Median RR Research Articles

Effect of subsequent chemotherapy on overall survival in first-line chemotherapy with targeted agents for patients with metastatic colorectal cancer: Systematic review and meta-analysis of randomized control trials.

782 Background: One of recent standard first line chemotherapies for metastatic colorectal cancer is doublet of cytotoxic agents, fluorouracil and oxaliplatin or irinotecan, in combination with target agent, bevacizumab, or anti-EGFR antibody as cetuximab or panitumumab for KRAS or RAS wild type (WT). In this decade, nevertheless progression free survival (PFS) of clinical trials was little improved, overall survival (OS) had been increased. Methods: We analyzed data from 14 recently published phase III randomized clinical trials in mCRC to correlate the percentage of patients receiving subsequent chemotherapy with the reported OS. Results: Median PFS and OS were 10.3 and 25.0 months, respectively. In all comer trials, median OS is significantly correlated with the percentage of patients who received subsequent chemotherapy after first line chemotherapy of their disease [regression coefficient (R2) = 0.85 p = 0.0018]. In trials with KRAS WT, a correlation between OS and the rate of subsequent therapy was modest [r2 = 0.605, p = 0.0637]. Median PFS and RR were not correlated with median OS. Conclusions: Our results support the strategy of making salvage chemotherapy available to all patients with advanced CRC to maximize OS. In addition, our findings suggest that, with the availability of effective salvage options, PFS might no longer be regarded as the appropriate surrogate end point of OS by which to assess the efficacy of a palliative first-line treatment in CRC.

Association of Biomarker-Based Treatment Strategies With Response Rates and Progression-Free Survival in Refractory Malignant Neoplasms

The impact of a biomarker-based (personalized) cancer treatment strategy in the setting of phase 1 clinical trials was analyzed. To compare patient outcomes in phase 1 studies that used a biomarker selection strategy with those that did not. PubMed search of phase 1 cancer drug trials (January 1, 2011, through December 31, 2013). Studies included trials that evaluated single agents, and reported efficacy end points (at least response rate [RR]). Data were extracted independently by 2 investigators. Response rate and progression-free survival (PFS) were compared for arms that used a personalized strategy (biomarker selection) vs those that did not. Overall survival was not analyzed owing to insufficient data. A total of 346 studies published in the designated 3-year time period were included in the analysis. Multivariable analysis (meta-regression and weighted multiple regression models) demonstrated that the personalized approach independently correlated with a significantly higher median RR (30.6% [95% CI, 25.0%-36.9%] vs 4.9% [95% CI, 4.2%-5.7%]; P < .001) and a longer median PFS (5.7 [95% CI, 2.6-13.8] vs 2.95 [95% CI, 2.3-3.7] months; P < .001). Targeted therapy arms that used a biomarker-based selection strategy (n = 57 trials) were associated with statistically improved RR compared with targeted therapy arms (n = 177 arms) that did not (31.1% [95% CI, 25.4%-37.4%] vs 5.1% [95% CI, 4.3%-6.0%]; P < .001). Nonpersonalized targeted arms had outcomes comparable with those that tested a cytotoxic agent (median RR, 5.1% [95% CI, 4.3%-6.0%] vs 4.7% [95% CI, 3.6%-6.2%]; P = .63; respectively; median PFS, 3.3 [95% CI, 2.6-4.0] months vs 2.5 [95% CI, 2.0-3.7] months; P = .22). Personalized arms using a "genomic (DNA) biomarker" had higher median RR than those using a "protein biomarker" (42.0% [95% CI, 33.7%-50.9%] vs 22.4% [95% CI, 15.6%-30.9%]; P = .001). The median treatment-related mortality was not statistically different for arms that used a personalized strategy vs not (1.89% [95% CI, 1.36%-2.61%] vs 2.27% [95% CI, 1.97%-2.62%]; P = .31). In this meta-analysis, most phase 1 trials of targeted agents did not use a biomarker-based selection strategy. However, use of a biomarker-based approach was associated with significantly improved outcomes (RR and PFS). Response rates were significantly higher with genomic vs protein biomarkers. Studies that used targeted agents without a biomarker had negligible response rates.

