Patient Selection Factors Research Articles

Individual patient factors associated with effective tinnitus treatment.

Little is known about patient factors that might influence outcomes of tinnitus interventions. Determining such factors would offer insights into why some individuals benefit from tinnitus intervention whereas others do not. The purpose of this study was to evaluate selected patient factors that may be associated with outcomes of tinnitus intervention. Factors studied include demographics, tinnitus characteristics, psychoacoustic tinnitus measures, audiometric data, and overall physical/emotional health status. A retrospective analysis was performed on data obtained from a controlled clinical study that compared factors associated with tinnitus relief after tinnitus masking and tinnitus retraining therapy. A total of 126 military veterans participated in this controlled clinical study. Of these, 89 completed outcome measures at both baseline and 12 mo and were included in the present analysis. A "responder" to intervention was identified as having a decrease (improvement) of 20 or more points on the Tinnitus Handicap Inventory between baseline and 12 mo. A "nonresponder" did not achieve a 20-point improvement on the Tinnitus Handicap Inventory. Individual patient factors were examined using independent t-tests or χ² analysis. A logistic regression model was used to determine how well each factor predicted treatment outcome (responder or nonresponder) while controlling for each of the other factors. Five patient factors were significantly different (p ≤ 0.05) between responders and nonresponders. Responders tended to (1) be younger in age; (2) have better low-frequency hearing sensitivity; (3) have greater problems with overall hearing; (4) be more likely to have tinnitus for shorter durations; and (5) perceive their tinnitus to be located "in the head" versus "in the ears." A logistic regression was then performed to determine how well each factor predicted the treatment outcome (responder versus nonresponder) while controlling for each of the other factors. RESULTS from the logistic regression revealed two of the five factors, localization of tinnitus and self-report of hearing problems, to be statistically significant. Examining the association of individual patient factors to a specific tinnitus intervention yielded several significant findings. Although these findings are not definitive, they reveal the capability that exists to perform these kinds of analyses to investigate relationships between individual patient characteristics and outcomes of intervention for tinnitus. Prospective research using systematic approaches is needed to identify these relationships that would contribute toward the ability to differentially predict outcomes of various tinnitus interventions. Obtaining this information would lead to more targeted therapy and ultimately more effective intervention.

Radioembolization of hepatic tumors.

Unresectable primary and metastatic liver tumors are a leading cause of cancer mortality and morbidity. This remains a challenging and key task for every oncologist despite significant advances that have been made with selective targeted systemic agents and in technology advances with radiotherapy delivery. Radioembolization (RE) is a technique of permanently implanting microspheres containing Yttrium-90 ((90)Y), a beta-emitting isotope with a treatment range of 2 mm, into hepatic tumors. This form of brachytherapy utilizes the unique dual vascular anatomy of the liver to preferentially deliver radioactive particles via the hepatic artery to tumor, sparing normal liver parenchyma. The main treatment inclusion criteria are patients with solid tumors, compensated liver functions, life expectancy of at least three months, and ECOG performance status 0-2. Benefit of RE has been proven in patients that have low-to-moderate extrahepatic disease burden, prior liver radiotherapy, heavy prior chemotherapy and biologic agent exposure, and history of hepatic surgery or ablation. Most of the clinical evidence is reported in metastatic colorectal, and neuroendocrine tumors (NET), and primary hepatocellular cancer. A growing body of data supports the use of RE in hepatic metastatic breast cancer, intrahepatic cholangiocarinoma, and many other metastatic tumor types. Side effects are typically mild constitutional and GI issues limited to the first 7-14 days post treatment, with only 6% grade 3 toxicity reported in large series. Potentially serious or fatal radiation induced liver disease is extremely rare, reported in only 1% or fewer in major series of both metastatic and primary tumors treated with RE. Currently, high priority prospective clinical trials are testing RE combined with chemotherapy in first line therapy for colorectal hepatic metastases, and combined with sorafenib for hepatocellular carcinomas (HCCs). Fortunately, this beneficial and now widely available therapy is being increasingly incorporated into the standard therapy algorithms of multidisciplinary GI cancer teams worldwide. This form of radiotherapy differs significantly from daily external beam radiotherapy in many ways, particularly in dose rate, dosimetric coverage and duration of radiation delivery, side effects, and patient selection factors. A wealth of experience using RE in solid tumors exists and ongoing major prospective clinical trials will soon clarify the role of RE in the management of metastatic colorectal liver metastases.

Phosphorylation of mTOR and S6RP predicts the efficacy of everolimus in patients with metastatic renal cell carcinoma.

