Timing Of Therapy Research Articles

Cholesterol Lowering in Older Adults: Should We Wait for Further Evidence?

Current guidelines for primary and secondary prevention of cardiovascular events in adults up to age 75years are well-established. However, recommendations for lipid-lowering therapies (LLT), particularly for primary prevention, are inconclusive after age 75. In this review, we focus on adults ≥ 75years to assess low-density lipoprotein-cholesterol (LDL-C) as a marker for predicting atherosclerotic cardiovascular disease (ASCVD) risk, review risk assessment tools, highlight guidelines for LLT, and discuss benefits, risks, and deprescribing strategies. The relationship between LDL-C and all-cause mortality and cardiovascular outcomes in older adults is complex and confounded. Current ASCVD risk estimators heavily depend on age and lack geriatric-specific variables. Emerging tools may reclassify individuals based on biologic rather than chronologic age, with coronary artery calcium scores gaining popularity. After initiating LLT for primary or secondary prevention, target LDL-C levels for older adults are lacking, and non-statin therapy thresholds remain unknown, relying on evidence from younger populations. Shared decision-making is crucial, considering therapy's time to benefit, life expectancy, adverse events, and geriatric syndromes. Deprescribing is recommended in end-of-life care but remains unclear in fit or frail older adults. After an ASCVD event, LLT is appropriate for most older adults, and deprescribing can be considered for those approaching the last months of life. Ongoing trials will guide statin prescription and deprescribing among older adults free of ASCVD. In the interim, for adults ≥ 75years without a limited life expectancy who are free of ASCVD, an LLT approach that includes both lifestyle and medications, specifically statins, may be considered after shared decision-making.

A Combined Cyto- and Histopathological Diagnostic Approach Reduces Time to Diagnosis and Time to Therapy in First Manifestation of Metastatic Spinal Disease: A Cohort Study.

Malignant spinal lesions (MSLs) are frequently the first manifestation of malignant disease. Spinal care, diagnostic evaluation, and the initiation of systemic therapy are crucial for outcomes in patients (pts) with advanced cancer. However, histopathology (HP) may be time consuming. The additional evaluation of spinal lesions using cytopathology (CP) has the potential to reduce the time to diagnosis (TTD) and time to therapy (TTT). CP and HP specimens from spinal lesions were evaluated in parallel in 61 pts (CP/HP group). Furthermore, 139 pts in whom only HP was performed were analyzed (HP group). We analyzed the TTD of CP and HP within the CP/HP group. Furthermore, we compared the TTD and TTT between the groups. The mean TTD in CP was 1.7 ± 1.7 days (d) and 8.4 ± 3.6 d in HP (p < 0.001). In 13 pts in the CP/HP group (24.1%), specific therapy was initiated based on the CP findings in combination with imaging and biomarker results before completion of HP. The mean TTT in the CP/HP group was 21.0 ± 15.8 d and was significantly shorter compared to the HP group (28.6 ± 23.3 d) (p = 0.034). Concurrent CP for MSLs significantly reduces the TTD and TTT. As a result, incorporating concurrent CP for analyzing spinal lesions suspected of malignancy might have the potential to enhance pts' quality of life and prognosis in advanced cancer. Therefore, we recommend implementing CP as a standard procedure for the evaluation of MSLs.

Cytology-histology correlation, time to diagnosis and time to therapy when cytology is performed in addition to biopsies in malignant spinal lesions of previously unknown malignant disease.

e14007 Background: Metastatic spinal lesions are the first manifestation of malignant disease in up to 30% of patients (pts). Spinal care, diagnostic evaluation and initiation of systemic therapy are crucial for outcome in pts with advanced cancer. Histopathology (HP) from bone specimens is time consuming and decalcification procedure can hamper diagnostic information. The additional evaluation of spinal lesions by cytopathology (CP) has the potential to reduce time to diagnosis (TTD) and time to therapy (TTT). Therefore, we performed simultaneous analysis of CP and HP specimens from suspected malignant spinal lesions to evaluate the diagnostic value of additional CP. This work was supported by the German Society for Spine Surgery (DWG). Methods: We obtained CP specimens by transpedicular, intralesional aspiration through a Yamshidi needle or touch preparation from solid tissue samples. CP and HP specimens from spinal lesions were evaluated in parallel in 54 pts (CP/HP group). We analyzed sensitivity and specificity of CP in reference to HP. Furthermore, we compared the TTD and TTT of CP/HP group with a retrospective cohort of 103 patients in whom only HP was performed (HP group). Results: The collection of CP samples was feasible without elongation of surgery time or any complications for the pts. In 52/54 (96%) pts a CP-specimen was successfully obtained. Of the 52 pts analyzed, multiple myeloma was diagnosed in 10 pts, solid malignancy in 34, 1 pt had lymphoma and 7 did not show malignancy. The most common solid malignancies were prostate cancer (n=9), breast cancer (n=5) and adenocarcinoma of the lung (n=5). The sensitivity and specificity of CP in reference to HP is 98% and 71%, respectively. The concordance of CP and HP in differentiating between hematologic or solid neoplastic lesions is 94.2%. TTD in the CP/HP group was significantly shorter compared to HP group (1.7±1.8 and 8.6±3.6 d, respectively; p&lt;0.001). In addition, TTT in the CP/HP group was significantly shorter than in the HP group (19.3±14.4 d and 31.4±24.7 d; p=0.003). In 24.1% of pts a specific tumor therapy was initiated based on CP diagnosis before obtaining the results of HP. Conclusions: The evaluation of CP from malignant spinal lesions shows high sensitivity and concordance with HP and reduced TTD and TTT. Therefore, CP in addition to HP from spinal lesions of suspected malignancy has the potential to improve quality of life and prognosis in pts with advanced cancer. We therefore recommend the implementation of additional CP to HP in previously undiagnosed malignant spinal lesions.

