations were included. Lesions were reviewed at three Flexible Spectral Imaging Color Enhancement (FICE) settings and Blue Filter (BF) by two gastroenterologists with experience in SBCE, blinded to each other's findings, who ranked the quality of delineation as better, equivalent or worse than conventional SBCE-WL. Inter-observer percentage of agreement was determined and analyzed with Fleiss Kappa (κ) coefficient. Lesions selected for the study included angioectasias (n = 39), ulcers/erosions (n = 49) and villous edema/atrophy (n = 12). Overall, the delineation of lesions was improved in 77% of cases with FICE 1, 74% with FICE 2, 41% with FICE 3 and 39% with the BF, with a percentage of agreement between investigators of 89% (κ = 0.833), 85% (κ = 0.764), 66% (κ = 0.486) and 79% (κ = 0.593), respectively. FICE 1 improved the delineation of 97.4% of angioectasias, 63.3% of ulcers/erosions and 66.7% of villous edema/atrophy with a percentage of agreement of 97.4% (κ = 0.910), 81.6% (κ = 0.714) and 91.7% (κ = 0.815), respectively. FICE 2 improved the delineation of 97.4% of angioectasias, 57.1% of ulcers/erosions and 66.7% of villous edema/atrophy, with a percentage of agreement of 89.7% (κ = 0.802), 79,6% (κ = 0.703) and 91.7% (κ = 0.815), respectively. FICE 3 improved the delineation of 46.2% of angioectasias, 24.5% of ulcers/erosions and none of the cases of villous edema/atrophy, with a percentage of agreement of 53.8% [κ = not available (NA)], 75.5% (κ = NA) and 66.7% (κ = 0.304), respectively. The BF improved the delineation of 15.4% of angioectasias, 61.2% of ulcers/erosions and 25% of villous edema/atrophy, with a percentage of agreement of 76.9% (κ = 0.558), 81.6% (κ = 0.570) and 25.0% (κ = NA), respectively. Virtual chromoendoscopy can improve the delineation of angioectasias, ulcers/erosions and villous edema/atrophy detected by SBCE, with almost perfect interobserver agreement for FICE 1.

Determinants of Executive Incentive Pay in Europe

In this paper we study possible determinants of the use of incentive pay for managers in European companies. Data from 5,000 firms in 15 countries are used to analyze the degree to which incentive pay is associated with national embeddedness, local labour market institutions, ownership, and internationalization of markets. We find that companies in countries with high scores on power distance and individualism tend to use incentive schemes for managers more frequently than companies with lower scores on these cultural dimensions. Centralized wage bargaining and unionization at the firm level tend to reduce the prevalence of such schemes. Incentive pay is less common in state-owned companies than in privately owned firms. The findings also reveal that the more global the market in which a firm operates, the greater the probability that it will implement incentive pay elements for its managers. Our results suggest that unions, national labour market institutions and social and cultural norms serve as buffers against the introduction of US-style compensation systems. _______________________________________________________________________________________ Denne artikkelen er lastet ned fra www.idunn.no. Reproduksjon eller annen videreformidling av artikkelen er ikke tillatt uten avtale med rettighetsforvalter. (PUBLISHER NOT AVAILABLE) , 1-14

Second Cancers After Treatment with Stanford V Regimen in Eastern Cooperative Oncology Group (ECOG) Pilot Study E1492 At a Median Follow up of 17 Years