Risk of incremental toxicities and associated costs of new anticancer drugs: a meta-analysis.

There are increasing reports of rare but serious toxicities caused by new anticancer drugs, and there are costs associated with their management. We identified anticancer drugs approved by the U.S. Food and Drug Administration from 2000 to 2011 and pivotal trials supporting their registration. Twelve frequent grade 3 to 4 adverse event (AEs) were weighted and pooled in a meta-analysis. Estimates of incremental drug prices and incremental costs for management of AEs were calculated according to type of new agent based on target specificity. We identified 41 studies comprising 27,539 patients and evaluating 19 experimental drugs. Agents directed against a specific molecular target on cancer cells had a lower incidence of grade 3 to 4 toxicities compared with controls (median risk ratio [RR], 0.67; P = .22), whereas less-specific targeted agents, including angiogenesis inhibitors (median RR, 3.39; P < .001) and chemotherapeutic agents (median RR, 1.73; P < .001), were more toxic. Risk was increased regardless of whether the control arm contained active treatment (RR, 2.11; P < .001) or not (RR, 3.02; P < .001). Median incremental drug price for experimental agents was $6,000 per patient per month. Median cost of managing toxicity was low compared with drug costs but higher than controls for treatment with less-specific targeted agents and chemotherapies. Newly approved anticancer drugs are associated with increased toxicity, except for agents with a specific molecular target on cancer cells. Management of toxicity leads to a small increase in overall cost of treatment. Frequency of toxicity and associated costs are likely higher in less-selected patients treated in general oncologic practice. Development of biomarker-driven agents should be encouraged.

Risk of Incremental Toxicities and Associated Costs of New Anticancer Drugs: a Meta-Analysis

ABSTRACT Aim: To quantify the frequency of serious toxicities caused by new anticancer drugs, and incremental costs associated with their management, according to the type of anticancer drugs. Methods: We identified anticancer drugs approved by the United States Food and Drug Administration during 2000-2011, and pivotal trials supporting their registration. Twelve frequent, grade III-IV adverse event (AEs) were weighted and pooled in a meta-analysis to obtain both relative and absolute excess risk in experimental groups compared to the control groups of the registration trials. Estimates of incremental drug prices, and costs for management of AEs were calculated according to types of new agents based on (1) target-specificity of the new drugs and (2) activity of comparator groups used in the pivotal trials. Costs were derived from pharmacy red book and literature, adjusted for inflation to reflect 2014 dollar value. Results: We identified 41 studies (27,500 patients) involving 19 experimental drugs. Agents directed against a specific molecular target on cancer cells (i.e., predictive biomarker) had a lower incidence of grade III-IV toxicities than the controls (median relative risk [RR] = 0.7, p = 0.2), whereas less-specific targeted agents, including angiogenesis inhibitors (median RR = 3.4, p Conclusions: Newly approved anticancer drugs are associated with increased toxicity and management of toxicity leads to an increase in overall cost of treatment except when agents with a specific molecular target on cancer cells are used. Adopting policy to encourage development of biomarker-driven drugs is encouraged. Frequency of toxicity and associated costs are likely higher in less selected patients treated in general oncologic practice. Disclosure: All authors have declared no conflicts of interest.

Long and short term QT-RR interval co-variability in type 2 diabetes.

This paper examines the long and short term co-variability of QT and RR intervals for diabetic patients to explore if the QT-RR co-variability could yield a noble index for the stratification of clinical severity of the disease. Twenty four hour Holter ECG recordings are made for 19 type 2 diabetic (T2DM) patients and 25 normal subjects. RR and QT intervals are extracted from ECG signals sampled at 200 Hz and their co-variability has been examined. To see the long term QT-RR co-variability, correlation coefficients and mutual entropies between QT and RR intervals have been estimated for original beat to beat intervals and smoothed median interval series of successive one hundred beats. Mutual entropy for both beat-to-beat and smoothed median QT and RR interval series showed statistically significant differences between T2DM and control subjects whereas differences in correlation coefficients showed significant difference only for beat-to-beat intervals. Mutual entropy between both beat-to-beat and smoothed median QT-RR interval sequences showed the equally well separation between T2DM patients and control subjects: Mutual entropy and serial correlation coefficients for beat to beat intervals are respectively 1.42 ± 0.33 (bits), 0.856 ± 0.055 for control and 0.752 ± 0.23 (bits), 0.756 ± 0.10 for T2DM patients. Scatter diagram between RR and QT intervals show apparent nonlinearity which validate this result. Short term QT-RR co-variability has been examined by spline smoothed QTc series and sporadic changes have been observed for the control subjects whereas no such changes are found in diabetic patients. This new phenomenon could be a mean for the clinical characterization of diabetes.