The Hydropathy Index of the HCDR3 Region of the B-Cell Receptor Identifies Two Subgroups of IGHV-Mutated Chronic Lymphocytic Leukemia Patients With Distinct Outcome.

The HCDR3 sequences of the B-cell receptor (BCR) undergo constraints in length, amino acid use, and charge during maturation of B-cell precursors and after antigen encounter, leading to BCR and antibodies with high affinity to specific antigens. Chronic lymphocytic leukemia consists of an expansion of B-cells with a mixed immature and “antigen-experienced” phenotype, with either a mutated (M-CLL) or unmutated (U-CLL) tumor BCR, associated with distinct patient outcomes. Here, we investigated the hydropathy index of the BCR of 138 CLL patients and its association with the IGHV mutational status and patient outcome. Overall, two clearly distinct subgroups of M-CLL patients emerged, based on a neutral (mean hydropathy index of -0.1) vs. negatively charged BCR (mean hydropathy index of -1.1) with molecular features closer to those of B-cell precursors and peripheral/mature B-cells, respectively. Despite that M-CLL with neutral HCDR3 did not show traits associated with a mature B-cell repertoire, important differences in IGHV gene usage of tumor cells and patient outcome were observed in this subgroup of patients once compared to both U-CLL and M-CLL with negatively charged HCDR3 sequences. Compared to M-CLL with negatively charged HCDR3 sequences, M-CLL with neutral HCDR3 sequences showed predominance of men, more advanced stages of the disease, and a greater frequency of genetic alterations—e.g., del(17p)—together with a higher rate of disease progression and shorter time to therapy (TTT), independently of other prognostic factors. Our data suggest that the hydropathy index of the HCDR3 sequences of CLL cells allows the identification of a subgroup of M-CLL with intermediate prognostic features between U-CLL and the more favorable subgroup of M-CLL with a negatively charged BCR.

Brain Tumor Reporting and Data System: A Pictorial Review

Brain tumors are a diverse group of neoplasms that are a source of substantial morbidity and mortality worldwide. Primary gliomas constitute almost all malignant brain tumors, with the most aggressive as well as most common form in adults, grade IV glioma or glioblastoma multiforme, carrying an especially poor prognosis. Neuroimaging is critical not only in the identification of CNS tumor but also in treatment-planning and assessing the response to therapy. Structured reporting continues to gain traction in radiology by reducing report ambiguity and improving consistency, while keeping referring clinicians and patients informed. The Brain Tumor Reporting and Data System (BT-RADS) is a relatively new paradigm that attempts to simplify and maximize consistency in radiologic reporting. BT-RADS incorporates MR imaging features, clinical assessment, and timing of therapy to assign each study a score or category, which is, in turn, linked to a management suggestion. The purpose of this pictorial review article is to familiarize radiologists and nonradiology neurologic specialists alike with BT-RADS, highlighting both advantages and limitations, in the hope that adoption of this system might ultimately facilitate more effective communication and improve consistency among reports.Learning Objective: To describe the features and underscore the advantages and disadvantages of the Brain Tumor Reporting and Data System (BT-RADS), a relatively new classification system that attempts to simplify and maximize consistency in radiologic reporting

Message from the President: It is occupational therapy's time to shine

Yesterday, I attended a memorial service for a very dear friend of mine and the comments opened with ‘who would have thought 12 months ago we would be meeting here today for this event?’ Well who w...

Management of chronic hepatitis B in special populations

Hepatitis B infection is an internationalhealthcare problem, particularly in developing areas.The hepatitis B virus (HBV) is frequently transmittedvia body fluids such as blood, semen, and vaginalsecretions. The majority of adults infected with thevirus recover, however 5%-10% are not capable toclear the virus and become chronically infected. Theprincipal treatment goals for patients with hepatitisB infection are to prevent progression of the liverdisease to cirrhosis or hepatocellular carcinoma. Theeffective nucleos(t)ide analogs (NAs) against hepatitisB virus (HBV) has improved the outcome ofpatients with chronic hepatitis B (CHB). Specialpopulations infected with chronic HBV includethose with decompensated cirrhosis, organ transplantation,pregnancy, extrahepatic manifestations,immunosuppressive-chemotherapy, co-infections(HIV-HCV- HDV), renal failure, hepatitis B virusinfection in children/adolescents and dental practice.These populations vary in their natural history andrisk of liver-related complications, the indicationsfor anti-HBV treatment in addition to the recommendationsconcerning the HBV drugs used, timeof therapy and expected endpoints. The aim ofthis review is to summarize the information on therelevance and treatment of HBV infection in suchspecial populations.