AbstractAbstract 4779 Purpose:The Stanford V regimen is a combined modality approach for treatment of Hodgkin lymphoma (HL). E1492, an ECOG pilot study, consisted of 12 weeks of Stanford V chemotherapy followed by 36 Gy radiation therapy (RT) to sites > 5 cm or macroscropic splenic disease at diagnosis. Efficacy results were reported previously (Horning et al. J Clin Onc 18, 2000). The study now has a median follow up of 17 years and patients have been followed for overall survival (OS) and development of second cancers. Methods:47 eligible patients with stage bulky mediastinal (mass > one third of the maximum intrathoracic diameter) stage I-II or stage III-IV HL were enrolled between March 1992 and February 1995. Patients were followed every 3 months during the first year off therapy, every 6 months during years 2–5 and annually thereafter. The ECOG database was reviewed for OS and reported second cancers. Patient characteristics at baseline, type of second cancer and time to development of second cancer were assessed. RT summary forms were reviewed for patients with second cancers. Results:41 patients were treated with combined modality therapy and 6 with chemotherapy alone. The median age was 32 years (range 20–56 years). The 5 and 10 year OS are 96%, and 89% respectively. Seven second cancers were reported, as shown in the Table. The cumulative incidence for second cancers accounting for death as a competing risk is 0.02 (95% CI, 0–0.06) at 5 years, 0.07 (95% CI, 0–0.14) at 10 years, and 0.15 (95% CI, 0.04–0.27) at 15 years. Complete details of the exact location, histologic subtype and subsequent management of second cancers were not available for review.Five of the 7 cancers [2 skin, 1 prostate, 2 acute myeloid leukemia (AML)] were not radiation-related. One patient developed AML after primary therapy as reported in the initial publication. A second patient developed AML 5 years after salvage therapy followed by autologous stem cell transplant for relapsed HL. It is likely the 2 cases of breast cancer were treatment related. Conclusion:Within the caveats of a retrospective analysis from a small cooperative group phase 2 trial, the mature 10 year OS of 89% and low frequency of secondary cancers are encouraging in comparison to historic treatment with combined modality treatment. Longer follow up of other Stanford V regimen data sets (i.e. United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244 and the Eastern Cooperative Oncology Group E2496) are required to confirm these findings.TablePatientAge (y) at RxAnn Arbor StageTime (y) from study registration to Second CancerType of Second CancerRT FieldCommentTreated with combined modality (n=5)136IX10BreastMantle and left chest wallSite of breast cancer unknown.228IV12Breast (DCIS)Bilateral supraclavicular; mediastinum; bilateral lungsBoth breasts received 15 Gy RT3156III8ProstateUpper para-aortic; right mesentericNo pelvic RT437II9AMLBilateral supraclavicular; mediastinumDeveloped 5 years post ASCT for relapsed HL538III14Skin (face)Bilateral supraclavicular; mediastinum; spleenNo RT to faceTreated with chemotherapy alone (n=2)645IVNASkin (lip)—7243IV1AML—Reported in original publicationAbbreviations: radiation therapy (RT); acute myeloid leukemia (AML); autologous stem cell transplant (ASCT); Not Available (NA); Hodgkin lymphoma (HL); bulky mediastinal disease (X); ductal carcinoma in situ (DCIS).1Note: Patient also diagnosed with renal cancer 1 month before start of RT;2Patient died. Disclosures:No relevant conflicts of interest to declare.

Outcome of adjuvant therapy for biliary tract cancers.

e14592 Background: There are high rates of recurrence following definitive surgery in patients (pts) with biliary tract cancers (BTCs). Our aim was to review patterns of use and effectiveness of adjuvant therapy (AT) (chemotherapy (CT) +/- radiotherapy (RT)) in pts who underwent definitive surgery for BTC at a tertiary referral centre (Princess Margaret Hospital, Toronto). Methods: The clinical/pathological characteristics, treatment details and survival data of all pts with a diagnosis of BTC who had definitive surgery from Jan 1987 to Sept 2011 were reviewed. Results: The cohort includes 297 pts of which 42% were male, with a median age of 63 yrs, performance status 0-1 in 88%. 56 (19%) had well differentiated, 144 (48%) moderately and 60 (2%) poorly differentiated tumors, 37 (12%) data not available (NA). 125 (42%) and 41 (14%) had R0/R1 resection respectively, 131 (44%) NA. 122 (41%) were node positive, 72 (24%) NA. AT was given in 78 (27%) pts, 49 receiving adjuvant CT and 29 concurrent CT/RT; 34% receiving AT in distal bile duct, 14% in gallbladder, 12% in intrahepatic and 27% in klatskin. 179 (60%) pts recurred; 56/78 (72%) in the AT group (grp) and 123/179 (68%) in non-AT grp, 40 (13%) NA. In the AT and non-AT grps, local recurrence was seen in 7/56 (13%) and 26/123 (21%), distant in 32/56 (57%) and 73/123 (59%), and both in 176/56 (30%) and 24/123 (20%) respectively. In multivariate analysis, node positivity, HR 0.54, 95% CI 0.37 – 0.77, (p=0.001) was the only prognostic factor of DFS after definitive surgery. In node positive population (n=48 with AT, 50 without AT), median DFS was greater in AT grp; 13.8mo vs. 10.4mo (p=0.068). DFS and overall survival (OS) for entire cohort is detailed in Table. Conclusions: Given the limits of this retrospective cohort analysis and potential bias to treat higher risk pts, it does appear that pts receiving adjuvant therapy with node positive disease derived DFS advantage following definitive surgery, though not significant, and is probably an effective option for node positive, curative resected, BTC. However, larger prospective trials are paramount. [Table: see text]

Thromboprophylaxis In Multiple Myeloma Patients Undergoing Immunomodulatory Therapy with Thalidomide and Lenalidomide: A Systematic Review and Meta-Analysis.