Association between initial prescribed minute ventilation and post-resuscitation partial pressure of arterial carbon dioxide in patients with post-cardiac arrest syndrome

BackgroundPost-cardiac arrest hypocapnia/hypercapnia have been associated with poor neurological outcome. However, the impact of arterial carbon dioxide (CO2) derangements during the immediate post-resuscitation period following cardiac arrest remains uncertain. We sought to test the correlation between prescribed minute ventilation and post-resuscitation partial pressure of CO2 (PaCO2), and to test the association between early PaCO2 and neurological outcome.MethodsWe retrospectively analyzed a prospectively compiled single-center cardiac arrest registry. We included adult (age ≥ 18 years) patients who experienced a non-traumatic cardiac arrest and required mechanical ventilation. We analyzed initial post-resuscitation ventilator settings and initial arterial blood gas analysis (ABG) after initiation of post-resuscitation ventilator settings. We calculated prescribed minute ventilation:MVmL/kg/min=tidalvolumeTV/idealbodyweightIBWxrespiratoryrateRRfor each patient. We then used Pearson’s correlation to test the correlations between prescribed MV and PaCO2. We also determined whether patients had normocapnia (PaCO2 between 30 and 50 mmHg) on initial ABG and tested the association between normocapnia and good neurological function (Cerebral Performance Category 1 or 2) at hospital discharge using logistic regression analyses.ResultsSeventy-five patients were included. The majority of patients were in-hospital arrests (85%). Pulseless electrical activity/asystole was the initial rhythm in 75% of patients. The median (IQR) TV, RR, and MV were 7 (7 to 8) mL/kg, 14 (14 to 16) breaths/minute, and 106 (91 to 125) mL/kg/min, respectively. Hypocapnia, normocapnia, and hypercapnia were found in 15%, 62%, and 23% of patients, respectively. Good neurological function occurred in 32% of all patients, and 18%, 43%, and 12% of patients with hypocapnia, normocapnia, and hypercapnia respectively. We found prescribed MV had only a weak correlation with initial PaCO2, R = -0.40 (P < 0.001). Normocapnia was associated with good neurological function, odds ratio 4.44 (95% CI 1.33 to 14.85).ConclusionsWe found initial prescribed MV had only a weak correlation with subsequent PaCO2 and that early Normocapnia was associated with good neurological outcome. These data provide rationale for future research to determine the impact of PaCO2 management during mechanical ventilation in post-cardiac arrest patients.

Long-Term Effect of Continuing Sports Activity in Competitive Athletes With Frequent Ventricular Premature Complexes and Apparently Normal Heart

The long-term outcome of athletes with frequent ventricular premature complexes (VPCs) and apparently normal heart has not been fully clarified. To evaluate the clinical and prognostic significance of VPCs and the influence of continuing sports activity during follow-up, we studied 120 healthy athletes (96 men; median age 16 years) in whom frequent VPCs (>100 VPCs/24 hours) were discovered by chance during preparticipation screening. All athletes were followed up for a median of 84 months. During follow-up, 96 underwent serial 24-hour Holter recording and 62 underwent serial echocardiography. The median number of VPCs/24 hours on basal Holter was 3,760. During follow-up, 81 athletes continued sports activity, whereas 39 did not. No athlete died or developed overt heart disease. The median number of VPCs/24 hours decreased in both athletes who continued sports activity and those who did not (from 3,805 to 1,124, p <0.0001 and from 5,787 to 1,298, p <0.0001, respectively). During follow-up, left ventricular ejection fraction slightly decreased to <55% in 9 of 62 athletes who, in respect to the remaining 53, had more VPCs/24 hours both in the basal state (12,000 vs 3,880) and during follow-up (10,702 vs 1,368), and a longer follow-up (95 vs 36 months). In conclusion, (1) frequent VPCs in athletes without heart disease have a long-term benign prognostic significance, (2) sporting activity does not modify this benign outcome, (3) during follow-up, the burden of VPCs decreases whether or not subjects continue sports activity, and (4) in 14.5% of athletes, ejection fraction slightly decreases over time.

