Retrospective Analysis Of Pooled Data Research Articles

Impact of robotic total mesorectal excision upon pathology metrics in overweight males with low rectal cancer: a pooled analysis of 836 cases.

The aim of this pooled analysis was to evaluate the impact of robotic total mesorectal excision (TME) on pathology metrics in Male Overweight patients with Low rectal cancer (MOL). This was a multicenter retrospective pooled analysis of data. Two groups were defined: MOL (Male, Overweight, Low rectal cancer) and non-MOL. Overweight was defined as BMI ≥ 25kg/m2. Low rectal cancer was defined as cancer within 6cm from the anal verge. The primary endpoints of this study were histopathological metrics, namely circumferential resection margin (CRM) (mm), CRM involvement rate (%), and the quality of TME. Circumferential resection margin (CRM) was involved if < 1mm. 836 (106 MOL and 730 non-MOL) patients that underwent robotic TME by six surgeons over 3years were compared. No significant differences in demographics and perioperative variables were found, except for operating time, distal margin, and number of lymph nodes harvested. CRM involvement rate did not significantly differ (7.5% vs. 5.5%, p = 0.395). Mean CRM was statistically significantly narrower in MOL patients (6.6 vs. 7.7mm, p = 0.04). Quality of TME did not differ. Distance of tumor from the anal verge was the only independent predictor of CRM involvement. Robotic TME may provide optimal pathology metrics in overweight males with low rectal cancer. Although CRM was a few millimeters narrower in MOL, the values were within the range of uninvolved margins making the difference statistically significant, but not clinically. Being MOL was not a risk factor for involvement of circumferential resection margin.

Concentrated urine, low urine flow, and postoperative elevation of plasma creatinine: A retrospective analysis of pooled data.

Elevations of plasma creatinine are common after major surgery, but their pathophysiology is poorly understood. To identify possible contributing mechanisms, we pooled data from eight prospective studies performed in four different countries to study circumstances during which elevation of plasma creatinine occurs. We included 642 patients undergoing mixed major surgeries, mostly open gastrointestinal. Plasma and urinary creatinine and a composite index for renal fluid conservation (Fluid Retention Index, FRI) were measured just before surgery and on the first postoperative morning. Urine flow was measured during the surgery. The results show that patients with a postoperative increase in plasma creatinine by >25% had a high urinary creatinine concentration (11.0±5.9 vs. 8.3±5.6 mmol/L; P< 0001) and higher FRI value (3.2±1.0 vs. 2.9±1.1; P< 0.04) already before surgery was initiated. Progressive increase of plasma creatinine was associated with a gradually lower urine flow and larger blood loss during the surgery (Kruskal-Wallis test, P< 0.001). The patients with an elevation > 25% also showed higher creatinine and a higher FRI value on the first postoperative morning (P< 0.001). Elevations to > 50% of baseline were associated with slightly lower mean arterial pressure (73 ± 10 vs. 80 ± 12 mmHg; P< 0.005). We conclude that elevation of plasma creatinine in the perioperative period was associated with low urine flow and greater blood loss during surgery and with concentrated urine both before and after the surgery. Renal water conservation-related mechanisms seem to contribute to the development of increased plasma creatinine after surgery.

Ribociclib (RIB) vs. palbociclib (PAL) in patients (pts) with hormone receptor-positive/HER2-negative/HER2-enriched (HR+/HER2-/HER2-E) advanced breast cancer (ABC): A head-to-head phase III study—HARMONIA SOLTI-2101/AFT-58.

TPS1125 Background: RIB and PAL are CDK4/6 inhibitors with demonstrated efficacy in terms of progression-free survival (PFS) and similar tolerability in pts with HR+/HER2- ABC when combined with endocrine therapy (ET). Only RIB has demonstrated a consistent, statistically significant, and clinically meaningful overall survival (OS) benefit across the MONALEESA (ML) phase III trials, while PALOMA trials failed to achieve similar outcome. Given effective treatments (Tx) may change underlying tumor biology (TB), it is hypothesized that RIB changes TB, enabling a better response to subsequent therapy and thus improving OS. RNA-based intrinsic subtyping reflects differences in TB and has strong prognostic and predictive value in HR+/HER2- ABC. Non-Luminal subtypes, as HER2-E and basal-like (BL), are relatively endocrine-resistant and have poorer prognosis than luminal. Tumors can switch subtypes over time to a more aggressive and less endocrine-responsive biology, which may also be reversed by effective Tx. A retrospective analysis of pooled data from ML 2/3/7 trials showed that HER2-E tumors had surprising benefit from RIB, while BL tumors did not. Pre/clinical data and indirect comparisons suggest that RIB may outperform PAL in HER2-E. Thus, choosing pts with HER2-E tumors as a means of a well defined TB with relative endocrine resistance provides the right setup for HARMONIA study to explore likely differential re-sensitization to endocrine therapy with RIB vs. PAL and ultimately testing which CDK4/6i prepares best for continued response and OS benefit. In addition, HARMONIA explores the value of earlier Tx with chemotherapy (paclitaxel) + anti PD-1 (tislelizumab) in pts with BL tumors to leverage learnings from treating ET-insensitive triple-negative BC. Methods: This is an international, multicenter, randomized, open-label, phase III study, using prospective pre-selection based on TB in pts with HR+/HER2- ABC, with HER2-E tumors (main cohort) and with BL tumors (exploratory cohort). HER2-E cohort will randomized pts 1:1 to RIB+ET (letrozole or fulvestrant) or PAL+ET. As per recent protocol amendment, BL cohort pts will be treated with paclitaxel plus tislelizumab, an anti PD-1 monoclonal antibody, pts may be offered to try RIB + ET first, and will remain eligible for paclitaxel + tislelizumab upon progression. Primary endpoint (EP): PFS per RECIST v1.1. Secondary EP: OS, PFS2, clinical benefit rate, duration and time to response, quality of life, and exploratory EP, including subtype switching between primary and metastatic tumor, and after trial Tx. Interim and primary EP analysis will be performed after 224 and 310 PFS events are observed (~80% power using one-sided 5% α). HARMONIA will recruit in Spain (55 sites), Portugal (5), and US (35) within SOLTI &amp; AFT network. Clinical trial information: NCT05207709 .

