Evolving or Immutable - Phase I Solid Tumor Trials in the Era of Precision Oncology.

Purpose: In the era of precision oncology (PO), systemic therapies for patients (pts) with solid tumors have shifted from chemotherapy (CT) to targeted therapy (TT) and immunotherapy (IO). This systematic survey describes features of trials enrolling between 2010-2020, focusing on inclusion criteria, type of dose escalation scheme (DES) utilized, and use of expansion cohorts (ECs). Methods: A literature search identified phase I studies in adults with solid tumors published January 1, 2000 - December 31, 2020 from 12 journals. We included only studies enrolling between 2010-2020 to better capture the PO era. Two reviewers abstracted data; a third established concordance. Results: Of 10,744 studies, 10,195 were non-topical or enrolled prior to 2010; 437 studies were included. The most common drug classes were TT (47.6%), IO (22%), and CT (6.9%). In studies which reported race, patients were predominantly white (61.7%) or Asian (25.7%), followed by black (6.5%) or other (6.1%). Heterogeneity was observed in the reporting and specification of study inclusion criteria. Only 40.1% of studies utilized ECs, and among the studies which used ECS, 46.6% were defined by genomic selection. Rule-based DES were used in 89% of trials; a 3+3 design was used in 80.5%. Of all drugs tested, 37.5% advanced to phase II, while 10.3% garnered regulatory licensure (for an indication tested in phase I). Conclusion: In the era of PO, TT and IO have emerged as the most studied agents in phase I trials. Rule-based DES, which are more relevant for escalating CT, are still chiefly utilized.

Evolving or immutable - phase I solid tumor trials in the era of precision oncology.

In the era of precision oncology (PO), systemic therapies for patients (pts) with solid tumors have shifted from chemotherapy (CT) to targeted therapy (TT) and immunotherapy (IO). This systematic survey describes features of trials enrolling between 2010 and 2020, focusing on inclusion criteria, type of dose escalation scheme (DES) utilized, and use of expansion cohorts (ECs). A literature search identified phase I studies in adults with solid tumors published January 1, 2000- December 31, 2020 from 12 journals. We included only studies enrolling between 2010 and 2020 to better capture the PO era. Two reviewers abstracted data; a third established concordance. Of 10,744 studies, 10,195 were non-topical or enrolled prior to 2010; 437 studies were included. The most common drug classes were TT (47.6%), IO (22%), and CT (6.9%). In studies which reported race, patients were predominantly white (61.7%) or Asian (25.7%), followed by black (6.5%) or other (6.1%). Heterogeneity was observed in the reporting and specification of study inclusion criteria. Only 40.1% of studies utilized ECs, and among the studies which used ECS, 46.6% were defined by genomic selection. Rule-based DES were used in 89% of trials; a 3+3 design was used in 80.5%. Of all drugs tested, 37.5% advanced to phase II, while 10.3% garnered regulatory licensure (for an indication tested in phase I). In the era of PO, TT and IO have emerged as the most studied agents in phase I trials. Rule-based DES, which are more relevant for escalating CT, are still chiefly utilized.

CXCR2 expression during melanoma tumorigenesis controls transcriptional programs that facilitate tumor growth.