BackgroundThe incidence of renal cell cancer (RCC) has been increasing for the past decade, and the 5-year survival for patients with metastatic RCC (mRCC) is rather low. Everolimus (RAD001), a new inhibitor for mammalian target of rapamycin (mTOR), is generally well tolerated, and demonstrates clinical benefit to patients with anti-VEGF-refractory mRCC. However, factors for selection of patients who may benefit from everolimus remain largely unknown. Here we aimed to explore potential molecular indicators for mRCC patients who may benefit from everolimus treatment.MethodsParaffin-embedded tumor tissue specimens derived from 18 mRCC patients before everolimus treatment, who participated the phase 1b trial of everolimus in VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI)-refractory Chinese patients with mRCC (clinicaltrials.gov, NCT01152801), were examined for the expression levels of phosphorylated AKT, mTOR, eukaryotic initiation factor 4E (eIF4E) binding protein-1 (4EBP1) and 40S ribosomal protein S6 (S6RP) by immunohistochemistry. Clinical benefit rate (complete response [CR], partial response [PR], plus stable disease [SD] ≥ 6 months) and progression-free survival time (PFS) were correlated with expression levels of these mTOR-associated molecules.ResultsIn these 18 patients, there were 1 PR, 15 SDs (including 9 SDs ≥ 6 months), and 2 progressive diseases (PD). The clinical benefit rate (CBR) was 55.6% (10/18), and the median PFS time was 8.4 months. Patients with positive expression of phospho-mTOR showed a better CBR (71.4% versus 0%, P = 0.023) and PFS time (11.3 versus 3.7 months, P = 0.001) than those patients with negative expression. The median PFS of patients with positive phospho-S6RP expression was longer (11.3 versus 3.7 months, P = 0.002) than that of patients negative for phospho-S6RP expression. However, expression levels of phospho-4EBP1 and phospho-AKT were unassociated to efficacy of everolimus treatment with respect to CBR and PFS. Co-expression of phosphorylated mTOR, S6RP and/or 4EBP1 may improve the predictive value of the biomarkers for patients treated with everolimus.ConclusionsThe expression levels of phospho-mTOR and phospho-S6RP may be potential predictive biomarkers for efficacy of everolimus in patients with mRCC. Combining examinations of phosphorylated mTOR, S6RP and/or 4EBP1 may be a potential strategy to select mRCC patients sensitive to mTOR inhibitor treatment.

Phosphorylation of mTOR and S6RP predicts the efficacy of everolimus in patients with metastatic renal cell carcinoma.

e15556 Background: Everolimus (RAD001), as a new inhibitor for mammalian target of rapamycin (mTOR) provides clinical benefit to patients with anti-VEGF-refractory metastatic renal cell carcinoma (mRCC). However, factors for selection of patients who will benefit from Everolimus remain uncovered. Here we aimed to explore the potential molecular indicators for mRCC patients who may benefit from everolimus treatment. Methods: Paraffin-embedded tumor tissue specimens derived from 18 mRCC patients, who participated the phase 1b trial of everolimus in VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI)-refractory Chinese patients with mRCC, were examined for the expression levels of phosphorylated AKT, mTOR, eukaryotic initiation factor 4E (eIF4E) binding protein-1 (4EBP1) and 40S ribosomal protein S6 (S6RP) by immunohistochemistry. Clinical benefit rate (complete response [CR], partial response [PR], plus stable disease [SD] ≥6 months) and progression-free survival time (PFS) were correlated with expression...

Patient and procedural characteristics for successful and failed immediate tracheal extubation in the operating room following cardiac surgery in infancy

Immediate extubation in the operating room after congenital heart surgery is practiced with rising frequency at many cardiac institutions to decrease costs and complications. Infants less than one year of age are also increasingly selected for this 'fast track'. However, factors for patient selection, success, or failure of this practice have not been well defined in this population, yet are critical for patient safety. To identify selection criteria, patient and procedural characteristics for successful or failed very early endotracheal extubation in the operating room immediately following infant heart surgery. A retrospective analysis was performed for 326 consecutive patients undergoing neonatal and infant heart surgery from 2009 to 2012. Extubation and reintubation data were taken from the institutional Society of Thoracic Surgeons database and patients' charts. Patient characteristics were derived using multivariable logistic regression models. Very early extubation in the operating room was performed for 130 of 326 neonates and infants (40%). Weight >4 kg, lesser procedural complexity, and absence of trisomy 21 were identified as significant predictors for attempted very early extubation. Of these patients, 12% required reintubation within 48 h following surgery, predominantly due to respiratory failure or for mediastinal re-exploration. Greater procedural complexity was associated with failed extubations. Reintubation was associated with prolonged hospitalization. Extubation immediately after infant heart surgery in the operating room can be safely achieved. However, our data suggest that patients undergoing more complex procedures should be selected more conservatively for immediate early extubation.