Metabolic and physiological responses to graded exercise testing in individuals with type 1 diabetes using insulin pump therapy.

To profile acute glycaemic dynamics during graded exercise testing (GXT) and explore the influence of glycaemic indicators on the physiological responses to GXT in adults with type 1 diabetes using insulin pump therapy. This was a retrospective analysis of pooled data from four clinical trials with identical GXT protocols. Data were obtained from 45 adults with type 1 diabetes using insulin pumps [(30 females); haemoglobin A1c 59.5 ± 0.5 mmol/mol (7.6 ± 1.0%); age 49.7 ± 13.0 years; diabetes duration 31.2 ± 13.5 years; V̇O2peak 29.5 ± 8.0ml/min/kg]. Integrated cardiopulmonary variables were collected continuously via spiroergometry. Plasma glucose was obtained every 3 min during GXT as well as the point of volitional exhaustion. Data were assessed via general linear modelling techniques with age and gender adjustment. Significance was accepted at p ≤ .05. Despite increasing duration and intensity, plasma glucose concentrations remained similar to rest values (8.8 ± 2.3 mmol/L) throughout exercise (p= .419) with an overall change of +0.3± 1.1 mmol/L. Starting glycaemia bore no influence on subsequent GXT responses. Per 1% increment in haemoglobin A1c there was an associated decrease in V̇O2peak of 3.8ml/min/kg (p< .001) and powerpeak of 0.33 W/kg (p< .001) concomitant with attenuations in indices of peripheral oxygen extraction [(O2 pulse) -1.2ml/beat, p= .023]. In adults with long-standing type 1 diabetes using insulin pump therapy, circulating glucose remains stable during a graded incremental cycle test to volitional exhaustion. Glycaemic indicators are inversely associated with aerobic rate, oxygen economy and mechanical output across the exercise intensity spectrum. An appreciation of these nexuses may help guide appropriate decision making for optimal exercise management strategies.

The effects of intimate partner violence on women's risk of HIV acquisition and engagement in the HIV treatment and care cascade: a pooled analysis of nationally representative surveys in sub-Saharan Africa

Achieving the 95-95-95 targets for HIV diagnosis, treatment, and viral load suppression to end the HIV epidemic hinges on eliminating structural inequalities, including intimate partner violence (IPV). Sub-Saharan Africa has among the highest prevalence of IPV and HIV worldwide. We aimed to examine the effects of IPV on recent HIV infection and women's engagement in the HIV care cascade in sub-Saharan Africa. We did a retrospective pooled analysis of data from nationally representative, cross-sectional surveys with information on physical or sexual IPV (or both) and HIV testing, from Jan 1, 2000, to Dec 31, 2020. Relevant surveys were identified from data catalogues and previous large-scale reviews, and included the Demographic and Health Survey, the AIDS Indicator Survey, the Population-based HIV Impact Assessment, and the South Africa National HIV Prevalence, Incidence, Behavior and Communication Survey. Individual-level data on all female respondents who were ever-partnered (currently or formerly married or cohabiting) and aged 15 years or older were included. We used Poisson regression to estimate crude and adjusted prevalence ratios (PRs) for the association between past-year experience of physical or sexual IPV (or both), as the primary exposure, and recent HIV infection (measured with recency assays), as the primary outcome. We also assessed associations of past-year IPV with self-reported HIV testing (also in the past year), and antiretroviral therapy (ART) uptake and viral load suppression at the time of surveying. Models were adjusted for participant age, age at sexual debut (HIV recency analysis), urban or rural residency, partnership status, education, and survey-level fixed effects. 57 surveys with data on self-reported HIV testing and past-year physical or sexual IPV were available from 30 countries, encompassing 280 259 ever-partnered women aged 15-64 years. 59 456 (21·2%) women had experienced physical or sexual IPV in the past year. Six surveys had information on recent HIV infection and seven had data on ART uptake and viral load suppression. The crude PR for recent HIV infection among women who had experienced past-year physical or sexual IPV, versus those who had not, was 3·51 (95% CI 1·64-7·51; n=19 179). The adjusted PR was 3·22 (1·51-6·85). Past-year physical or sexual IPV had minimal effect on self-reported HIV testing in the past year in crude analysis (PR 0·97 [0·96-0·98]; n=274 506) and adjusted analysis (adjusted PR 0·99 [0·98-1·01]). Results were inconclusive for the association of ART uptake with past-year IPV among women living with HIV (crude PR 0·90 [0·85-0·96], adjusted PR 0·96 [0·90-1·02]; n=5629). Women living with HIV who had experienced physical or sexual IPV in the past year were less likely to achieve viral load suppression than those who had not experienced past-year IPV (crude PR 0·85 [0·79-0·91], adjusted PR 0·91 [0·84-0·98], n=5627). Past-year physical or sexual IPV was associated with recent HIV acquisition and less frequent viral load suppression. Preventing IPV is inherently imperative but eliminating IPV could contribute to ending the HIV epidemic. Canadian Institutes of Health Research, the Canada Research Chairs Program, and Fonds de recherche du Québec-Santé. For the French, Spanish and Portuguese translations of the abstract see Supplementary Materials section.