AbstractAbstract 1090 Background:The incidence of venous thromboembolism (VTE) in patients with multiple myeloma (MM) is high in patients treated with thalidomide (T)- and lenalidomide (L)-based regimens containing dexamethasone (D) and/or cytotoxic chemotherapy (C). Consensus guidelines recommend routine thromboprophylaxis but reliable data from randomized controlled trials are lacking. Recent observational studies have suggested that thromboprophylaxis might be efficacious in decreasing the risk of VTE in this population. Purpose:To determine the absolute rates of VTE with and without different thromboprophylactic agents (ASA, warfarin, low-molecular-weight-heparin [LMWH]) in patients with newly diagnosed or previously treated MM receiving T- or L-based regimens. Data Source:A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews of published studies up to Jan 2010. Results:A total of 66 studies were included in the analyses. Of these, 61 (4264 patients) and 5 (1119 patients) assessed T- and L-based regimens, respectively.Thalidomide-based regimensThe rates of VTE (per 100 patient-cycles) in patients with newly diagnosed MM treated with T-based regimens:MM TreatmentNo prophylaxisAny prophylaxisASAWarfarin 1-1.25 mg/dProphylactic LMWHTherapeutic anticoagulationT alone (95% CI)1.3NANANA0.5NA(0.4-2.7)(0.4-0.6)(n=380)(n=64)TD (95% CI)4.12.62.32.82.11.6(2.8-5.9)(2.1-3.2)(0.9-7.9)(2.0-3.9)(1.1-3.6)(0.2-4.1)(n=628)(n=993)(n=80)(n=387)(n=446)(n=80)The rates of VTE (per 100 patient-months) in patients with previously treated MM managed with T-based regimens:MM TreatmentNo prophylaxisASAWarfarin 1-1.25 mg/dProphylactic LMWHTherapeutic doses of anticoagulationT alone (95% CI)0.4NANA0NA(0.2-0.8)(0-1.72)(n=706)(n=17)T+ prednisone (95% CI)0.6NANANANA(0.2-1.1)(n=258)TC (95% CI)0.40.4NANA(0.01-1.2)(0.01-0.9)(n=38)(n=37)TD (95% CI)0.8NANANANA(0.1-2.1)(n=321)TDC agents (95% CI)0.9NA2.4NA0(0.3-1.8)(1.3-4.0)(0-2.2)(n=321)(n=102)(n=18)TDC including doxorubicin (95% CI)6.7NA3.5NA(0.5-18.9)(1.2-6.5)(n=331)(n=50)Lenalidomide-based regimensThe rates of VTE (per 100 patient-cycles) in patients with newly diagnosed MM treated with L-based regimens:MM TreatmentNo prophylaxisAny prophylaxisASALD (95% CI)0.80.70.9(0.07-2.0)(0.5-1.1)(0.5-1.5)(n=278)(n=349)(n=172)The rate VTE (per 100 patient-months) in patients with previously treated MM managed with L-based regimens:MM TreatmentNo prophylaxisASALD (95% CI)0.7 (0.4–0.9)(n=361)NALDC including doxorubicin (95% CI)NA0.6 (0.01–2.1)(n=131)None of the studies reported major bleeding events. Limitations:The definition for VTE varied across studies. Most studies did not outline the diagnostic criteria for VTE. Data are not available (NA) for all prophylaxis regimens. Conclusion:Patients with newly diagnosed or previously treated MM receiving T- or L-based regimens are at high risk of VTE. It is uncertain whether thromboprophylaxis provides a clear benefit, especially in those receiving L-based therapy or have previously treated disease. Randomized controlled trials are needed to address this important clinical need. Disclosures:Lee:Eisai: Research Funding; Sanofi Aventis: Consultancy, Honoraria; Leo Pharma: Consultancy; Pfizer: Consultancy, Honoraria; Bayer: Honoraria; Boehringer Ingelheim: Consultancy, Honoraria, Speakers Bureau.