Self-expanding metal stents in palliative malignant oesophageal dysplasia.

Oesophageal cancer is the sixth leading cause of cancer-related death worldwide. At the time of presentation, more than half of patients with oesophageal cancer have advanced disease not eligible for curative resection. Due to this, the treatment of oesophageal malignancy is usually palliative, with the main aim to relieve dysphagia, maintain nutritional intake and occlusion of tracheoesophageal fistulas. Palliative surgery offers the optimal alleviation for oesophageal obstruction symptoms such as dysphagia and vomiting. However, due to the poor prognosis, the short survival time, the significant morbidity and mortality rate for surgical intervention, this treatment option cannot be justified to less invasive non-surgical techniques such as oesophageal stenting. Oesophageal stenting has now become the treatment option of choice for palliative oesophageal malignancy. The previously used covered plastic stents were related with high migration rates and nowadays have been superseded by self-expandable metal stents (SEMS) which comparably have significantly lower migration rates, whilst at the same time provide safe, rapid and effective symptomatic relief. Herein, we present an up to date review of the current literature regarding malignant oesophageal stenting. In particular, the authors will detail important factors in patient selection, indications, contraindications, procedural steps, complications and stent design.

Patient Selection for Spinal Cord Stimulators: Mental Health Perspective

Research has shown that psychosocial factors can predict poor outcome for spinal cord stimulation (SCS) for patients with chronic pain, substantiating the need for standardized assessment techniques to incorporate psychosocial factors in patient selection. Presurgical psychological assessment is often required for SCS. Best practices include clinical interviews by psychologists and use of standardized measures of psychosocial risk factors. Psychologists should assess mental health and social risk factors, as well as an individual's understanding of SCS and expectations for pain relief, while consulting with physicians to support a multidisciplinary based patient selection. In addition, psychologists take part in preparing patients who were initially deemed unsuitable for SCS by providing recommendations and potential access to clinical care addressing psychological issues in chronic pain. Barriers to presurgical psychological assessments include limited access to skilled psychologists and issues with feasibility and appropriateness of standardized measures, and further work is needed to improve standardized methodology.

Abstract W MP5: The Global Impact of Recent Intra-Arterial Therapy (IAT) Randomized Controlled Trials on Current and Future Stroke Practice

Background and Objective: Recent RCTs have failed to show benefit of intra-arterial therapy (IAT). We sought to determine whether these trials have affected the views and practice of IAT amongst stroke-treating physicians. Methods: An international web-based survey was sent to 753 stroke-treating physicians across the globe. Results: 322 physicians responded (43% rate); 25% were interventionalists; 80% practice in 24/7 IAT capable centers (fig 1). IAT volume per year prior to the RCTs (fig 2) has now decreased according to nearly half of the respondents. Physicians are now more selective (59%) while a third made no changes in pursuing IAT and 6% “do not pursue IAT anymore” (fig 3). Although 76% still perceive IAT is effective under certain criteria, two thirds said they feel “less obligated” to offer IAT. When asked about the RCTs, respondents felt the devices were outdated (36%), patient selection methods were “not optimal” (32%), recanalization rates could have been better (25%) or the trials should have been better designed (20%). Interestingly, centers currently enrolling in IAT trials intervene on large proportions of patients outside of studies (fig 4). The single most important factor in patient selection is shown in fig 5. Over half prefer a CT modality for patient selection; while 16% chose MRI and 11% use clinical criteria only when deciding to pursue IAT. Finally, three quarters of the contributors said that patients should be taken to IAT only in the context of clinical trials to test its efficacy, 21% said IAT should be continued “outside of trials” and only 3% pronounced it not useful (fig 6). Conclusion: While the results of recent RCTs have changed the views of stroke treating physicians, IAT continues to be practiced worldwide. The majority of our respondents is more selective and awaits results of new trials with the stent retrievers and better selection methods. Despite endorsing the practice of IAT only within trials, over half are still treating cases outside studies.

Comparison of outcomes after single-port laparoscopic cholecystectomy in relation to patient body mass index.