Dementia is Associated With Poorer Quality of Care and Outcomes After Stroke: An Observational Study.

To determine whether preexisting dementia is associated with poorer quality of care and outcomes after stroke in the acute hospital phase. This was a retrospective analysis of pooled data from the Australian Stroke Foundation national audit conducted in 2015 and 2017. Dementia status was obtained from the medical records. Processes of care to assess quality included: stroke unit care, time-dependent therapy, nursing/allied health assessments, and preparation for discharge. Outcomes included in-hospital complications, independence on discharge, and destination. Logistic regression was used to examine associations between dementia status and processes of care. Multilevel random effects logistic regression, with level defined as hospital, was used to examine associations between dementia status and outcomes. There were 683/7,070 (9.7%) audited patients with dementia included. Patients with dementia were less likely to be treated in stroke units (58.3% vs 70.6%), receive thrombolysis if an ischemic stroke (5.8% vs 11.1%), have access within 48 hours to physiotherapy (56.4% vs 69.7%) or occupational therapy (46.8% vs 55.6%), see a dietitian if problems with nutrition (64.4% vs 75.9%), or have mood assessed (2.6% vs 12.3%). Patients with dementia were more likely to receive no rehabilitation (adjusted odds ratio 1.88, 95% confidence interval 1.25, 2.83) and be discharged to residential care (adjusted odds ratio 2.36, 95% confidence interval 1.50, 3.72). People with dementia received poorer quality of care and had worse outcomes after stroke. Our findings raise questions regarding equity and the need for better understanding of why the quality of care differs after stroke for people with dementia.

In vivo validation of resting full-cycle ratio and diastolic pressure ratio: simultaneous measurement with instantaneous wave-free ratio.

The diastolic pressure ratio (dPR) and resting full-cycle ratio (RFR) are considered to be almost identical to the instantaneous wave-free ratio (iFR) in the retrospective analysis of pooled data. The aim of this study was to investigate the direct comparison of iFR and these new resting indexes in real world practice. Two pressure wires were inserted and placed in the distal part of the same coronary artery. The measurement of the iFR and the other resting indexes was performed simultaneously. A total of 54 lesions from 23 patients were subject to physiological study. In 49 lesions, iFR and other resting indexes were also measured in hyperemic conditions. The general correlation between iFR and other resting indexes was excellent in both resting and hyperemic conditions (r2 = 0.99; mean difference - 0.001 ± 0.021; p < 0.001; and r2 = 0.99; mean difference - 0.012 ± 0.025; p < 0.001, respectively). This correlation was maintained in various subgroup analyses. A diagnostic change between iFR and other resting indexes occurred in three cases (3%) when a fixed cut-off point (≤ 0.89) was applied. There was no diagnostic change when a hybrid zone (0.86 ≤ iFR ≤ 0.93) was considered. The new resting indexes and iFR showed very high correlation in real world practice. A diagnostic change only occurred in three cases (3%) when a fixed cut-off point (≤ 0.89) was applied.

Evaluation of Cxbladder and Adjudication of Atypical Cytology and Equivocal Cystoscopy