BACKGROUND: Though the CXCR2 chemokine receptor is known to play a key role in cancer growth and response to therapy, a direct link between expression of CXCR2 in tumor progenitor cells during induction of tumorigenesis has not been established. METHODS: To characterize the role of CXCR2 during melanoma tumorigenesis, we generated tamoxifen-inducible tyrosinase-promoter driven BrafV600E/Pten-/-/Cxcr2-/- and NRasQ61R/INK4a-/-/Cxcr2-/- melanoma models. In addition, the effects of a CXCR1/CXCR2 antagonist, SX-682, on melanoma tumorigenesis were evaluated in BrafV600E/Pten-/- and NRasQ61R/INK4a-/- mice and in melanoma cell lines. Potential mechanisms by which Cxcr2 affects melanoma tumorigenesis in these murine models were explored using RNAseq, mMCP-counter, ChIPseq, and qRT-PCR; flow cytometry, and reverse phosphoprotein analysis (RPPA). RESULTS: Genetic loss of Cxcr2 or pharmacological inhibition of CXCR1/CXCR2 during melanoma tumor induction resulted in key changes in gene expression that reduced tumor incidence/growth and increased anti-tumor immunity. Interestingly, after Cxcr2 ablation, Tfcp2l1, a key tumor suppressive transcription factor, was the only gene significantly induced with a log2 fold-change greater than 2 in these three different melanoma models. CONCLUSIONS: Here, we provide novel mechanistic insight revealing how loss of Cxcr2 expression/activity in melanoma tumor progenitor cells results in reduced tumor burden and creation of an anti-tumor immune microenvironment. This mechanism entails an increase in expression of the tumor suppressive transcription factor, Tfcp2l1, along with alteration in the expression of genes involved in growth regulation, tumor suppression, stemness, differentiation, and immune modulation. These gene expression changes are coincident with reduction in the activation of key growth regulatory pathways, including AKT and mTOR.

Dual Src and EGFR inhibition in combination with gemcitabine in advanced pancreatic cancer: phase I results : A phase I clinical trial.

Pancreatic adenocarcinoma remains a major therapeutic challenge, as the poor (<8%) 5-year survival rate has not improved over the last three decades. Our previous preclinical data showed cooperative attenuation of pancreatic tumor growth when dasatinib (Src inhibitor) was added to erlotinib (EGFR inhibitor) and gemcitabine. Thus, this study was designed to determine the maximum-tolerated dose of the triplet combination. Standard 3 + 3 dose escalation was used, starting with daily oral doses of 70 mg dasatinib and 100 mg erlotinib with gemcitabine on days 1, 8, and 15 (800 mg/m2) of a 28-day cycle (L0). Nineteen patients were enrolled, yet 18 evaluable for dose-limiting toxicities (DLTs). One DLT observed at L0, however dasatinib was reduced to 50 mg (L-1) given side effects observed in the first two patients. At L-1, a DLT occurred in 1/6 patients and dose was re-escalated to L0, where zero DLTs reported in next four patients. Dasatinib was escalated to 100 mg (L1) where 1/6 patients experienced a DLT. Although L1 was tolerable, dose escalation was stopped as investigators felt L1 was within the optimal therapeutic window. Most frequent toxicities were anemia (89%), elevated aspartate aminotransferase (79%), fatigue (79%), nausea (79%), elevated alanine aminotransferase (74%), lymphopenia (74%), leukopenia (74%), neutropenia (63%), and thrombocytopenia (63%), most Grade 1/2. Stable disease as best response was observed in 69% (9/13). Median progression-free and overall survival was 3.6 and 8 months, respectively. Dasatinib, erlotinib, and gemcitabine was safe with manageable side effects, and with encouraging preliminary clinical activity in advanced pancreatic cancer.

On the Use of DSC-MRI for Measuring Vascular Permeability.