Local specialty pharmacy and specialty clinic collaboration assists access to hepatitis C direct-acting antivirals

ObjectivesTo measure prescribed time to therapy (TtT) and sustained virologic response (SVR). Secondary objectives were to assess insurance appeals and copay assistance amount facilitated by a local specialty pharmacy (LSP). MethodsThis descriptive, retrospective study used a joint clinical and pharmacy database of patients who were prescribed direct-acting antivirals (DAAs) at a single-center liver specialty clinic and received LSP services from December 2013 to December 2015. ResultsAmong 388 patients prescribed DAAs, 364 (94%) patients, who were 18 years of age or older, initiated DAA therapy, and received LSP services, were included in the study. Of these, 211 (58.0%) had cirrhosis, 159 (43.7%) had previous treatment, and 57 (15.7%) had previous liver transplants. Most patients had commercial insurance (n = 249; 68.4%), and 295 (81.0%) required prior authorization. Insurance initially denied coverage to 70 patients (19.2%), for who the LSP drafted appeals for 60 (85.7%). Copay information was available for 154 LSP patients. Although 66 had initial copays of more than $20 per month, the LSP was able to assist most (98.1%; n = 151) with copay reductions to $20 or less. Full financial assistance was received for 20 patients without insurance or any DAA coverage. Among 171 patients with SVR and prescribed TtT information, mean TtT was 12 days (median 4 days), and most received medications within 10 days (n = 122; 71.3%). The overall intention-to-treat SVR rate was 86.8%; the per-protocol (PP) SVR rate was 93.8%. ConclusionCollaboration between providers and an LSP minimized delay in therapy, lowered rates of DAA denial, facilitated patient financial assistance, and helped to optimize clinical outcomes. The PP-SVR rate for this study was similar to rates reported in the literature and higher than expected, considering the inclusion of earlier-generation DAAs and many patients with advanced liver disease.

Quality of life in patients treated with lipoprotein apheresis

Elevated levels of low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] are known risk factors for atherosclerosis and cardiovascular events. Although lipoprotein apheresis (LA) yields optimal outcomes for patients suffering from progressive cardiovascular disease (CVD; coronary, peripheral, and cerebrovascular arterial disease) in the presence of hyperlipoproteinemia (LDL-C > 100 mg/dL or Lp(a) > 60 mg/dL), LA primarily serves as a "last-resort therapy". Extant findings show that the incidence of new cardiovascular events can be reduced by regular LA. However, it remains unclear whether improvements to the quality of life (QOL) improvement produced by the positive impact on the course of cardiovascular disease outweighs the therapy's time consuming and invasive character. We surveyed 36 patients (32 men and 4 women; age 53 ± 13 years [mean + standard deviation]) undergoing regular LA therapy to assess the effects of apheresis on QOL. QOL was evaluated in 29 patients on regular lipoprotein apheresis treatment using the Medical Outcomes Study 36-item Short Form Health Survey (SF-36), the Beck Depression Inventory (BDI), and a newly developed questionnaire for assessing QOL in patients undergoing LA. Patients treated with LA showed lower QOL scores regarding mental aspects and equal scores regarding physical aspects compared to the general population, analogue to the results of patients on hemodialysis (SF-36). Analysis of BDI scores showed apheresis patients did not meet criteria for depression diagnosis, although their depression scores were higher than the general population. Compared to the pre-apheresis period, patients described an improvement of their physical and mental fitness, less angina pectoris and no treatment related pain were reported (apheresis questionnaire). Apheresis treatment appears to reduce the subjective physical complaints of patients. The partly impaired mental health in patients undergoing apheresis may be attributed to the underlying severe cardiovascular disease. The procedure itself is generally tolerated without major complaints, suggesting the benefits of apheresis exceed any negative effects on patient QOL.

Identifying a Gene Expression (GEP)-Based Model Predicting for Progression from AMM to Cmm Requiring Therapy in S0120 Patients Treated at Mirt