Background and Objectives:Single-port laparoscopic cholecystectomy may contribute to a paradigm shift in the field of laparoscopic cholecystectomy surgery by providing patients with benefits beyond those observed after other surgical procedures. This study was designed to evaluate clinically meaningful differences in operative outcomes between obese and nonobese patients after single-port laparoscopic cholecystectomy.Methods:Data were collected retrospectively from 172 patients who had undergone single-port laparoscopic cholecystectomy performed by the same surgeon at a single medical center between January and December 2011. For the outcome analysis, patients were divided into nonobese and obese patient groups according to their body mass index (<25 kg/m2 vs ≥25 kg/m2).Results:Demographic and clinical data did not differ significantly between obese patients (n = 65) and nonobese patients (n = 107). In addition, statistically significant differences pertaining to most measured surgical outcomes including postoperative hospital stay, bile spillage, additional port use, and open conversion were not detected between the groups. However, the two groups differed significantly regarding operative time such that nonobese patients had shorter operative times than obese patients (P < .05).Conclusion:The results of this study showed that operative time for single-port laparoscopic cholecystectomy was the only difference between obese and nonobese patients. Given this result, body mass index may not be as relevant a factor in patient selection for single-port laparoscopic cholecystectomy as previously thought.

Topoisomerase 2α status in invasive breast carcinoma - comparison of its clinical value according to immunohistochemical and fluorescence in situ hybridization methods of evaluation.

The main purpose of the study was to compare topoisomerase 2α (TOP2A) status in invasive breast carcinomas to the outcome of a therapy containing neoadjuvant treatment with anthracyclines (a combination chemotherapy treatment for breast cancer, namely AC [cyclophosphamide, doxorubicin]). To achieve these goals we created a method of evaluation with criteria based on two methods used in the present study (immunohistochemical [IHC] and fluorescence in situ hybridization [FISH]). The threshold for positive immunohistochemically evaluated status was set for all cases with: nuclear stain intensity score 3+ in 10% or more nuclei and nuclear stain intensity score 2+ in 50% or more nuclei. Our results suggest that TOP2A status may be used as a predictive factor for patient selection for protocols which include anthracyclines as one of the chemotherapeutics. Both methods, IHC and FISH, are suitable for implementation for diagnostic purposes, but IHC positive status measured according to the criteria presented above is the best predictor of longer disease-free survival (DFS) according to our study. Immunohistochemical also gave satisfactory results in all analyzed cases in comparison to only 60% of cases analyzed by FISH.

Outcomes of autologous or allogeneic stem cell transplantation for non-Hodgkin lymphoma

Transplant outcomes of autologous or allogeneic stem cell transplantation (SCT) have not been elucidated as a single cohort in non-Hodgkin lymphoma (NHL). We analyzed the outcomes of 270 adult recipients receiving autologous (auto) SCT (n = 198) or allogeneic (allo) SCT (n = 72) for NHL between the years 2000 and 2010. Five-year overall survival rates for B and T cell NHL were 58% and 50%, respectively (allo-SCT 51% vs. 54% for B and T-cell NHL, and auto-SCT 60% vs. 47% for B and T cell lymphoma, respectively). In multivariate analysis, the number of chemotherapy regimens and disease status pre-SCT were independently associated with long-term outcome after SCT (for both auto- and allo-SCT). We conclude that the type of transplantation offered to patients, based on patient selection and disease-related factors, can achieve long-term survival, highlighting the importance of further improvement in disease control and reducing procedure-related mortality. The role of transplantation needs to be reevaluated in the era of targeted therapy.

Bedside Teaching: general and discipline-specific teacher characteristics, criteria for patient selection and difficulties.

Objective: With regard to bedside teaching (BST), which has an important function in medical education for practicing history taking and clinical examination, only few studies can be found which define recommendations for its realization. However, difficulties with this teaching method are often reported in evaluations. Hence, the goal of this study is to collect important general requirements for bedside teaching and to identify important aspects of patient selection.Methods: A newly designed questionnaire with closed and open questions concerning the organisation, the execution and the design of BST as well as patient selection was sent to a total of 134 teachers from the departments of surgery, internal medicine and psychiatry. The collected data were analysed using quantitative and qualitative methods.Results: Teachers from internal medicine were significantly older than teachers from both other disciplines. In surgery, a significantly higher number of hours was taught by younger residents. Patient consent and the match of their diseases to the learning objectives were stated to be the most important factors for patient selection across disciplines. Psychiatrists put significantly more emphasis on patients’ German language skills according to their own declaration. By trend, an acute deterioration of the state of health was mentioned more often in surgery to lead to an exclusion from BST. Conclusion: With regard to planning of content, organisation and patient selection for BST, aspects mentioned by teachers as well as discipline specific characteristics should be considered for and addressed during teacher trainings.