BackgroundCxbladder diagnostic tests combine genomic information from urinary mRNA with phenotypic information to either rule out low-risk individuals or identify patients at a high risk of urothelial carcinoma (UC). ObjectiveTo evaluate the performance of Cxbladder and urine cytology, and Cxbladder's adjudication of atypical cytology and equivocal cystoscopy. Design, setting, and participantsThis is a retrospective analysis of pooled data from three prospective Cxbladder clinical trials and one real-world clinical study. Physicians were blinded to Cxbladder results, and Cxbladder providers were blinded to clinical results. This study analyzed diverse urology practices in the USA, Australia, and New Zealand. A total of 1784 consecutive, prospectively recruited patients with hematuria or previously diagnosed UC provided 852 samples with both local cytology and Cxbladder results; 153 had atypical cytologies and 14 had both atypical cytology and equivocal cystoscopy. Outcome measurements and statistical analysisNegative predictive value (NPV) and proportion of tumors missed for Cxbladder and local cytology, and evaluation of Cxbladder for adjudicating atypical cytology and equivocal cystoscopy. Results and limitationsCxbladder ruled out 35% of patients and NPV 97% (95% confidence interval [CI] 94–98%) compared with 93% (95% CI 91–94%) for cytology; Cxbladder missed 8.5% and cytology missed 63% of tumors. UC was diagnosed in 26/153 cases of atypical cytology (17%). Cxbladder correctly adjudicated all these patients including those with both atypical cytology and equivocal cystoscopy; these patients had a positive Cxbladder result and were diagnosed with UC by pathology. The incidence of patients with both atypical cytology and equivocal cystoscopy is low. ConclusionsCxbladder correctly adjudicated all patients diagnosed with UC among those with atypical cytology and equivocal cystoscopy, and outperformed cytology for accurately identifying patients who do not have UC. Patient summaryCxbladder accurately rules out patients who do not have cancer, and adjudicates cytology and cystoscopy with inconclusive results, minimizing the need for patients to undergo further unnecessary tests and procedures.

Incidence rates of inflammatory bowel disease in patients with psoriasis, psoriatic arthritis and ankylosing spondylitis treated with secukinumab: a retrospective analysis of pooled data from 21 clinical trials

ObjectivesHere, we present the reported incidence rates of inflammatory bowel disease (IBD) in patients receiving treatment with secukinumab for psoriasis (PsO), psoriatic arthritis (PsA) or ankylosing spondylitis (AS), in a...

Association Between Magnetic Resonance Imaging–Proton Density Fat Fraction and Liver Histology Features in Patients With Nonalcoholic Fatty Liver Disease or Nonalcoholic Steatohepatitis

Patients with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) often require histologic assessment via liver biopsy. Magnetic resonance imaging (MRI)-based methods for measuring liver triglycerides based on proton density fat fraction (PDFF) are increasingly used as a noninvasive tool to identify patients with hepatic steatosis and to assess for change in liver fat over time. We aimed to determine whether MRI-PDFF accurately reflects a variety of liver histology features in patients with NAFLD or NASH. We performed a retrospective analysis of pooled data from 3 phase 2a trials of pharmacotherapies for NAFLD or NASH. We collected baseline clinical, laboratory, and histopathology data on all subjects who had undergone MRI analysis in 1 of the trials. We assessed the relationship between liver PDFF values and liver histologic findings using correlation and area under the receiver operating characteristic (AUROC) analyses. As an ancillary analysis, we also simulated a clinical trial selection process and calculated subject exclusion rates and differences in population characteristics caused by PDFF inclusion thresholds of 6% to 15%. In 370 subjects, the mean baseline PDFF was 17.4% ± 8.6%. Baseline PDFF values correlated with several histopathology parameters, including steatosis grade (r= 0.78; P < .001), NAFLD activity score (NAS, r= 0.54; P < .001), and fibrosis stage (r= -0.59; P<.001). However, PDFF did not accurately identify patients with NAS ≥ 4 (AUROC= 0.72) or fibrosis stage ≥3 (AUROC= 0.66). In a theoretical trial of these subjects, exclusion ratesincreased as PDFF minimum threshold level increased. There were no significant differences in cohort demographics when PDFF thresholds ranging from 6% to 15% were used, and differences in laboratory and histopathology data were small. In an analysis of patients with NAFLD or NASH, we determined that although The MRI-PDFF correlated with steatosis grade and NAS, and inversely with fibrosis stage, it was suboptimal in identification of patients with NAS >4 or advanced fibrosis. Although MRI-PDFF is an important imaging biomarker for continued evaluation of this patient population, liver biopsy analysis is still necessary.

Diurnal and racial variance of white blood cell parameters in early phase clinical trials: a retrospective analysis of pooled data from multiple phase I trials

Diurnal and racial variance of white blood cell parameters in early phase clinical trials: a retrospective analysis of pooled data from multiple phase I trials

Cerebro- and Cardio-vascular Responses to Energy Drink in Young Adults: Is there a Gender Effect?

Background and Purpose: Energy drinks (EDs) are suspected to induce potential adverse cardiovascular effects and have recently been shown to reduce cerebral blood flow velocity (CBFV) in young, healthy subjects. Gender differences in CBFV in response to EDs have not previously been investigated, despite the fact that women are more prone to cardiovascular disturbances such as neurocardiogenic syncope than men. Therefore, the aim of this study was to explore gender differences in cerebrovascular and cardiovascular responses to EDs.Methods: We included 45 subjects in a retrospective analysis of pooled data from two previous randomized trials carried out in our laboratory with similar protocols. Beat-to-beat blood pressure, impedance cardiography, transcranial Doppler, and end-tidal carbon dioxide (etCO2) measurements were made for at least 20 min baseline and for 80 min following the ingestion of 355 mL of a sugar-sweetened ED. Gender and time differences in cerebrovascular and cardiovascular parameters were investigated.Results: CBFV was significantly reduced in response to ED, with the greatest reduction observed in women compared with men (−12.3 ± 0.8 vs. −9.7 ± 0.8%, P < 0.05). Analysis of variance indicated significant time (P < 0.01) and gender × time (P < 0.01) effects. The percentage change in CBFV in response to ED was independent of body weight and etCO2. No significant gender difference in major cardiovascular parameters in response to ED was observed.Conclusions: ED ingestion reduced CBFV over time, with a greater reduction observed in women compared with men. Our results have potential implications for women ED consumers, as well as high-risk individuals.