Background: The definition of high risk smoldering multiple myeloma (HR-SMM) is in flux. There are several models using serologic, bone marrow and radiologic data that predict for time to progression (TTP) to clinical myeloma (CMM). Lenalidomide and Dexamethasone in HR-SMM is reported to delay onset of end organ damage and improve overall survival, stressing the clinical utility of early intervention. We previously reported a GEP70 based score cutoff (<-0.26), when applied to the S0120 population, that improved the predictive power (R2) of standard clinical variables by 11%. The combination of GEP70 score >-0.26, serum M spike ≥3g/dL, and involved SFLC >25 mg/dL identified a subset of patients with 67% risk of progression at 2 years. With longer follow up, we now examine whether unique gene probe sets can be identified at the AMM stage that portend an earlier time to therapy (TTT).Patients and Methods: We identified 105 patients with AMM who had baseline GEP data on our S0120 protocol, after IRB approval for retrospective data review, and evaluated each of 54,675 Affymetrix gene probes for their potential to predict TTT. Probes were ranked by their q-values; we found 40 probes with q-value < 0.05 and 7 probes with q-value < 0.01; the top probe had a q-value of 0.00066. Scores based on the number of significant probes at these cut-points were computed by subtracting the sum of the expressions of the up-regulated probes from the sum of the expressions of the down-regulated probes, then dividing by the total number of probes.Results: In the GEP40 model, an optimal cut-point for risk of progression was identified at 7.05. The 3-year TTT probability was 83% with scores >=7.05 and only 11% for patients with values under this threshold (Figure 1A; p<0.0001). TTT probabilities also differed markedly when examined by score quartiles, attesting to a gene dose effect (Figure 1B). For the Q1 subset of 26 patients, only 4% required therapy in 3 years. Univariate Cox analysis for TTT yielded age>65 (HR: 2.3), Albumin<3.5g/dl (HR: 3.7), M-protein>3g/dl (HR: 4.99), BM plasmacytosis>=10% (HR: 12.2), GEP70>-0.26 (HR: 3.4), GEP40>=7.05 (HR: 16.41), GEP proliferation index > -0.26 (HR: 2.8), GEP PR subgroup (HR: 9.4) and GEP PolyPC >11.6 (HR: 0.22) to be significant. In the multivariate model, GEP40>=7.05 was the most significant (HR: 13.7), followed by SFLC>10mg/dl and M-protein>3g/dl. GEP40 score positively correlated with proliferation index (R: 0.804), and showed no correlation with GEP polyPC score (R: -0.156). Next, we used recursive partitioning on data from 72 patients and identified 23 patients with GEP40 score >=7.05 of whom 22 suffered TTT by 3 years (87%). Among the remaining 49 patients with GEP40 <7.0325, a further cut-point of age >59 years identified 24 patients, of whom 11 suffered progression with a 3 year TTT estimate of 25%. In the 25 patients with GEP40 <7.0325 and age <59 years, no patient progressed to CMM, with a 3 year TTT estimate of 0%. The GEP7 and GEP1 models, at optimal cut-offs, yielded equivalent positive and negative predictive values compared to the GEP40 model, albeit with less power.Conclusion:Gene expression profiling can readily identify a subset of AMM patients who are high risk for progression to CMM. Further refinement of GEP based risk scoring can be achieved by combining clinical and correlative variables to select the super HR-SMM for intervention trials. [Display omitted] [Display omitted] DisclosuresZangari:Norvartis: Membership on an entity’s Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. Van Rhee:Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Millennium: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Dhodapkar:Celgene: Research Funding. Morgan:Celgene Corp: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees; Myeloma UK: Membership on an entity’s Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity’s Board of Directors or advisory committees; The Binding Site: Membership on an entity’s Board of Directors or advisory committees; MMRF: Membership on an entity’s Board of Directors or advisory committees.

A Prognostic Index for Patients with Refractory or in First Relapsed Acute Myeloid Leukemia Treated with FLAG-Ida or Flago-Ida

INTRODUCTION AND AIMSAlmost seventy percent of Acute Myeloid Leukemia (AML) patients will relapse. Fludarabine, Ara-C, Idarrubicine, G-CSF (FLAG-Ida) and FLAG-Ida and Gentuzumab-Ozogamicin (FLAGO-Ida) is frequently used before allogenic stem cell transplant (ASCT). There are several studies analyzing the risk factors for survival in relapsed/refractory patients, but none of them were performed exclusively in patients treated with FLAG-Ida. We analyzed the results of in the Spanish trials conducted by PETHEMA. We also present a predictive score system of survival prognosis based on the data of the patients enrolledMETHODSThis is a retrospective, multicentre study of the PETHEMA AML epidemiologic Registry. In PETHEMA protocols 98,99,2007,2010 and 2011, FLAG-Ida was included as salvage treatment in patients relapsed or resistant after a 2ndinduction based in 3+7. In PETHEMA trial 2007, FLAG-Ida (or FLAGO-Ida) was administered if complete remission (CR) was not attained in the first induction cycle. The use of FLGO in PETHEMA 2007 trial depended on the availability of GO for each centre.We use overall survival (OS) as final end point of the analysis. Univariate survival analysis was performed by Long-Rank test. Stepwise backward variable selection and Cox proportional hazard multivariable analysis was performed (covariables selected if p<0.01). Bootstrap analysis was performed to contrast the model. We stratified time to therapy (TTT) in three stratus: refractory, relapsed in more than 1 year or less than 1 year. Refined Medical Research Council (MRC) cytogenetic risk stratification was used (patients with relapsed t(8;21) had the same OS as adverse group).RESULTSWe analyzed 259 patients consecutively registered between 1999 and 2012. The median age was 52 (16-76) and the median follow-up of the patients still alive was 23 months. Only 38 (14%) patients received FLAGO-Ida as salvage treatment. Favorable karyotype (inv 16) and t(8;21) was present in 13 (6%) and 11 (5%) respectively; intermediate in 145 (62%) and adverse in 62 (21%). Previous ASCT was performed in 86 patients (33%). The number of patients who achieved CR or CR without recovery of peripheral counts (CRi) was 132 (52%), PR in 23 (9%). Resistance accounted for 75 (29%) and death for 24 (9%). For the purposes of the current study, we decided to include patients with t(8;21) in the group of adverse karyotype group due to the similar median OS compared with MRC adverse karyotype (Median OS,0,42 vs 0,45 years). In univariate analysis karytotype (p=0.0001), FLT3-ITD positive (p=0.005), previous transplant (comparing no transplant, autologous and allogenic, p=0.012) and time to relapse (comparing refractory vs <12 months vs >12 months; p=0.0002) were significant risk factors. Contrary to other studies previous ASCT was associated to better outcome (median OS=2.3years, p=0.012). In multivariate analyses, the following variables remained as independent risk factors for survival: TTT (p=0.003), cytogenetic risk (p<0.00001), FLT3 (p=0.001), previous SCT (p=0.003). A simplified scoring system for survival in patients receiving FLAG-Ida or FLAGO-Ida was raised using the significant variables: cytogenetics (favorable: 0 points, intermediate 2 points, adverse 4 points), previous SCT (ASCT: 0, no SCT: 1, auto: 2), TTT (relapse>12 months: 0, refractory: 2, relapsed<12 months: 4,) and FLT3-ITD (wild type=0, mutated=2 points,). We stratified into three groups: Low-risk (0-4 points, 27% of patients, median OS 10.3 years), Intermediate-risk (5-8 points, 30% of patients, median OS 1.3 years), and high-risk (>8 points, 44.6% of patients, median OS 0.4 years). CONCLUSIONSThis retrospective study based on an Epidemiologic Registry, shows that in primary refractory and first relapsed AML patients, the use FLAG-Ida or FLAGO-Ida salvage regimens lead to 52% of second CR. In addition, we have developed a scoring system using FLT3-ITD, refined cytogenetics, previous ASCT and TTT that can predict survival, identifying before administering FLAG-IDA a good prognosis population representing 27% of patients in which FLAG-IDA (followed by ASCT) can be an optimal therapy. This prognostic index should be validated in an independent cohort. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Timing of Neuraxial Pain Interventions Following Blood Patch for Post Dural Puncture Headache