Matched‐pair and propensity score comparisons of outcomes of patients with clinical stage I non–small cell lung cancer treated with resection or stereotactic radiosurgery

Stereotactic body radiotherapy (SBRT) is an alternative to surgery for clinical stage I non-small cell lung cancer (NSCLC), but comparing its effectiveness is difficult because of differences in patient selection and staging. Two databases were combined which contained patients treated from 1999 to 2008 by lobectomy (LR, n = 132), sublobar resection (SLR, n = 48), and SBRT (n = 137) after negative staging. Univariate and multivariate analysis were performed for survival (OS), total recurrence control (TRC comprises local-regional and distant control), and locoregional control (LRC) in our entire population. A matched-pair analysis was also performed that compared surgery and SBRT results. Median follow-up for the entire study population was 25.8 months. On univariate analysis, OS was significantly worse with SBRT and also correlated with histology, the Charlson comorbidity index, tumor size, and aspirin use; TRC correlated only with histology; and no variable significantly correlated with LRC. OS was significantly poorer for SBRT in the matched-pair analysis than for patients treated with surgery, but TRC and LRC were not significantly different between these groups. Multivariate analyses including propensity score as a covariate (controlling for all factors affecting treatment selection) found that OS correlated only with Charlson comorbidity index, and TRC correlated only with tumor grade. LRC correlated only with tumor size with or without propensity score correction. This retrospective study has demonstrated similar OS, LRC, and TRC with SBRT or surgery after controlling for prognostic and patient selection factors. Randomized clinical trials are needed to better compare the effectiveness of these treatments.

An Ounce of Prevention Is Better Than a Pound of Cure: A Patient-Centered Approach to Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide. Though it is less commonly seen in the United States, age-adjusted incidence rates have tripled here over the last three decades, and overall survival remains poor for those with advanced disease. Host factors, including viral hepatitis, metabolic syndrome, alcohol use, and genetic disorders, contribute to HCC pathogenesis, both singly and in combination. HCC is notable for having particularly varied etiologies in different populations. Hepatitis B vaccination programs have begun to show dramatic decreases in HCC incidence, but for those with other underlying risk factors, primary prevention efforts have been disappointing. In the article that accompanies this editorial, Tsan et al provide compelling evidence for an association between statin use and a significantly lower risk of HCC development in patients with hepatitis C infection (HCV). The authors examine a population-based cohort of 260,864 patients infected with HCV from Taiwan between January 1, 1999, and December 31, 2010. Both dose and duration responses to statin use were seen, with a hazard ratio of 0.33 for HCC development in those taking higher cumulative daily doses. The results were statin specific, and were not seen with other lipid-lowering agents. Unlike most randomized trials evaluating statin use and cancer incidence, follow-up in this observational study was relatively long, at just over 10 years. Just as important, there was no increase in hepatotoxicity seen with use of statins in patients with underlying HCV, which has been a concern about using these agents in patients with liver disease. These data are consistent with several other observational studies suggesting that statins may decrease the risk of HCC in patients with other underlying liver diseases. In addition, Nielsen et al recently reported a decrease in overall and cancer-related mortality among statin users using the Danish Civil Registration System, a database enviable for its completeness. Statin use was also recently shown to be an independent predictor of decreased HCC recurrence after resection. Finally, there are at least two small randomized trials suggesting a survival benefit of giving pravastatin to patients with existing HCC. However, randomized data do not support a preventive effect for statins in HCC. A recent meta-analysis evaluated seven observational studies, as well as pooled data from 26 randomized controlled trials evaluating statin use. The authors found a 40% reduction in risk of HCC in the observational studies, but no benefit attributable to statins in the randomized trials. Such differences between observational studies and randomized trials are not unusual, and may reflect length of follow-up and patient selection factors such as risk and country of origin. Additionally, observational studies are susceptible to bias. The study by Tsan et al has several limitations related to its design. First, because the differences between the groups are seen after just 28 to 89 cumulative daily doses of statin therapy (hazard ratio [HR] 0.66), one might suspect that other nonbiologic factors are playing a role. Second, confounding by indication can be seen if those with more advanced liver disease are less likely to be given a statin because of concerns for hepatotoxicity (or less concern about high lipids) in patients with advanced cirrhosis. The authors stratify by cirrhosis status and still show that the protective effects persisted in both groups. However, it is possible that cirrhosis, especially compensated cirrhosis, may not have been diagnosed or recorded in most practice settings. The authors could have also excluded cases found early in the observational period to prevent inclusion of latent or prevalent HCC, and to make reverse causation less likely. In addition, more detailed HCV treatment data would have been interesting to assess. The authors acknowledge that not all possible confounders were adjusted for, including body mass index, smoking, and other indicators of health and socioeconomic status. Finally, concomitant use of potentially beneficial medications such as metformin was not adjusted for in the analysis. In support of the findings of Tsan et al, there is a biologic rationale for why statins may benefit patients with HCV. Statins inhibit cholesterol synthesis and block the formation of geranylgeranylated protein, both thought to be important for HCV replication. Statin use may also improve viral response to hepatitis C therapy. Finally, statins may act as anticancer agents, exerting antiproliferative effects via targeting hydroxymethylglutaryl coenzyme A reductase, and interfering with lipid rafts which mediate cell signaling and apoptosis. Perhaps most important, statins have shown clinical efficacy in the treatment of patients with metabolic syndrome, a constellation of problems including diabetes, hypertension, obesity, and hyperlipidemia. Age-adjusted prevalence rates of metabolic syndrome in the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 12 APRIL 2

Effect of geographic variability for pancreatectomy rates on outcomes in patients with stage I and II pancreatic adenocarcinoma.