Safety of Lenalidomide (LEN) 10mg in Non-Del(5q) Versus Del(5q) in the Treatment of Patients (Pts) with Lower-Risk Myelodysplastic Syndromes (MDS): Pooled Analysis of Treatment-Emergent Adverse Events (TEAEs)

▪Introduction: Anemia represents the main therapeutic challenge in pts with lower-risk MDS (Fenaux P, Adès L. Blood. 2013;121:4280-6). Prospective studies evaluating LEN for the treatment of red blood cell transfusion-dependent pts showed significant clinical activity in both non-del(5q) and del(5q) International Prognostic Scoring System-defined lower-risk MDS (Raza A, et al. Blood. 2008;111:86-93; Santini V, et al. Blood. 2014;124:abstract 409; List A, et al. N Engl J Med. 2006;355:1456-65; Fenaux P, et al. Blood. 2011;118:3765-76). Hematologic adverse events (AEs) are common, but manageable, with LEN treatment (Giagounidis A, et al. Ann Hematol. 2008;87:345-52). However, there has been no direct comparison of safety profiles in non-del(5q) and del(5q) pts. This pooled analysis compared the incidence of AEs in LEN-treated lower-risk MDS pts with or without del(5q).Methods: This retrospective analysis of pooled data from 7 prospective clinical trials compared the incidence of AEs in LEN-treated lower-risk MDS pts with or without del(5q). The non-del(5q) group included 416 pts from 4 studies: MDS-005 (n = 160), MDS-002 (n = 215), MDS-001 (n = 24), and PK-002 (n = 17). The del(5q) group included 243 pts from 5 studies: MDS-003 (n = 148), MDS-004 (n = 69), MDS-007 (n = 11), MDS-001 (n = 8), and PK-002 (n = 7). A TEAE was defined as an AE that began or worsened in severity on or after the first dose of LEN through to 28 days after the last dose of LEN. Pts received the recommended starting dose of 10 mg LEN for ≥ 1 cycle; in study MDS-005, pts with impaired creatinine clearance (CrCl; ≥ 40 to < 60 mL/min) had a LEN 5 mg starting dose in order to achieve a similar area under the curve as pts with normal CrCl who were receiving LEN 10 mg.Results: Among the LEN-treated lower-risk MDS pts with or without del(5q) in this pooled analysis, the most commonly reported TEAEs (any grade) occurring in ≥ 5% of pts were hematologic: neutropenia [49.3% vs 73.7% for non-del(5q) vs del(5q), respectively], thrombocytopenia (37.3% vs 64.2%), and anemia (16.8% vs 20.2%). Overall, 84.6% of non-del(5q) pts and 96.3% of del(5q) pts experienced grade 3-4 hematologic TEAEs, including neutropenia [45.2% vs 72.0% for non-del(5q) and del(5q), respectively], thrombocytopenia (31.3% vs 52.7%), and anemia (11.8% vs 12.8%) (Table). Non-hematologic TEAEs were similar for both non-del(5q) and del(5q) pts, except deep-vein thrombosis (1.2% vs 4.9%, respectively) and hypertension (0.2% vs 3.7%). Acute myeloid leukemia was reported as a TEAE in 3 non-del(5q) and 9 del(5q) pts. Bleeding events (any grade) occurring concurrently with grade 3-4 thrombocytopenia were observed in 20.7% of non-del(5q) and 24.4% of del(5q) pts. Infection (any grade) occurring concurrently with grade 3-4 neutropenia was observed in 33.6% of non-del(5q) and 54.0% of del(5q) pts. Analysis of grade 3-4 hematologic TEAEs for pts receiving long-term (> 12 months) LEN treatment by time of onset (0 to 6, > 6 to 12, and > 12 to 18 months) showed that onset rates of grade 3-4 neutropenia during the first 6 months were higher versus rates at > 6 to 12 months for non-del(5q) (42.9% vs 19.5%, respectively) and del(5q) pts (65.4% vs 21.3%). Rates decreased similarly for thrombocytopenia in non-del(5q) (13.0% vs 5.2%) and del(5q) pts (40.4% vs 6.6%). At > 12 to 18 months, onset rates of neutropenia and thrombocytopenia for non-del(5q) pts were 15.6% and 9.1%, respectively; rates for del(5q) pts during this period were 23.5% and 4.4%.Grade 3-4 TEAEs resulted in discontinuation of LEN in 27.4% of non-del(5q) and 20.6% of del(5q) pts (Table); however, the criteria for discontinuation differed between studies.Conclusions: In this analysis of pooled data from 7 studies, the safety profiles of LEN-treated lower-risk MDS pts were similar between non-del(5q) and del(5q) pts. Neutropenia and thrombocytopenia were the most common TEAEs in both groups; however, the frequency of these TEAEs was lower in non-del(5q) pts. Among non-del(5q) and del(5q) pts receiving long-term treatment with LEN, onset rates of thrombocytopenia and neutropenia were lower at > 6 to 12 months versus the first 6 months of treatment. In summary, TEAEs in lower-risk MDS pts with or without del(5q) treated with LEN 10 mg for ≥ 1 cycle are predictable, well characterized, and clinically manageable. [Display omitted] DisclosuresAlmeida:Shire: Speakers Bureau; Bristol Meyer Squibb: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy. Off Label Use: Lenalidomide used to treat MDS patients without del(5q). Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Giagounidis:Celgene Corporation: Honoraria. Hellström-Lindberg:Celgene Corporation: Research Funding. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Skikne:Celgene Corporation: Employment, Equity Ownership. Hoenekopp:Celgene International: Employment, Equity Ownership. Séguy:Celgene International: Employment. Zhong:Celgene Corporation: Employment, Equity Ownership. Fenaux:CELGENE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding.