Curative intended radiation therapy for young patients with invasive uterine cervical carcinoma: Clinical outcomes in 105 patients in a Japanese multi-institutional study

e16558 Background: Recently, the number of young patients with invasive uterine cervical carcinoma is increasing in Japan because of earlier sexual activity and low rate of receiving screening test of uterine cervical carcinoma in Japan. However, no large studies have been performed so far to evaluate the clinical outcomes of curative intended radiation therapy for young patients with invasive uterine cervical carcinoma in Japan. Then, the current study was designed. Methods: One hundred and five patients under 40 years old were registered in the mulitiinstitutional study. The median age was 34.5 years old (range: 24–39 years old). According to FIGO, clinical stage was as follows. Stage Ib/IIa/IIb/IIIa/IIIb/IVa were 10/4/38/2/47/3, respectively. The median maximal tumor diameter was 5.5 cm (range: 2–9.2 cm). Curative intended radiation therapy was the combination of high-dose rate intracavitary brachytherapy (HDR-ICBT) combined with external beam radiation therapy (ERT). The total dose of ERT ranged from 44 Gy to 68 Gy. The total dose of HDR-ICBT to point A ranged from 12 Gy to 48 Gy. Eighty five patients received chemotherapy. Results: The 5-year overall survival rate and local control rate of all patients was 58.4 % and 59.3 %, respectively. The 5-year overall survival rates of stage Ib/IIa/IIb/IIIa/IIIb/IVa were 90.0 %/not available (NA)/73.8%/100%/37.4%/0%, respectively. The 5-year local control rates of Stage Ib/IIa/IIb/IIIa/IIIb/IVa were 80.0 %/50.0 %/73.8 %/100 %/54.6 %/NA, respectively. Sixteen patients experienced grade 3 or greater late radiation morbidity. Conclusions: Clinical outcomes of stage I-II in the young were equivalent to the Japanese standard treatment results of all ages. However, clinical outcomes of stage IIIb and IVa in the young were worse than those of all ages (5-year OS of all ages in Japan: IIIb: 50 %, IVa: 25 %). No significant financial relationships to disclose.

Sequential use of sorafenib and sunitinib in renal cancer: Retrospective analysis in 90 patients

5038 Background: Sorafenib (So) and sunitinib (Su) have been recently approved for the treatment of advanced renal cell carcinoma (RCC). Following this approval, sequential use of both drugs is often proposed, although very few data are available to support it. Material and Methods: We reviewed all patients (pts) who received sequentially So-Su or Su-So in the last 3 years from 4 sites in France. All pts had been enrolled in clinical studies or in the extended access programs. In all patients demography, prognostic factors (MSKCC score), number of metastatic sites, best response (BR) and PFS with each treatment were recorded. Some patients are still too early for response and PFS assessment under the second treatment. Results: 68 pts first received So while 22 pts received Su first (continuous dosing in 12, intermittent in 10). Results under the first treatments were as follows: median PFS 26.1 wks, mean duration of treatment 33.2 wks; and median PFS was 22 wks, mean duration of treatment 26.9 wks for So and Su respectively. BR in terms of partial response (PR), stable disease (SD), progressive disease (PD) is given in the table . 2 pts stopped So because of toxicity and response is not available (NA), and 22 pts (NE) are too early in the course of the second treatment. Overall, PR rate was 17.6% for So and 22.7% for Su. PR or SD was observed as best response in the second treatment in both sequences. Only 6 pts had PD with both drugs: all of them had 3 or more metastatic sites and were in intermediate or poor MSKCC risk groups. Conversely, 4 pts had PR with both drugs, and were in good (n=2) or intermediate (n=2) risk groups. 11 pts only have died so far. Conclusions: these results suggest the lack of cross resistance between So and Su, and support the sequential use of So and Su in RCC. Updated data will be presented at ASCO. [Table: see text] No significant financial relationships to disclose.