240 Background: Low usage of pancreatectomy for stage I/II pancreatic cancer in the US has been reported, yet it is not clear to what extent this reflects underutilization of resection versus appropriate selection of operative candidates. To address this, we examined the geographic variation in pancreatectomy. Methods: We queried the US Surveillance, Epidemiology, and End Results (SEER) data for stage I/II pancreatic head cancer diagnosed from 2004-2009. Factors included in multivariate analyses (MVA) were age, gender, race, stage, and geographic region and primary endpoints were rate of pancreatectomy and median survival. Results: 10,520 patients with stage I (n=2,068) and stage II (n=8,452) pancreatic head cancer were analyzed. Pancreatectomy was performed in 528 patients (25.5%) with stage I disease and in 4,295 patients (50.8%) with stage II disease (overall resection rate=45.9%). Rates of resection significantly varied across the 18 SEER regions after controlling for age, gender, race, and stage in MVA (p&lt;0.0001). For the analysis, SEER regions were divided into groups of high/medium/low rates of resection (56.3%, 46.6%, and 41.1%, respectively). Median survival in the high resection regions was 12 months, which was significantly longer than in low and medium resection regions (both=10 months, p&lt;0.0001). MVA confirmed that regions with high resection rates have improved survival while controlling for age, gender, and race (Table). Conclusions: Pancreatectomy rates vary highly across geographic regions, and areas with higher rates of resection are associated with better outcome. These data may reflect poor adherence to treatment guidelines, which possibly reflects a lack of confidence in the effectiveness of pancreatectomy or expertise in performing the procedure. Studies that control for patient selection factors are underway to further elucidate these important findings. [Table: see text]

Abstract 19458: Prevalence of Neoplastic and Non-Neoplastic Incidental Findings as Detected by Computed Tomography in Severe Aortic Stenosis: Single Center PARTNER Trial Data

Background: In the emerging era of Trans catheter aortic valve replacement (TAVR), CT is important tool for precise screening and procedural outcomes. Non cardiac incidental findings of malignancy are an important clinical concern. Methods and results: We retrospectively evaluated the findings from 64-slice screening CT scans performed on 318 patients with severe aortic stenosis (AS) prior to evaluation forTAVR. A total of 235 patients received contrast imaging. Detailed analysis of cardiac and non cardiac structures revealed presence of lung cancer in 10 patients (3%) and Bronchogenic carcinoma in 5 patients (2%), breast cancer in 9 patients (3%), 4 patients with colon cancer (1%) and 4 with lymphoma(1%), 2 with prostate cancer and 1 with renal cell carcinoma and multiple myeloma(1%). Conclusions: CT is important factor in patient selection for TAVR but reporting of non-cardiac findings must be meticulous. There is a significant proportion of patients with the incidental finding of Neoplasia.

Abstract 9964: Vorapaxar, a Platelet Thrombin-Receptor Antagonist, in Medically Managed Patients with Non-ST-Segment Elevation Acute Coronary Syndrome: Results from the TRACER Trial