A new tool for QT interval analysis during sleep in healthy and obstructive sleep apnea subjects: a study on women

By monitoring the Q wave/T wave (QT) interval computed from electrocardiography (ECG) signals during sleep, it is possible to create a link between the ventricular repolarization and sleep stages. In this study, we aimed to find a robust and simple approach to automatically determine the fiducials on each 30-s sleep epoch, such as the Q, R, and T-end points, on long sleep ECG recordings in order to statistically analyze the effect of obstructive sleep apnea (OSA) and sleep stages on QT intervals. This is a retrospective study in which the ECG data extracted from the polysomnography recordings of 7 healthy women and 5 women with OSA, acquired in a sleep laboratory, were used. Experts annotated the sleep stage and OSA presence information for each 30-s epoch. Later, we visually selected epochs with clean signals from a total of 8324 epochs. On the selected epochs, we determined R peaks on each heartbeat, and by aligning each ECG portion corresponding to a heartbeat using those R points, we computed an average ECG signal for each epoch. On the average ECG signals, we developed a novel approach to find the Q and T-end points. With the help of Bazzet's formula, we computed the corrected QT interval (QTc) values for each epoch using the QT and the median RR interval. Finally, we analyzed the QTc values for the different sleep stages and healthy or OSA groups. We employed statistical approaches such as the Mann--Whitney U test, Freidman's test, and the Wilcoxon signed-rank test. As a result of this study, we found that OSA has a prolongation effect on the total duration of the ventricular depolarization and repolarization. We also observed that the QTc values computed in each sleep stage were significantly different between the healthy and OSA groups. Additionally, we discovered that within the healthy group, the QTc values were distinctive in the different sleep stages.

Interventions to improve the use of systematic reviews in decision-making by health system managers, policy makers and clinicians

Systematic reviews provide a transparent and robust summary of existing research. However, health system managers, national and local policy makers and healthcare professionals can face several obstacles when attempting to utilise this evidence. These include constraints operating within the health system, dealing with a large volume of research evidence and difficulties in adapting evidence from systematic reviews so that it is locally relevant. In an attempt to increase the use of systematic review evidence in decision-making a number of interventions have been developed. These include summaries of systematic review evidence that are designed to improve the accessibility of the findings of systematic reviews (often referred to as information products) and changes to organisational structures, such as employing specialist groups to synthesise the evidence to inform local decision-making. To identify and assess the effects of information products based on the findings of systematic review evidence and organisational supports and processes designed to support the uptake of systematic review evidence by health system managers, policy makers and healthcare professionals. We searched The Cochrane Library, MEDLINE, EMBASE, CINAHL, Web of Science, and Health Economic Evaluations Database. We also handsearched two journals (Implementation Science and Evidence and Policy), Cochrane Colloquium abstracts, websites of key organisations and reference lists of studies considered for inclusion. Searches were run from 1992 to March 2011 on all databases, an update search to March 2012 was run on MEDLINE only. Randomised controlled trials (RCTs), interrupted time-series (ITS) and controlled before-after studies (CBA) of interventions designed to aid the use of systematic reviews in healthcare decision-making were considered. Two review authors independently extracted the data and assessed the study quality. We extracted the median value across similar outcomes for each study and reported the range of values for each median value. We calculated the median of the two middlemost values if an even number of outcomes were reported. We included eight studies evaluating the effectiveness of different interventions designed to support the uptake of systematic review evidence. The overall quality of the evidence was very low to moderate.Two cluster RCTs evaluated the effectiveness of multifaceted interventions, which contained access to systematic reviews relevant to reproductive health, to change obstetric care; the high baseline performance in some of the key clinical indicators limited the findings of these studies. There were no statistically significant effects on clinical practice for all but one of the clinical indicators in selected obstetric units in Thailand (median effect size 4.2%, range -11.2% to 18.2%) and none in Mexico (median effect size 3.5%, range 0.1% to 19.0%). In the second cluster RCT there were no statistically significant differences in selected obstetric units in the UK (median effect RR 0.92; range RR 0.57 to RR 1.10). One RCT evaluated the perceived understanding and ease of use of summary of findings tables in Cochrane Reviews. The median effect of the differences in responses for the acceptability of including summary of findings tables in Cochrane Reviews versus not including them was 16%, range 1% to 28%. One RCT evaluated the effect of an analgesic league table, derived from systematic review evidence, and there was no statistically significant effect on self-reported pain. Only one RCT evaluated an organisational intervention (which included a knowledge broker, access to a repository of systematic reviews and provision of tailored messages), and reported no statistically significant difference in evidence informed programme planning.Three interrupted time series studies evaluated the dissemination of printed bulletins based on evidence from systematic reviews. A statistically significant reduction in the rates of surgery for glue ear in children under 10 years (mean annual decline of -10.1%; 95% CI -7.9 to -12.3) and in children under 15 years (quarterly reduction -0.044; 95% CI -0.080 to -0.011) was reported. The distribution to general practitioners of a bulletin on the treatment of depression was associated with a statistically significant lower prescribing rate each quarter than that predicted by the rates of prescribing observed before the distribution of the bulletin (8.2%; P = 0.005). Mass mailing a printed bulletin which summarises systematic review evidence may improve evidence-based practice when there is a single clear message, if the change is relatively simple to accomplish, and there is a growing awareness by users of the evidence that a change in practice is required. If the intention is to develop awareness and knowledge of systematic review evidence, and the skills for implementing this evidence, a multifaceted intervention that addresses each of these aims may be required, though there is insufficient evidence to support this approach.