Erratum

Plant, Cell & EnvironmentVolume 29, Issue 6 p. 1191-1191 Free Access Erratum This article corrects the following: Brassinosteroids and plant function: some clues, more puzzles L. L. HAUBRICK, S. M. ASSMANN, Volume 29Issue 3Plant, Cell & Environment pages: 446-457 First Published online: March 14, 2006 First published: 12 May 2006 https://doi.org/10.1111/j.1365-3040.2006.01535.xAboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat The paper ‘Brassinosteroids and plant function: some clues, more puzzles’ by Haubrick & Assmann (2006), contains a number of errors. The following is the corrected text. Table 1: For the BES1/BZR2 and BZR1 genes, the cell locus should be listed as C→Nu, to indicate the movement of the gene product from the cytoplasm to the nucleus in response to application of brassinolide. Table 1 footnote should read: Cellular locations were identified by green fluorescent protein (GFP) gene fusions and confocal microscopy or by subcellular fractionation and immunoblot. Proteins that have not been specifically localized in these ways were labelled as NA (data not available). Abbreviations for cell loci: C, cytosol; ER, endoplasmic reticulum; Nu, nucleus; PM, plasma membrane; V, vacuole. Other abbreviations: ABA, abscisic acid; BL, brassinolide; BR, brassinosteroid; DEB, 1,2:3,4-diepoxybutane; EMS, ethyl methane sulphonate; T-DNA, transfer DNA. *In very young cells DET3: GFP was detected in the PM and ER. In mature cells fluorescence coincided with the vacuolar membrane, and possibly the cytosol. Figure 1 legend should read: Figure 1. Effect of brassinosteroids on Arabidopsis. (a) Exogenous application of brassinosteroid can partially rescue germination of gibberellin-deficient Arabidopsis seeds. (b) Many of the BR-related mutants exhibit a de-etiolated phenotype when grown in the dark. For wild-type seedlings, low concentrations (nM range) of brassinosteroids can stimulate hypocotyl elongation and primary root growth, while higher concentrations (µM range) of either brassinosteroids or ABA inhibit hypocotyl elongation and primary root growth. Roots of several BR response mutants of Arabidopsis (bin2, bri1, bin5) are hypersensitive to ABA and exhibit increased inhibition of primary root growth in response to exogenous application of ABA. Abbreviations: ABA, abscisic acid; BR, brassinosteroid; bin2 and bin5, brassinosteroid-insensitive 2 and 5; bri1, brassinosteroid-insensitive 1; cpd, constitutive photomorphogenesis and dwarfism; det2, de-etiolated 2. The following reference should be included: Khripach V., Zhabinskii V. & de Groot A. (2000) Twenty years of brassinosteroids: steroidal plant hormones warrant better crops for the XXI century. Annals of Botany86, 441–447. The publisher would like to apologize for these errors and for any confusion caused. REFERENCE Haubrick L.L. & Assmann S.M. (2006) Brassinosteroids and plant function: some clues, more puzzles. Plant, Cell & Environment 29, 446– 457. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Volume29, Issue6June 2006Pages 1191-1191 ReferencesRelatedInformation

Radiographic study of the prevalence of periodontal bone loss in Australian school‐aged children attending the Royal Dental Hospital of Melbourne

To investigate the prevalence of alveolar bone loss around the first permanent molars, and first and second deciduous molars in Australian school-aged children attending the Royal Dental Hospital of Melbourne. Nine hundred and ninety-five records were examined for useable bitewing radiographs. From these, radiographs of 542 Australian school children aged 5-12 years were used. The cervical-enamel junction (CEJ) to the alveolar bone crest (ABC) distance was measured using the transparent ruler on the magnifier. Each inter-dental site that was readable was scored as one for the following categories: not available (NA); no bone loss (NBL)- the CEJ-ABC was < or =2 mm; questionable bone loss (QBL): the distance from the CEJ-ABC was >2 and <3 mm; and definite bone loss (DBL): the distance from the CEJ to ABC was > or =3 mm. Seventy-one children (13.0%) were found to have 83 DBL sites, as determined by bone levels >3.0 mm from the CEJ. Seventy children had QBL lesions only, 50 children had DBL only and 21 children had both. The overall prevalence of bone loss was 26%. Second deciduous molars were found to be the most affected teeth with almost 75% lesions being distal. These teeth comprised 50% of the DBL lesions. Children of Asian-Far Eastern origin had a higher percentage of sites with bone loss compared with children of Caucasian origin, being 29.5% and 19.7%, respectively, but lower than that of children of Middle-Eastern origin (35.2%). When the data were analysed with relation to age, there was no relationship between age and prevalence of bone loss. In the population studied, there was an overall prevalence of periodontal bone loss of 26% and DBL of 13% in an Australian school-aged group. Calculus was detected infrequently and, where present, was associated with bone loss.