First-line gefitinib for elderly patients with advanced NSCLC harboring EGFR mutations. A combined analysis of North-East Japan Study Group studies

Objective: To assess outcomes of elderly patients with advanced NSCLC harboring an EGFR mutation treated with gefitinib, as well as safety and impact on quality of life (QoL).Methods: We performed a retrospective analysis of pooled data from one Phase III and two Phase II studies of 71 patients aged ≥ 70 years with a performance status of 0 – 2. The main outcome measures were progression-free survival (PFS), overall survival (OS) and response rate (RR), as well as incidence of adverse events and time to 9.1% deterioration in QoL.Results: Median PFS (14.3 vs 5.7 months, p < 0.001) and overall RR (73.2 vs 26.5%, p < 0.001) in the gefitinib group were superior to those in the standard chemotherapy group, whereas median OS was not significantly different (30.8 vs 26.4 months, p = 0.42). Elevation of aspartate transaminase and/or alanine transaminase (18.3%) was the most common adverse event, and one treatment-related death (pneumonitis) occurred. Time to 9.1% deterioration in the QoL domains of pain and dyspnea, anxiety, and daily functioning was similar between the two age groups.Conclusion: First-line gefitinib is efficacious with acceptable toxicity in relatively fit elderly patients with advanced NSCLC harboring an EGFR mutation.

Abstract T MP81: Combination Therapy of Intravenous Glycoprotein IIb-IIIa Inhibitors and Low Dose Tissue Plasminogen Activator for Acute Ischemic Stroke

Introduction: Glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibitors block platelet aggregation following fibrinolysis. No phase III randomized clinical trial has assessed efficacy of combination therapy [Gp IIb/IIIa + IV tissue plasminogen activator (tPA)] to standard of care in acute ischemic stroke. Aim: To conduct a retrospective pooled analysis of data from published prospective studies and randomized phase 1 and 2 trials, to assess efficacy and safety profile of IV combination therapy (Gp IIb/IIIa inhibitors and tPA) in management of acute ischemic stroke. Methods: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed and EMBASE databases, and 3 reviewers independently selected studies reporting safety endpoints and outcome measures in acute ischemic stroke patients treated with low dose tPA + eptifibatide. Demographic/ clinical variables: sex, age, NIH stroke scale (NIHSS) at presentation and Time-to-treatment, Safety endpoint: symptomatic intracranial hemorrhage (sICH), as well as outcome measures: Death at 90 days and modified Rankin score (mRS) 0-1 were consolidated into the two groups. tPA arm of the NINDS tPA trial was included in the tPA only group. Weighted means and proportions were calculated for numeric and categorical variables respectively. Bivariate analysis to compare baseline descriptors, safety endpoints and outcome measures consisted of Fisher’s exact test. Results: 188 patients comprised the combination therapy arm, whereas the IV tPA arm had 218 patients. Mean NIHSS in the two groups were 12.8 and 14.6 respectively. Mean time-to-treatment was 2.3 hours in combination therapy arm and 2.55 hours in the tPA arm. Treatment with combination therapy was associated with a better functional outcome (mRS 0-1) (OR 1.79, 95% CI 1.15 - 2.80, p &lt;0.01) at 90 days. There was also a significant reduction in the rate of sICH (OR 0.26, 95% CI 0.07 - 0.83) in the combination therapy group. Death at 90 days was not significantly different in the 2 groups (OR 1.26, 95% CI 0.73 - 2.18). Conclusion: Combination of low dose IV tPA with Gp IIb/IIIa inhibitor is associated with a better functional outcome at 90 days, as well as a reduction in sICH rates in patients with acute ischemic stroke, as compared to 0.9g/kg IV tPA.