Effectiveness of community- and workplace-based interventions to manage musculoskeletal-related sickness absence and job loss: a systematic review

ObjectivesTo assess the effectiveness of community- and workplace-based interventions to reduce sickness absence and job loss in workers with musculoskeletal disorders (MSDs).MethodsWe identified relevant randomised controlled trials (RCTs) and cohort...

Systematic comparative analysis of efficacy of EGFR tyrosine kinase inhibitors (TKIs) in the frontline versus salvage therapy of NSCLC.

7602 Background: Randomized trials showed equivalent overall survival outcome for patients treated with EGFR TKIs or standard cytotoxic chemotherapy in the frontline setting. The best sequence of administration of these agents has become uncertain. We conducted a systematic review of published clinical trials of EGFR TKI in the frontline setting versus later settings. Methods: Published trials of erlotinib or gefitinib therapy for NSCLC were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library). All prospective studies of single agent therapy with erlotinib or gefitinib were independently identified by two authors for inclusion in the analysis. Demographic data, treatment response, progression-free and overall survival (PFS; OS) were extracted for systematic analysis using Comprehensive Meta Analysis software (Version 2.0). Outcome data were pooled and reported as weighted means of median age, RR, PFS and OS. We compared the weighted means between 1st line and all other lines of therapy. In order to exclude the effect of patient selection bias and ethnicity, we compared within subgroups of studies with the following characteristics: randomized phase III trials (RCT), studies out of Asia (A) and studies outside Asia (N-A). Results: A total of 205 studies were reviewed and 57 studies enrolling 8,768 patients were eligible for this analysis. Weighted overall median age was 51.2 yrs (55.7 for 1st line vs. 49.1 for salvage); 55.2, 36.0 and 60.5 yrs for RCT, A and N-A populations respectively. Conclusions: Early use of EGFR TKIs in the frontline setting results in superior clinical outcome compared to delayed use in the salvage setting. However, there was no significant difference between early and delayed use in the non-Asian patient population. Supported by NIH P01 CA116676. TKO, FRK and SSR are Distinguished Cancer Scholars of the Georgia Cancer Coalition. Patient population RR (%) PFS (months) OS (months) 1st line Subsequent lines P value 1st line Subsequent lines 1st line Subsequent lines Overall 30.5 15.8 <0.0001 5.1 3.4 15.1 8.6 Asians 44.7 25.6 <0.0001 6.4 4.1 18.9 10.9 Non-Asian 10.6 10.5 0.94 3.2 2.8 18.8 10.9 RCT 47.2 9.9 <0.0001 6.8 2.2 20.5 7.0