Post dural puncture headache (PDPH) is a common complication of interventional neuraxial procedures. Larger needle gauge, younger patients, low body mass index, women (especially pregnant women), and “traumatic” needle types are all associated with a higher incidence of PDPH. Currently, an epidural blood patch is the gold-standard treatment for this complication. However, despite the high PDPH cure rate through the use of this therapy, little is known about the physiology behind the success of the epidural blood patch, specifically, the time course of patch formation within the epidural space or how long it takes for the blood patch volume to be resorbed by the body. Of the many unanswered and debated topics related to PDPH and epidural blood patches, one additional specific question that may alter clinical management is when it is safe for patients who have experienced a disruption of the thecal space and have undergone this procedure to have a subsequent epidural or spinal procedure, such as a neuraxial anesthetic (i.e. a spinal anesthetic for an elective outpatient procedure) or an interventional pain procedure for chronic pain management. This question becomes more unclear if the new procedure includes a steroid medication. As an example, an older patient presents with a history of lumbar disc disease and during lumbar epidural steroid injection, an inadvertent wet tap occurs leading to PDPH. Following management with fluids, caffeine, medications, and a successful epidural blood patch, it remains unclear as to when would be the best time frame to consider a second lumbar epidural steroid injection. We identified the 3 main risk factors of subsequent interventional neuraxial procedures as (1) disruption of the epidural blood patch and ongoing reparative processes, (2) epidural procedure failure, and (3) infection. We looked at the literature, and summarized the existing literature in order to enable health care professionals to understand the time course of dural repair as well as the risks of subsequent neuraxial procedures after epidural blood patches. This review poses the question using an evidence based review to discuss the appropriate time course to proceed. Key words: Post dural puncture headache, epidural steroid injection, wet tap, timing of therapy

CD38 Variation in Chronic Lymphocytic Leukemia

Abstract 4576 Background:Chronic lymphocytic leukemia (CLL) has a highly variable clinical course. Some patients require treatment early while others can be monitored without therapy. CD38 expression has been shown in multiple cohorts to have prognostic significance. An elevated percentage of CD38 positive CLL lymphocytes at the time of diagnosis is correlated with a more rapid need for therapy and a shorter overall survival. The extent to which CD38 varies during the course of CLL, including after therapy, has only been evaluated in a limited fashion. Methods:From a cohort of over 500 CLL patients at the Duke University and Durham VA Medical Centers, we selected 136 patients in whom we had measured CD38 expression by flow cytometry on two or more occasions. We determined the first, maximum, minimum, and range (maximum – minimum) CD38 values. We compared these values to other molecular prognostic markers using Wilcoxon tests and assessed the prognostic significance of these values using Cox proportional hazard models and Kaplan-Meier analyses. Results:Of the 136 patients, 70% were male and 88% Caucasian, with a median age of 60. The majority had low clinical stage at diagnosis—either Rai stage 0 (68%) or 1 (19%). Molecular prognostic markers were also generally favorable. Eighty-two (67%) patients had mutated IGHV status, 69 (51%) were ZAP70 negative, and 76 (63%) had either 13q deletion or normal cytogenetics, determined by fluorescent in situ hybridization. CD38 expression was measured a median of 5.5 times (2 – 19). The median time between the first and last CD38 measurements was 1206 days (81 – 4109). The median values were 6% (0.6 – 99) for maximum CD38, 1.5% (0 to 84.5) for minimum CD38, and 4.9% (0.2 to 95.3) for CD38 range. Maximum, minimum, and CD38 range were significantly lower in patients with mutated compared to unmutated IGHV status (p < 0.005 for all parameters, Wilcoxon rank sum test). Elevated maximum and CD38 range were significantly associated with a more rapid time to therapy (TTT) and shorter overall survival (OS) in a univariate Cox proportional hazards model (p < 0.03 for all, Wald test). In a multivariate Cox proportional hazards model including first CD38 and maximum CD38 values, only maximum CD38 remained statistically significant. We found that patients with high CD38 variation (CD38 range greater than the median) had significantly shorter TTT and OS than patients with low CD38 variation (p = 0.002 for both, log rank test). Using receiver operator characteristic analyses, we determined that the best cut-off for dichotomizing the first CD38 according to TTT and OS in the entire Duke/Durham VA CLL cohort was 11%. Using this cut-off, 15 patients (11%) converted from CD38 negative to CD38 positive. Using the standard 30% cut-off, 14 patients (10%) converted from CD38 negative to CD38 positive. Patients with a first CD38 measurement less than 11% and subsequent measurements above 11% had a favorable OS, similar to patients with low CD38 for all measurements (p = 0.002, log rank test). However, patients with a first CD38 measurement less than 30% who had subsequent measurements above 30% had an inferior OS, similar to patients with high CD38 for all measurements (p = 0.006, log rank test). Lastly, among 24 patients with CD38 measurements before and after first therapy, the percentage of CD38 positive cells increased in 19 patients (79%), with a median value of 3.2% before to 6.9% after therapy (p = 0.005, Wilcoxon signed rank test). Conclusions:CD38 values vary as patients transition across the disease trajectory. This variation appears to have prognostic significance, with high variation associated with faster time to first therapy and shorter overall survival. Additionally, in our cohort, a patient's maximum CD38 value had more prognostic significance than a single initial measurement. Thus, longitudinally measuring CD38 throughout the clinical course of CLL could aid in the management of CLL patients, refining the initial prognostic assessment, and improving patient counseling and decision making. Disclosures:No relevant conflicts of interest to declare.