Preliminary Findings from the Prospective Multicenter Surveillance, Epidemiology and Risk Factors for Thrombotic Thrombocytopenic Purpura (SERF-TTP) Study.

Background: Due to the rarity of TTP (approximately 4 cases per million), epidemiologic data and correlative laboratory samples from a prospectively identified incident cohort of TTP patients are needed.Methods: SERF TTP is a NHLBI-funded 15-site study targeted to identify 300 incident TTP patients and 600 age-/gender-matched community controls.Results: From nine IRB-approved collaborating sites, 22 incident TTP cases and 17 controls have been interviewed. Data and plasma (acute and convalescent samples) are available for 19 TTP patients (Table 1). Their mean age is 42.5 years (range, 20 – 80 years), and 90% are female. Using the Rose-Eldor TTP Scoring system based on platelets, creatinine, hemoglobin, and neurologic function, 37% would be classified as severely ill (score > 4 of a maximum 8 points). Mean time from symptom onset to diagnosis was 9.2 days, median 5.5 days (range, 0 to 33 days). Severity of TTP was poorer for the 5 patients whose treatment did not begin for at least 16 days (16–33 days) versus the other 14 patients (mean Rose-Eldor score of 4.6 versus 4). Medications which had been prescribed to the patients prior to TTP onset included herbal supplements (n= 5) and hormone replacement therapy or oral contraceptives (n= 6). All patients received at least daily therapeutic plasma exchange (TPE). A platelet count >150,000 was reached at a mean of 9.4 days following TPE initiation. At 30-days follow-up, all patients were alive, although 3 had an exacerbation requiring daily TPE reinstitution. Fourteen patients (78%) experienced an adverse event, including allergic reactions to plasma (n=9), citrate-related toxicity (n=9) and venous access complications (n=2) including one with major hemorrhage requiring transfer to the intensive care unit.Conclusion: The clinical characteristics of the SERF-TTP cohort are similar to those reported from large single-site studies, although the survival rate (100% versus 71% and 83%) is higher. Only a minority of incident TTP cases in the modern era present with renal insufficiency or neurologic findings - highlighting the importance of developing reliable diagnostic laboratory testing.Clinical Characteristics at PresentationStudyPlatelets <100,000Hgb <10 or Hct <.3Cr > 2mg/dlFeverNeurologic symptomsMortalitySERF-TTP n=1995%79%32%11%47%0%Washington University (1) (excluding HSCT/FK506 cases) n= 2896%82%29%32%50%29%Oklahoma TTP-HUS Registry (2) (ADAMTS13 < 5%) n=18100%100%22%NA (Not Available)56%17%(1)Zheng XL, Kaufman RM et al. Blood. 2004; 103: 4043; (2)Vesely SK, George JN et al. Blood. 2003; 102: 60. HSCT: Hematopoetic stem cell transplantation, FK-506: Tacrolimus.

Intraperitoneal chemotherapy for ovarian carcinoma: results of long-term follow-up.

To determine long-term survival and predictors of recurrence in a retrospective cohort of patients with epithelial ovarian cancer treated with intraperitoneal (IP) chemotherapy. Records were reviewed of 433 patients who received IP therapy for ovarian cancer between 1984 and 1998; follow-up data were available for 411 patients. IP therapy was provided as consolidation therapy (n = 89), or for treatment of persistent (n = 310) or recurrent (n = 12) disease after surgery and initial systemic therapy; therapy usually consisted of platinum-based combination therapy. Statistical analysis included tests for associations between potential prognostic factors, and between prognostic factors and survival. Survival probabilities were estimated by Kaplan-Meier methods, and prognostic factors for survival were evaluated by a Cox proportional hazard model. The mean age of patients was 52 years (range, 25 to 76 years). Distribution by stage and grade was as follows: stage I, 7; II, 24; III, 342; IV, 52; not available (NA), 8; and grade 1, 30; 2, 99; and 3, 289; NA, 15. The median survival from initiation of IP therapy by residual disease was none, 8.7 years; microscopic, 4.8 years; less than 1 cm, 3.3 years; more than 1 cm, 1.2 years. In a multivariate analysis, the only significant predictors of long-term survival were grade and size of residual disease at initiation of IP therapy. Prolonged survival was observed in selected patients receiving IP platinum-based therapy. It is not possible to determine the contribution of IP therapy to survival in this study. A relationship between size of disease at the initiation of IP therapy and long-term survival was demonstrated.