Leadership, Job Well-Being, and Health Effects—A Systematic Review and a Meta-Analysis

The aim of this systematic literature analysis was to study the association between leadership and well-being at work and work-related health. These intermediate outcomes are supposed to predict work-related loss of productivity and disability at work. Original articles published in 1970 to 2005 were searched in MEDLINE and PsycINFO databases in a systematic manner. The main search terms were leadership, job satisfaction, well-being, sick leave, and disability pension. Out of 303 references, 93 publications were retrieved. In addition, other sources produced 69 articles. The strength of evidence was evaluated comprehensively. Altogether, 109 articles were thoroughly analyzed; our conclusions are based on 27 articles providing the best evidence. There was moderate evidence that leadership is associated with job well-being (risk ratio [RR] 1.40, range 1.36 to 1.57), sick leave (RR 0.73, range 0.70 to 0.89), and disability pension (RR 0.46, range 0.42 to 0.59). The evidence was weak on that leadership is associated with job satisfaction (median RR 2.23, range 1.30 to 3.51) but not with job performance (RR 1.13, range 0.55 to 1.20). There is a relative lack of well-founded prospective studies targeting the association between leadership and employee health, but the few available good studies suggest an important role of leadership on employee job satisfaction, job well-being, sickness absences, and disability pensions. The relationship between leadership and job performance remains unclear.

Lenalidomide (Len) in combination with dexamethasone (Dex) is more effective than Dex alone at first relapse and provides better outcomes when used early rather than as later salvage therapy in relapsed multiple myeloma (MM)

7600 Background: High-dose Dex remains a standard therapy for relapsed or refractory MM. Lenalidomide is a novel, oral, immunomodulatory drug (IMiD) that has activity against MM with additive effects when combined with Dex. At the interim analysis of MM-009/010, Len/Dex achieved a significant benefit over Dex, providing a longer median TTP, higher response rates, and higher CR rates. Aim: This prospective subgroup analysis was performed to determine the potential benefit of starting Len/Dex at first relapse by analyzing outcomes versus Dex among patients (pts) who had received only 1 versus &gt;1 prior line of therapy. Methods: Pts who had received 1–3 prior treatments and were not refractory to Dex were randomized to either oral lenalidomide (25 mg daily for 3 weeks every 4 weeks) plus Dex (40 mg on Days 1–4, 9–12, 17–20 every 4 weeks for 4 months, then 40 mg on Days 1–4 every cycle thereafter) or placebo plus Dex. The EBMT criteria were used for response. Randomization was stratified at entry by number of prior therapies (1 versus &gt; 1). Results: Of 692 randomized pts, 241 pts (34%) received only 1 prior therapy. Those receiving 2nd-line Len/Dex had a significantly longer median TTP (66 vs. 20 wks) and a higher RR (CR + PR); (63% vs. 26%) versus those receiving 2nd-line Dex. After a median follow-up of 12.1 mos for all pts, 2nd-line Len/Dex provided significantly improved overall survival (OS) (hazard ratio 1.85, P = 0.03) versus 2nd-line Dex. Among the 451 pts who had received &gt; 1 prior line of therapy, the median TTP (44 vs. 20 wks), RR (57% vs. 20%), and OS (hazard ratio 1.50, P = 0.03) were higher with Len/Dex vs. Dex. Response to Len/Dex was superior to that of Dex regardless of the type of prior therapy. Comparing pts who received Len/Dex as 2nd-line versus later salvage therapy, the median TTP was longer and response rates higher in pts treated in second-line. Conclusions: Len/Dex provided higher response rates and improved TTP compared with Dex at first relapse and beyond. TTP and response rates were superior when Len/Dex was administered earlier at first relapse compared with its use as later salvage therapy. These data support the use of Len/Dex for pts as 2nd-line therapy for relapsed MM. [Table: see text]