Modern and conventional prognostic markers of chronic lymphocytic leukaemia in the everyday haematological practice

The impact of modern prognostic markers on clinical course of chronic lymphocytic leukaemia (CLL) in everyday practice has been not yet well defined, especially in large series of patients. Therefore, the goal of this study was to assess the influence of conventional as well as modern prognostic factors on overall survival (OS) and time to therapy (TTT) of patients with CLL. We retrospectively analysed data of all patients consecutively entered into the databases of five large academic centres in the Czech Republic. The total of 1300 patients was included in the analysis. Through the use of uniparametric analysis, it was determined that gender, clinical stage Rai II-IV, unmutated IgVH status, deletion 17p (for both 5% and 20% cut-off), deletion 11q, ZAP-70 positivity and high expression of CD38 had significant negative influence on OS. TTT was significantly influenced by gender, Rai stage, IgVH status, deletion 11q, deletion 17p, deletion 13q and CD38 expression. Multiparametric analysis revealed that OS was significantly influenced by gender, age, IgVH status and deletion 17p. If only patients who died of CLL were included, gender, age, Rai stage, IgVH status and deletion 17p had significant influence on OS. Based on our results, the examination of biological prognostic markers can give an insight into the possible disease evolution in daily clinical practice. Biological prognostic markers are, however, not ready (maybe except deletion 17p in younger patients) to be used for guidance of therapy at least outside of clinical trials.

Investigation on family members' pre-operative anxiety and nursing demands before eye-ground examination under general anesthesia in sick-children

Objective To investigate family members' anxiety status and nursing demands and analyze the related factors.Methods Anxiety level and nursing demands of 82 family members were investigated by nurses with self-designed Strate-Trait Anxiety Inventory and the questionnaires one day before eye-ground examination for children with retinoblastoma.Results State anxiety and trait anxiety scores of family members were higher than those of general population model (Male:t=7.826,P<0.01; Female:t=15.278,P<0.01). The state anxiety was related to family member gender, temporal separation from RB children during the operation and worrying about this time's therapy outcome (P<0.05); while the trait anxiety was mainly related to chemotherapy history, temporal separation from RB children during the operation and history of eye-ground examination under general anesthesia (P<0.05). Nursing demands included RB children terror alleviation (72.0%), good nursing skills (70.7%), gentle temper (64.6%) and disease knowledge popularization (48.8%), etc.Conclusions Family members' anxiety level was related to multiple factors, and appropriate nursing measures should be provided according to their characteristics so as to alleviating family members' anxiety level and to ensure favorable cooperation of RB children. Key words: Retinoblastoma; Eye-ground examination under general anesthesia; Family members; Anxiety; Nursing demands

Frequency and Prognostic Impact of CD8 Expression In 5,523 Patients with Chronic Lymphocytic Leukemia (CLL) In Relation to Chromosomal Aberrations, IGHV Mutational Status and ZAP-70 Expression.