Purpose: This is a prespecified post-randomization subgroup analysis to evaluate efficacy and safety outcomes of vorapaxar in the TRACER trial in patients that were medically managed without revascularization procedures during index hospitalization. Methods: Vorapaxar, a novel platelet-protease-activated receptor-1 antagonist, was randomized with placebo in 12,944 patients with NSTE ACS. We explored the effect of vorapaxar vs placebo among medically managed patients at discharge (n=4194; 32.4 %) vs those undergoing revascularization (n=8750; 67.6%) from discharge to end of follow-up, with adjustments for baseline differences. Events rates are provided as 2-yr Kaplan-Meier estimates. Results: The medically managed patients were more likely to be older and female and have prior MI, prior CABG, and decreased renal function. The 2-yr event rate of the primary outcome (CV death, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization) was 16.9% with vorapaxar and 17.3% with placebo (HR 0.95; 95% CI 0.81-1.14), with no interaction between study drug and management strategy (p=0.63). The rate of the key secondary endpoint (CV death, MI, and stroke) was 13.9% with vorapaxar and 15.1% with placebo (HR 0.88; 95% CI 0.73-1.07), with no interaction (p=0.86). Lower MI rates were observed in medically managed patients treated with vorapaxar (9.3% vs 11.1% [HR 0.79; 95% CI 0.63-0.99). Vorapaxar significantly increased GUSTO moderate or severe bleeding in medically managed patients (HR 1.52; 95% CI 1.04-2.22) and in patients undergoing revascularization (HR 1.32; 95% CI 0.99-1.76). In the medical group, intracranial hemorrhage (ICH) occurred in 18 patients with vorapaxar and in 1 patient with placebo, whereas ICH occurred in 17 vorapaxar patients and 9 placebo patients treated with revascularization, with no significant interaction (p=0.056). Conclusion: In patients with NSTE ACS treated medically, the efficacy of vorapaxar was consistent with the main findings of the TRACER trial. Bleeding hazard with vorapaxar tended to be higher in medically treated patients, possibly due to patient selection factors.

Rates and Outcomes of Follicular Lymphoma Transformation in the Rituximab Era: A Report From the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource

AbstractAbstract 1546 Background:Follicular lymphoma (FL) is an incurable disease with an undefined optimal management strategy. Global priorities in goals of care are avoidance of death and transformation to aggressive subtypes. Retrospective series, – most including patients diagnosed before ubiquitous rituximab use, - describe diverse rates of transformation with a common consensus of 3% per year, and with a median survival post transformation of less than 2 years. This study sought to characterize transformation events in a prospective observational series begun after diffusion of early rituximab use in FL. Methods:Newly diagnosed FL patients were prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) from 2002–2009. Clinical data were abstracted from medical records using a standard protocol. Patients were actively followed for retreatment, transformation, and death. Inclusion criteria for this analysis were initial diagnosis of grade I-IIIa FL. Exclusion criteria for this cohort include composite diffuse large B-cell lymphoma (DLBCL), FL grade IIIb, or evidence of clinical or pathological transformation at the time of FL diagnosis. Transformation was defined as refractory/recurrent disease with either a) biopsy confirmed subtype of FLIIIb, DLBCL or higher grade B-cell lymphoma; or b) clinical indication of transformation (sudden rise in LDH, rapid discordant localized nodal growth, new involvement of unusual extranodal sites, new B symptoms or hypercalcemia). Risk of transformation was analyzed via time to transformation using a death as a competing risk. Time to transformation was defined as the date of initial FL diagnosis to date of transformation. Overall survival was defined as the date of initial diagnosis to date of death or last known follow-up for patients still alive. Results:There were 631 newly diagnosed grade I-IIIa FL patients with a median age at enrollment of 60 years (range 23–93). 54% were male. The most common types of initial therapy were observation (33%), rituximab (R) monotherapy (12%), alkylator based chemotherapy +/− R (22%), and anthracycline based chemotherapy +/− R (20%). At a median follow-up of 60 months (range 11–110), 79 patients had died, 311 patients had an event (death, progression, or retreatment), and 60 patients (9.5%) had transformed. Transformation was biopsy proven in 48 of the 60 patients (80%). The overall transformation rate at 5 years (TX5) was 10.7% (95% CI: 8.3%–13.8%) (Figure 1). Time to transformation was associated with a FLIPI score of 3–5 (HR=2.37, 95% CI 1.28–4.39, p=0.006), but was not significantly associated with other standard clinical characteristics. Risk of transformation was different in the common initial treatment groups with the highest rate in patients who were initially observed (TX5=14.4%) and lowest rate in patients who initially received R monotherapy (TX5=3.2%)(p=0.058). Outcome after transformation was inferior to MER subjects with de-novo diagnosed DLBCL (p<0.0001). The median overall survival from date of transformation was 44 months (95% CI: 22-NA). Survival after transformation was superior in patients who transformed greater than 18 months after FL diagnosis compared to patients who transformed earlier (5 yr OS =70% vs 20%) (p=7 ×10−5), and for those initially observed (median unreached) versus those patients who were initially treated with alkylator or anthracycline based chemotherapy (median survival of 11 months)( p=0.016). Conclusions:Follicular transformation rates in this modern large prospective observational study are similar to risk of death without transformation and slightly lower at 5 years than most previous reports. Post-transformation prognosis is substantially better than described in older series. These observed differences may be a function of the prospective nature of the study design, modern management strategies, or patient selection factors. Initial management strategies may influence the risk of transformation. Marked survival differences following early vs. late transformation suggest that these may be different biologic events. [Display omitted] [Display omitted] Disclosures:Link:Genentech: Consultancy, Research Funding; Celgene: Consultancy; Millenium: Consultancy. Johnston:Novartis: Consultancy.