Clinical Course Of Patients with Small Cell Lung Cancer As Second Primary Malignancy

Objective: To evaluate the clinical course of patients with small cell lung cancer (SCLC) as second primary malignancy. Methods: Among the 355 patients diagnosed with SCLC at Helen and Harry Gray Cancer Center of Hartford Hospital Connecticut USA between 1988 and 1998, the records of 48 patients, which had been diagnosed with other malignancies before their diagnosis of SCLC, were retrospectively reviewed. Results: Forty-eight patients (13.5%) were diagnosed with other malignancies prior to their SCLC among which 43 had documented smoking history and 93% of them (40/43) were current/ former smokers. Of the 28-second primary SCLC patients who were treated with standard method, 11 (39.3%) achieved CR, 12 (42.8%) achieved PR, and the RR was 82.1%. The median survival of the 28 treated with standard method was 11.3 months (5.1-77.7 months), while that of the rest 19 untreated patients (1 of 20 was lost to follow-up) was only 2.0 months (0.5-34.0 months). There was no significant difference in the median survival and RR between 165 treated first primary SCLC (13.5 months and 77.6% respectively) and 28 treated secondary primary SCLC (11.3 months and 82.1% respectively) (P>0.05). The patients who had prostate cancer were older and subjected to less treatments than those with skin cancer, so their survival was shorter than the latter (3.5 months vs. 15 months, P<0.05). Conclusion: The response and survival of the treated patients with SCLC as a second malignancy showed no difference as compared to the treated ones with SCLC only. Therefore, an active medical treatment is important to relieve symptom and prolong survival of the second primary SCLC patients.

Acute testing of the rate-smoothed pacing algorithm for ventricular rate stabilization.

We evaluated the capability of a new pacemaker-based rate-smoothing algorithm (RSA) to reduce the irregular ventricular response of AF. RSA prevents sudden decreases in rate using a modified physiological band and flywheel feature. Twelve patients (51 +/- 21 years) with hemodynamically tolerated AF of 4 months to 20 years duration were studied. Atrial and ventricular leads were connected to the external pacemaker device in the electrophysiology laboratory. Consecutive RR intervals during AF were measured at baseline and after ventricular pacing with RSA ON. Ventricular pacing with the rate smoothing algorithm reduced maximum RR intervals (1,207 +/- 299 vs 855 +/- 148 ms, P = 0.0005), with no significant change in the minimum RR interval (401 +/- 55 vs 393 +/- 74 ms, P = 0.292). A small shortening of the mean RR interval (634 +/- 153 vs 594 +/- 135 ms, P = 0.007) was seen with no change in the median RR interval (609 +/- 153 vs 595 +/- 143 ms, P = 0.388). There was a 43% reduction in RR standard deviation (145 +/- 52 vs 82 +/- 28, P = 0.0005), 49% reduction in mean absolute RR interval difference (MAD) (152 +/- 64 vs 77 +/- 34, P = 0.0005) and MAD/mean RR ratio (0.23 +/- 0.05 vs 0.13 +/- 0.04, P = 0.0005). We conclude that rate-smoothed pacing effectively reduces RR variability of AF in the acute setting.

Abnormal autonomic control of the cardiovascular system in syndrome X

Anomalies of autonomic control of the coronary circulation may play a role in the development of syndrome X (angina pectoris, ischemia-appearing results on exercise test, and normal coronary arteriograms). Twenty-six patients with syndrome X and 20 healthy sex- and age-matched control subjects were studied by means of analysis of heart rate variability during 24-hour Hotter monitoring. Spectral and nonspectral parameters of heart rate variability were investigated. Mean heart rate was similar in patients with syndrome X and in control subjects. Patients with syndrome X had significantly lower standard deviation of all normal RR intervals, a lower percentage of adjacent normal RR intervals >50 ms in difference (126.4 ± 22 vs 149 ± 43 ms, p <0.05; 6.3 ± 4 vs 11.2 ± 7%, p <0.05; respectively), and a trend toward lower values of time-domain parameters. Lower values of total power and low frequency were also observed in patients with syndrome X (1273 ± 693 vs 1790 ± 989 ms 2, p <0.05; 406 ± 176 vs 729 ± 455 ms 2, p <0.01, respectively). An inverse correlation between heart rate and measures of heart rate variability was found in syndrome X but not in control subjects. High- and low-frequency power showed a similar circadian pattern in syndrome X patients and control subjects. Patients and control subjects were then allocated into 2 groups according to the median RR duration: syndrome X1 and control 1 with high mean heart rate, and syndrome X2 and control 2 with low mean heart rate. The syndrome X1 group had a significantly lower standard deviation of all normal RR intervals, root-mean-square difference of successive RR intervals, percentage of adjacent normal RR intervals >50 ms different, and high and low frequency than did the syndrome X2, control 1, and control 2 groups. In conclusion, patients with syndrome X have a sympathovagal balance shifted toward sympathetic predominance that is more evident in those with an increased mean heart rate. This dysfunction appears to persist throughout the 24 hours and may indicate heterogeneity in autonomic function in syndrome X.