AbstractAbstract 4616Chronic lymphocytic leukemia (CLL) is an indolent lymphoma with largely heterogeneous clinical course. Identifying patients which benefit from early therapy is one of the most important issues in the management of CLL. Besides patient-specific characteristics and applicability of different treatment approaches the decision on therapy is based on conventional prognostic parameters as well as on chromosomal aberrations, IgVH mutational status and expression of ZAP-70, which all have been shown to be independently associated with outcome. The expression of CD8 has been rarely observed in CLL and its prognostic impact is unclear yet. In order to clarify the frequency of CD8 expression, its correlation to established prognostic parameters as well as its prognostic impact we analyzed a total of 5,523 patients with CLL by multiparameter flow cytometry including the expression of CD8 between August 2005 and August 2010. Fluorescence in situ hybridization (FISH) applying a standard set of probes for the detection of del(6q), del(11q22.3) (ATM), trisomy 12, del(13q14) (D13S25, D13S319), and del(17p13) (TP53) was performed in 3,407 patients. IGHV mutational status was determined and evaluable in 2,845 patients. Clinical follow-up data was available in 1,021 patients (median follow-up: 21.3 months). 61 patients (1.1%) showed an expression of CD8 (antibody clone B9.11, Immunotech, France) as compared to isotype used as negative control. CD8+ vs. CD8- cases did not differ in age (mean±SD: 70.3±9.7 vs. 68.3±10.4 years, n.s.) and the male/female ratio was 1.11 vs. 1.61 (n.s.). There were no significant differences in WBC count (mean±SD, 31.7±33.9 vs. 36.1±53.1 × 10e9/l) and hemoglobin level (Hb, mean±SD, 13.6±2.0 vs. 13.2±2.1 g/dl), while platelet counts were higher in CD8+ vs. CD8- cases (229±72 vs. 194±99 × 10e9/l, p=0.021). In CD8+ vs. CD8- cases chromosomal aberrations were detected by FISH analysis with the following frequencies: del(6q), 5.9% vs. 3.1%, n.s.; del(11q22.3), 17.1% vs. 10.7% (n.s.); trisomy 12, 20.0% vs. 14.5% (n.s.); del(13q14), 66.7% vs. 59.8% (n.s.); del(13q14) as sole chromosomal aberration, 41.2% vs. 45.5% (n.s.); del(17q13), 2.9% vs. 5.7% (n.s.). The IGHV status was mutated in 79.3% vs. 60.4% (p=0.054) in CD8+ vs. CD8- cases. Patients with CD8 expression had a significantly shorter time to therapy (TTT) as compared to CD8- patients (median TTT, 12.0 vs. 77.1 months, p=0.008). The following parameters showed a significant relation to a shorter TTT in univariate Cox analyses: CD8 positivity, p=0.011, relative risk (RR)=2.87; higher WBC count, p=0.008, RR=1.01 per 10 × 10e9 increase; del(11q22.3), p<0.001, RR=1.97; del(17p13), p=0.005, RR=1.72; higher % of CLL cells with ZAP-70 expression (antibody clone SBZAP, Immunotech, France), p=0.011, RR=1.04 per 10% increase. Parameters significantly related to a longer TTT in univariate Cox analyses were: higher Hb level, p<0.001, RR=0.86 per 1 g/dl; higher platelet count, p=0.021, RR=0.98 per 10 × 10e9 increase; and del(13q14) as sole chromosomal aberration, p<0.001, RR=0.58. Multivariate analysis identified two parameters to be independently related to a shorter TTT: higher ZAP-70 expression (p=0.002) and CD8 positivity (p=0.036), while a higher Hb level (p<0.001) and del(13q14) as sole chromosomal aberration (p=0.011) were identified to be independently related to a longer TTT. This data supports the further evaluation of the prognostic impact of CD8 expression in CLL in order to define its role in identifying the most appropriate timepoint for therapy and the most appropriate treatment modality for patients with CLL. Disclosures:Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Cytogenetic Aberrations In Splenic Marginal Zone Lymphoma (SMZL): A Study On 134 Cases

AbstractAbstract 1996Splenic marginal zone lymphoma (SMZL) belongs to the most frequently occurring mature B-cell neoplasms besides chronic lymphocytic leukemia, lymphoplasmacytic lymphoma (LPL), mantle cell lymphoma, follicular lymphoma, and hairy cell leukemia. Data on cytogenetic abnormalities in SMZL is limited although these may facilitate the differentiation between SMZL and other mature B-cell neoplasms with similar immunophenotypic features like LPL. Thus, cytogenetic analysis may be a valuable tool in diagnosing these cases and may in addition give prognostic information. We therefore analyzed bone marrow samples from 134 patients with SMZL as identified by their typical immunophenotype in parallel by multiparameter flow cytometry (MFC) and chromosome banding analysis (CBA). In addition, fluorescence in situ hybridization (FISH) analysis was performed in 92/134 patients applying a standard panel of probes targeting del(6q), del(11q22.3) (ATM), trisomy 12, del(13q14) (D13S25, D13S319), del(17p13) (TP53), and t(11;14) while del(7q) was analyzed in ten cases only. The patients′ ages ranged from 41.3 to 89.4 years (median, 71.0 years), the male/female ratio was 1.35:1.00. In 73 patients (54.5%) an aberrant karyotype was identified by CBA. Specifically, these aberrations were classified into the following categories: complex karyotype (defined as at least three structural or numeric aberrations), 10.4%; del(7q), 4.5%; t(11;14), 3.7%; other deletions, 6.7%; trisomies, 6.0%, other translocations, 4.5%; and other aberrations, 18.5%. FISH analysis identified the following chromosomal aberrations: del(6q), 4/74 (5.4%); del(11q22.3), 7/90 (7.8%); trisomy 12, 10/78 (12.8%); del(13q14), 12/92 (13.0%); del(17p13), 11/89 (12.4%); and del(7q), 5/10 (50.0%). Cases with aberrant karyotypes as identified by CBA did not differ in age from other cases (69.0±11.3 vs. 69.5±9.2, n.s.), however, they had a non-significantly higher percentage of lymphoma cells as identified by MFC (23.3±22.9% vs. 16.6±20.4%, p=0.089). Interestingly, cases in which FISH analysis identified a trisomy 12 had a lower percentage of lymphoma cells as identified by MFC as compared to those without trisomy 12 (11.2±11.7% vs. 26.9±24.3%, p=0.003). There were no significant differences in the percentage of lymphoma cells as identified by MFC for the other chromosomal aberrations detected by FISH analysis. The presence of del(6q) was associated with a significantly shorter time to therapy (TTT) as compared to cases without del(6q) (median 1 month vs. not reached/59% at 3 years, p=0.034). A similar trend was observed for del(11q) (median 1 month vs. not reached/62% at 3 years, p=0.061). Within the five cases with del(7q) no events have been observed so far for TTT. Regarding chromosomal aberrations detected by CBA the presence of either complex aberrations, t(11;14), or aberrations other than deletions and translocations was associated with a shorter TTT as compared to cases with remaining chromosomal aberrations or normal karyotype (median 1.0 months vs. not reached/71% at 3 years, p=0.015). This data suggests that chromosomal aberrations can be detected in bone marrow samples infiltrated by SMZL in about half of the cases independently of the degree of infiltration. Specific aberrations may confer prognostic information and thus yield clinically important information. Disclosures:Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Monoclonal B-Cell Lymphocytosis (MBL) Is Closely Related to Chronic Lymphocytic Leukemia (CLL) and May Be Better Classified as Early-Stage CLL.