Combination therapy of intravenous glycoprotein IIB/IIIA inhibitors and tissue plasminogen activator for acute ischemic stroke.

Retrospective pooled analysis of data from published prospective studies and randomized phase 1 and 2 trials was done to assess efficacy and safety profile of intravenous combination therapy [glycoprotein IIb/IIIa inhibitors and IV tissue plasminogen activator (tPA)] in management of acute ischemic stroke. We searched Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, and EMBASE databases; two reviewers independently selected studies reporting safety endpoints and outcome measures in acute ischemic stroke patients treated with combination therapy. tPA arm of the National Institute of Neurological Disorders and Stroke (NINDS) tPA trial was included in tPA-only group. Weighted means and proportions were calculated for numeric and categorical variables respectively. Bivariate analysis using Fisher's exact test was done to compare baseline descriptors, safety endpoints, and outcome measures. Combination therapy arm included 188 patients and IV tPA arm had 218 patients. Mean National Institutes of Health Stroke Scale (NIHSS) in two groups were 12.8 and 14.6, respectively. Mean time-to-treatment was 2.3 hours in combination therapy arm and 2.55 hours in tPA arm. Treatment with combination therapy was associated with significant reduction in rate of symptomatic intracranial hemorrhage (sICH) [odds ratio (OR) 0.26, 95% cumulative incidence (CI) 0.07 0.83, P value 0.01). Difference in better functional outcome at 90 days (OR 0.87, 95% CI 0.59-1.30, P value 0.54) and death at 90 days (OR 1.16, 95% CI 0.69-1.93, P value 0.60) were not significantly different in two groups. Combination of low dose IV TPA with glycoprotein IIb/IIIa inhibitors is associated with reduction in sICH rates in patients with acute ischemic stroke as compared to standard dose of IV tPA.

2145 ANTERIOR TRANSVAGINAL MESH- HOW “SERIOUS” ARE THE COMPLICATIONS AND ARE THEY REVERSIBLE?

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Pelvic Prolapse1 Apr 20122145 ANTERIOR TRANSVAGINAL MESH- HOW “SERIOUS” ARE THE COMPLICATIONS AND ARE THEY REVERSIBLE? Dominic Lee, Benjamin Dillon, Gary Lemack, Alexander Gomelsky, and Philippe Zimmern Dominic LeeDominic Lee Dallas, TX More articles by this author , Benjamin DillonBenjamin Dillon Dallas, TX More articles by this author , Gary LemackGary Lemack Dallas, TX More articles by this author , Alexander GomelskyAlexander Gomelsky Shreveport, LA More articles by this author , and Philippe ZimmernPhilippe Zimmern Dallas, TX More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.2316AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Following two FDA warnings on the use of trans-vaginal mesh in women with pelvic organ prolapse, we reviewed our series of patients referred with anterior mesh related complications. METHODS Following IRB approval, a retrospective analysis of pooled data from 2 tertiary institutions managing complications of anterior transvaginal mesh (ATM) from 2006 to March 2011 was conducted. Data recorded included mesh type, symptoms leading to surgical removal, and clinical outcome. Minimal follow-up was 6 months. RESULTS Fifty-eight women underwent anterior vaginal wall mesh removal. Mean age was 54.6 years (range: 32-80) and duration of follow-up 13.3 months (range: 6-67.3). Time from original surgery to mesh excision was 20.9 months (range: 2.2-59.8). Overall, 44 patients had removal of ATM mesh only, while 31 of 44 had mid urethral sling (MUS) takedown as well. Fourteen patients had ATM removal combined with apical and/or posterior mesh removal and of these, 9 also had MUS takedown. ProliftTM was the predominant mesh kit material (28), followed by PerigeeTM (14), AvaultaTM (10) and various others (8). Nineteen of 58 patients (32.7%) had prior mesh removal attempts. Vaginal mesh extrusion (75%), dyspareunia (73%) and pelvic pain (41%) were the commonest presenting complaint, in addition to one case of vesico-vaginal fistula. Three cases required an abdominal approach. Seventy-four surgeries were required for maximal anterior mesh excision. Thirteen additional procedures were required for recurrent cystocele (4) and secondary stress urinary incontinence (9). Forty-two of 58 were women remained sexually active (73%) postoperatively and reported improvement in dyspareunia with 18 having no pain (42.8%), 12 mild pain (28.6%) and 3 moderate pain (7.1%). Chronic pelvic pain was improved in most patients with 7 women reporting no pain (30.4%), 9 mild pain (39.1%) and 5 moderate pain (21.7%). Two patients had mesh erosion recurrence, and 1 intra-operative ureteric injury was successfully repaired primarily on mesh removal. CONCLUSIONS : In this combined series, ATM removal provided symptom relief in over 75% of women. Residual issues of dyspareunia, chronic pelvic pain, prolapse recurrence, and recurrent mesh extrusion remain in a substantial minority. Some ATM complications are life-altering and intervention “may or may not correct the complication” [FDA October 2008]. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e866 Peer Review Report Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Dominic Lee Dallas, TX More articles by this author Benjamin Dillon Dallas, TX More articles by this author Gary Lemack Dallas, TX More articles by this author Alexander Gomelsky Shreveport, LA More articles by this author Philippe Zimmern Dallas, TX More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Targeting the tumor vascular supply with vascular disrupting agents.