Prognostic value of electrophysiology testing in asymptomatic patients with Wolff-Parkinson-White pattern.

The prognostic value of electrophysiology testing was studied in 75 asymptomatic patients with the Wolff-Parkinson-White electrocardiographic pattern. All patients underwent electrophysiology testing at entry to the study and were followed up annually for a total of 348 patient-years (median, 4.3 years). There were 44 male and 31 female patients, and age at enrollment ranged from 7 to 77 years (mean, 34 +/- 14 years). The median effective refractory period of the accessory pathway was 293 msec (interquartile range, 280-310 msec), and the median shortest RR interval between preexcited beats during atrial fibrillation (SRR) [corrected] was 274 msec (240-320 msec). Twenty-three patients had an SRR of 250 msec or less and eight patients had a median shortest SRR interval of 200 msec or less. Twelve patients had inducible sustained reciprocating tachycardia, 10 patients had inducible nonsustained reciprocating tachycardia, and 23 patients had inducible sustained atrial fibrillation. Twenty patients (27%) lacked retrograde conduction over the accessory pathway. No patient died suddenly during a median follow-up of 4.3 years. Six patients (8%) became symptomatic with documented supraventricular tachycardia, of whom two underwent operative ablation of their accessory pathways. No patient with absent retrograde accessory pathway conduction during the electrophysiology study became symptomatic. Inducible sustained or nonsustained reciprocating tachycardia at electrophysiology study did not predict the development of subsequent symptomatic supraventricular tachycardia. Nine patients lost preexcitation during follow-up. Age at enrollment (relative risk/decade, 1.4; 95% confidence interval, 1.0-1.8) and anterograde accessory pathway refractory period (relative risk, 1.06/10 msec; 95% confidence interval, 1.0-1.12) were independent predictors of loss of preexcitation.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of atrial fibrillation and atrioventricular conduction (including Wolff-Parkinson-White syndrome) in sudden death

A short refractory period of the accessory pathway is considered a major threat for sudden death in patients with Wolff-Parkinson-White syndrome and atrial fibrillation. RR interval and QRS signal analysis together with signal analysis of a bipolar high right atrial electrogram were obtained in six patients with Wolff-Parkinson-White syndrome and either induced or spontaneous atrial fibrillation. A record of a sufficiently long episode of atrioventricular (AV) conduction by way of the bypass tract that could be used for satisfactory RR interval sequence and QRS analysis was obtained from only one patient. The results were compared with those of a representative patient with atrial fibrillation and normal AV nodal-His conduction. In a patient with Wolff-Parkinson-White syndrome, atrial fibrillation and AV conduction by way of the bypass tract may exhibit high ventricular rates (median RR intervals of about 300 ms) and long/short RR interval ratios of just over 1 (RR intervals not exceeding 400 ms). The right atrial electrogram showed a noiselike excitation pattern. This study suggests that rather than a short refractory period of the bypass tract, it is lack of concealed conduction, responsible for the presence of long RR intervals, that allows the ventricles to reach very high ventricular rates and at times to fibrillate. The normal AV nodal-His system seems to protect the heart against high ventricular rates and ventricular fibrillation during atrial fibrillation by its relatively long refractory period and capacity to induce long RR intervals by means of concealed conduction.