Abstract 2349Poster Board II-326Monoclonal B-cell lymphocytosis (MBL) is separated from chronic lymphocytic leukemia (CLL) mainly by the somewhat arbitrary cut-off of 5000/μl CLL-phenotype cells in peripheral blood. While MBL in general shows an indolent clinical course this is also true for early-stage CLL. This may call into question the adequateness of separating MBL from CLL. Therefore, we prospectively analyzed a series of 298 cases with MBL by immunophenotyping, fluorescence in situ hybridization (FISH; probes for detection of del(6q21), del(11q22.3) (ATM), +12, del(13q14) (D13S25, D13S319), del(17p13) (TP53), and t(11;14)(q13;q32) (IGH-CCND1)), chromosome banding analysis (CBA) and molecular genetics (analysis of IgVH mutation status) for parameters which are established as prognostically relevant in CLL. Data was compared to a previously published series of 356 cases with CLL (Cytometry B Clin Cytom 2009;Epub.). Male:female ratio was similar for MBL and CLL (2.1:1 vs. 1.8:1, n.s.) as was mean±SD age (66.5±10.5 vs. 65.7±10.2 years, n.s.). Mean±SD cells with CLL phenotype in peripheral blood amounted to 2,417±1,497/μl in MBL and to 27,771±39,607/μl in CLL (p<0.001). ZAP-70 expression (mean±SD MFI ratio T-cells:B-cells 4.3±3.0 vs. 5.1±3.3, p=0.011) and CD38 expression (mean±SD % positive cells 33.5±28.9 vs. 26.5±31.5, p=0.004) were stronger in MBL. FISH analysis revealed similar frequencies of del(11q22.3) (8.1% vs. 11.7%, n.s.). In contrast, +12 (22.8% vs. 13.7%, p=0.003) and t(11;14) (2.1% vs. 0.0%, p=0.008) were observed more frequently in MBL while del(6q21) (1.8% vs. 6.1%, p=0.008), del(13q14) (45.1% vs. 64.3%, p<0.001), del(13q14) as sole abnormality (35.0% vs. 47.7%, p=0.002), and del(17q13) (1.4% vs. 8.0%, p<0.001) were more frequent in CLL. CBA demonstrated a normal karyotype (31.5% vs. 21.6%, p=0.004) and trisomies (10.7% vs. 6.2%, p=0.045) more often in MBL while deletions were observed less often (30.5% vs. 39.3%, p=0.021). Analysis of IgVH revealed a mutated status more frequently in MBL (76.3% vs. 60.6%, p<0.001). Thus, while some good risk parameters have been encountered more frequently in MBL compared to CLL there was no clear predominance of all good risk parameters but rather a mixed distribution between MBL and CLL. We next analyzed the prognostic impact of the above parameters in cases with MBL. Time to therapy (TTT) was negatively affected by a higher CD38 expression (p=0.007), del(11q22.3) (p=0.01), the presence of independent clones as identified by CBA, and an unmutated IgVH status (p=0.001). Multivariate analysis revealed a higher CD38 expression (p=0.026) as the only independent parameter affecting TTT. Overall survival (OS) was negatively affect by del(6q21) (p=0.001) and by the presence of independent clones as identified by CBA (p=0.056) while a normal karyotype by CBA was associated with a better OS (p=0.031). When analyzing both MBL and CLL cohorts together, +12 (p=0.011) was found to be related to shorter TTT and del(13q14) as sole abnormality (p=0.038) and a higher ZAP-70 ratio T-cells:B-cells (p=0.007) were related to longer TTT. Neither the amount of cells with CLL phenotype in peripheral blood nor the presence of MBL were significantly related to TTT. The only parameters independently related to TTT were del(11q22.3) (p=0.007) and +12 (p=0.037). Parameters negatively affecting OS were MBL (p=0.006), the presence of independent clones as identified by CBA (p=0.038) and a female gender (p=0.047). Multivariate analysis demonstrated MBL (p=0.021) and the presence of independent clones as identified by CBA (p=0.046) as independently related to OS. The present data indicates that biologic characteristics of CLL are found in MBL and that there is no general predominance of good risk parameters in MBL as compared to CLL. Thus, MBL may not be considered a distinct disease but rather an early stage of CLL. This is further supported by the lack of impact of MBL as compared to CLL on the TTT. Furthermore, it is suggested that cases classified as MBL should undergo assessment of prognostic parameters including CBA as one prognostic parameter as shown for CLL cases. Disclosures:Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Dicker:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.