Drug Development for Chronic Cancers: Time to Think Differently?

As the treatments for epithelial cancers have inched forward, the chronic management of patients with high performance status has become a common problem in the practice of oncology. This conundrum is clearly illustrated by the excellent, yet negative, randomized trial by Colombo et al that accompanies this editorial. This large, well-designed clinical trial tested another modestly active agent, patupilone, in comparison with pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant ovarian cancer. Sadly, this study did not meet its prespecified superiority end point, namely an overall survival improvement compared with the use of PLD. What drug development lessons can be learned from yet another trial that fails to meet its designed superiority outcome? There are several potential points for consideration by solid tumor oncologists and gynecologic oncologists as we design strategies to incrementally improve the lives of patients with cancer until we find the rare breakthroughs that will irrefutably extend patient survival. First, we need to acknowledge that the barriers for achieving major advances are formidable. Previously treated solid tumors have been selected in a devilishly Darwinian crucible of genetic instability, heterogeneity, and mutagenic primary therapy. Drug-resistant cancers tend to be broadly refractory to additional agents, regardless of mechanism. Platinum-resistant tumor response rates to topotecan, PLD, and trabectedin are all half of what would be expected in the untreated or platinum-sensitive patient groups. Without a predictive biomarker to enrich for patients who are likely to benefit, many nonresponders will be present in both arms of a randomized trial in platinum-resistant ovarian cancer, making it difficult to detect small but potentially important signs of clinical benefit. This low response rate and the brief duration of improvement combine to dictate very large and costly sample sizes. Yet even adequately sized superiority trials like that of Colombo et al are likely to fail. Table 1 details the recent phase III randomized trials in platinum-refractory ovarian cancer. From these trials, performed over more than a decade, it is apparent that classic chemotherapy development has hit a glass ceiling in platinum-resistant ovarian cancer. One must conclude that inferiority is a real possibility in these trials (because the approved drugs have reproducible, modest effects), therapeutic equivalence is an optimistic outcome, and superiority to current treatment is a distant, unlikely achievement. New superiority trials with classic chemotherapy must be regarded like third Hollywood marriages: a “triumph of hope over experience.” Second, our models for predicting success are unreliable. The phase II experience that led to this phase III trial is not yet published but is described as a single-arm, nonrandomized study. These modestly sized, nonrandomized trials are treacherous guides and have increasingly been criticized for their lack of predictive power. The reliability of single-arm, phase II trials is undermined by undefined patient selection factors and the wide variability that is caused by the

The effects of arthroscopic joint debridement in the knee osteoarthritis: results of a meta-analysis

Knee osteoarthritis is one of the most common orthopaedic diseases. Therapeutic options for this disease include conservative treatments and arthroscopic debridement and partial or complete replacement. This meta-analysis aimed to collect and analyse the available information on the effects of arthroscopic joint debridement related to the clinical outcomes, the required conversion to replacement and the factors for patient selection. A search for publications was performed in the PubMed, Cochrane and EMBASE medical databases. The primary search resulted in a total of 1,512 citations. The results from 30 papers were included in this study. The extracted dates were listed in a standardised protocol. The statistical evaluation was performed using Comprehensive Meta-analysis software (V2 Biostat, Englewood, NJ, USA). No randomised study that compared conservative and arthroscopic treatments for knee osteoarthritis was found. Most studies reported middle-term results after arthroscopic operations. The results of these studies showed excellent or good outcomes in more than 60 % of all patients. These results were correlated with a significant increase in the knee scores from baseline to follow-up; the standardised difference in means was 2.3 (CI 95 % 1.5-3.0, p < 0.001). The required conversion rate to replacement increased as the follow-up interval increased. The rates were as follows: 1 year-6.1 % (CI 95 %, 2.1-16.6 %), 2 years-16.8 % (CI 95 %, 10.2-26.3 %), 3 years-21.7 % (CI 95 %, 15.5-29.1 %) and 4 years-34.1 % (CI 95 %, 22.8-47.6 %). The mean survival time was 42.7 (CI 95 %, 14.5-71.1) months. Numerous factors influenced the outcome, including the radiological stage of the osteoarthritis and individual patient factors (e.g. time of history of osteoarthritis, weight and smoking). The local knee findings, such as axial dysalignment, missing effusion and massive crepitus, were also correlated with patient outcome. Arthroscopic joint debridement is a potential and sufficient treatment for knee osteoarthritis in a middle-term time interval. This procedure results in an excellent or good outcome in approximately 60 % of patients in approximately 5 years. Systematic review of studies, Level III.