Historically the role of tumor histology in the selection of treatment for lung cancer was limited to differentiation between small cell lung cancer and non-small cell lung cancer (NSCLC). More recently, the importance of tumor histology in the selection of appropriate treatment for patients with advanced stage NSCLC has been elucidated. In a randomized phase II trial of carboplatin and paclitaxel alone or with lowor high-dose bevacizumab, an increased risk of grade 3 pulmonary haemorrhage was seen in patients with squamous histology (1). As a result, these findings led to the exclusion of patients with squamous histology from phase III trials of bevacizumab in advanced stage NSCLC (2, 3). In addition to its role in reducing a specific adverse event, histological subtypes are also associated with efficacy with recent data indicating pemetrexed combined with cisplatin being more effective in patients with nonsquamous than squamous cell histology (4). Poorer survival has been reported in squamous cell histology in both treatment arms of a phase III study of chemotherapy with or without sorafenib (5) and also in patients receiving chemotherapy combined with motesanib (6). Tumor vascular supply is a major target in anti-cancer treatment and intense research efforts has resulted in a range of agents approved for clinical use. Vascular targeting strategies can be classified into several approaches including an antiangiogenic approach by targeting vascular endothelial growth factor (VEGF) and its receptors through monoclonal antibodies (bevacizumab) and tyrosine kinase inhibitors (vandetanib, sorafenib). This approach inhibits endothelial proliferation and migration, targeting new blood vessel formation of smaller, solid tumors with a major effect on the periphery of the tumor. A second method is the vascular disrupting approach. Vascular disrupting agents (VDAs) act primarily on endothelial cells and pericytes of established tumor vasculature, resulting in blood vessel occlusion, tumor ischemia and necrosis with a major effect on the central part of the tumor (7, 8). The VDAs currently in clinical development include vadimezan (ASA404), plinabulin (NPI-2358) and combretastatin A4 phosphate (CA4P). ASA404 (5,6-dimethylxanthenone-4-acetic acid or DMXAA) is a small-molecule, flavonoid tumor-vascular disrupting agent. The major mode of action of ASA404 antitumor activity is to induce the synthesis of tumor necrosis factor (TNF)-alpha. In addition, ASA404 can induce vascular endothelial cell apoptosis in tumors independently of TNF-alpha induction (9). In this issue of the Journal of Thoracic Disease, McKeage and Jameson report on a retrospective analysis of pooled data from phase II studies of ASA404 to compare safety and efficacy between squamous and non-squamous NSCLC patients (10). Data from untreated patients with advanced stage NSCLC who were randomized to receive up to carboplatin (C) and paclitaxel (P) alone or

Comparative outcomes of squamous and non-squamous non-small cell lung cancer (NSCLC) patients in phase II studies of ASA404 (DMXAA) - retrospective analysis of pooled data.

ASA404 (5,6-dimethylxanthenone-4-acetic acid) is a small-molecule, flavonoid tumor-vascular disrupting agent. Pooled data from phase II studies were analyzed retrospectively to compare safety and efficacy between squamous and non-squamous non-small cell lung cancer (NSCLC) patients. Data from previously untreated patients with stage IIIb/IV NSCLC who were randomized to receive up to six cycles of carboplatin (C; AUC 6 mg/ml•min) and paclitaxel (P; 175 mg/m(2)) alone or with ASA404 (1200 mg/m(2)), or enrolled in an extension study to receive CP and ASA404 (1800 mg/m(2)), were analyzed. Differences between subgroups were calculated using Fisher's exact test. Of the 108 enrolled patients, safety data from the 104 patients included in the safety population were pooled to compare results between histological subgroups (squamous vs non-squamous) and treatment (CP alone vs CP + ASA404). Addition of ASA404 to the standard chemotherapy regimen did not appear to substantially increase toxicity, and there were no serious adverse events associated with bleeding, pulmonary hemorrhage, or hemoptysis. Activity with CP + ASA404 appeared improved over CP alone, with median survival 10.2 vs 5.5 months in squamous, and 14.9 vs 11.0 months in non-squamous populations, respectively. This analysis is limited by its retrospective nature, and by the small size of the overall group, treatment and disease subgroups. However, as ASA404 appears to have a similar safety and activity profile in patients with squamous and non-squamous NSCLC, the findings support inclusion of both groups of patients in ongoing definitive phase III trials of ASA404 (NCT00832494).

Maintenance of clinical efficacy following dose reduction of ixabepilone plus capecitabine (Cape) in patients (pts) with anthracycline (A) and taxane (T) pretreated (pretx) metastatic breast cancer (MBC): A retrospective analysis of pooled data from two phase III clinical studies (046/048).

1051 Background: Ixabepilone 40 mg/m2 (ixabepilone 40) is approved in combination with Cape for treatment of MBC, but this dose may subsequently be reduced to 32 mg/m2 to manage toxicity. Anecdotal...