BACKGROUND AND PURPOSE: Contrast agent extravasation has been shown to confound brain tumor perfusion measurements with DSC-MR imaging, necessitating the use of correction techniques (eg, Weisskoff, Bjornerud). Leakage parameters (K2 and K(a)) postulated to reflect vessel permeability can be extracted from these correction methods; however, the biophysical interpretation of these parameters and their relationship to commonly used MR imaging measures of vascular permeability (eg, contrast agent volume transfer constant, [K(trans)]) remain unclear. Given that vascular density, as assessed by blood volume, and vascular permeability, as reflected by K(trans) (and potentially K2 or K(a)), report on unique and clinically informative vascular characteristics, there is a compelling interest to simultaneously assess these features. MATERIALS AND METHODS: We acquired multiecho DSC-MR imaging data, allowing the simultaneous computation and voxelwise comparison of single- and dual-echo derived measures of K2, K(a) and K(trans) in patients with glioma. This acquisition enabled the investigation of competing T1 and T2* leakage effects and TE dependency on these parameters. RESULTS: K2 and K(a) displayed nonsignificant (P = .150 and P = .060, respectively) voxelwise linear correlations with K(trans), while a significant (P < .001) inverse relationship was observed between K2 and Ka (coefficient of determination [r(2)] = 0.466-0.984). Significantly different (P < .005) mean estimates were found between voxels exhibiting predominately T1 and T2* effects for K2 and K(a). K(trans), however, was observed to be similar between these voxels (0.109 versus 0.092 minutes(-1)). Significant differences (P < .001) in extracellular-extravascular volume fraction (v(e)) (0.285 versus 0.167) were also observed between cohorts. Additionally, K2 and K(a) were found to have a significant quadratic relationship (P = .031 and P = .005, respectively) with v(e). CONCLUSIONS: Estimates of vascular permeability in brain tumors may be simultaneously acquired from multiple-echo DSC-MR imaging via K(trans); however, caution should be used in assuming a similar relationship for K2 and K(a).

Adjuvant chemoradiation therapy for pancreatic adenocarcinoma: who really benefits?

BACKGROUND: The role of adjuvant chemoradiation therapy (CRT) in pancreatic cancer remains controversial. The primary aim of this study was to determine if CRT improved survival in patients with resected pancreatic cancer in a large, multiinstitutional cohort of patients. STUDY DESIGN: Patients undergoing resection for pancreatic adenocarcinoma from seven academic medical institutions were included. Exclusion criteria included patients with T4 or M1 disease, R2 resection margin, preoperative therapy, chemotherapy alone, or if adjuvant therapy status was unknown. RESULTS: There were 747 patients included in the initial evaluation. Primary analysis was performed between patients that had surgery alone (n=374) and those receiving adjuvant CRT (n=299). Median followup time was 12.2 months and 14.5 months for survivors. Median overall survival for patients receiving adjuvant CRT was significantly longer than for those undergoing operation alone (20.0 months versus 14.5 months, p=0.001). On subset and multivariate analysis, adjuvant CRT demonstrated a significant survival advantage only among patients who had lymph node (LN)-positive disease (hazard ratio 0.477, 95% CI 0.357 to 0.638) and not for LN-negative patients (hazard ratio 0.810, 95% CI 0.556 to 1.181). Disease-free survival in patients with LN-negative disease who received adjuvant CRT was significantly worse than in patients who had surgery alone (14.5 months versus 18.6 months, p=0.034). CONCLUSIONS: This large multiinstitutional study emphasizes the importance of analyzing subsets of patients with pancreas adenocarcinoma who have LN metastasis. Benefit of adjuvant CRT is seen only in patients with LN-positive disease, regardless of resection margin status. CRT in patients with LN-negative disease may contribute to reduced disease-free survival.

Interaction index and different methods for determining drug interaction in combination therapy.

Studying and understanding the joint effect of combined treatments is important in pharmacology and in the development of combination therapies. The Loewe additivity model is one of the best general reference models for evaluating drug interactions. Based on this model, synergy occurs when the interaction index is less than one, while antagonism occurs when interaction index is greater than one. We expanded the meaning of the interaction index, and propose a procedure to calculate the interaction index and its associated confidence interval under the assumption that the dose-effect curve for a single agent follows Chou and Talalay's median effect equation. In addition, we review four response surface models based on the Loewe additivity model using a single parameter to determine drug interactions. We describe each of these models in the context of Loewe additivity model and discuss their relative advantages and disadvantages. We also provide S-PLUS/R code for each approach to facilitate the implementation of these commonly used methods.

COX-2 involvement in breast cancer metastasis to bone.

Cyclooxygenase-2 (COX-2) is expressed in 40% of human invasive breast cancers. Bone is the predominant site of metastasis in case of breast cancer. We investigated the role of COX-2 in a suitable mouse model of breast cancer metastasis to bone using the whole-body luciferase imaging of cancer cells. We provide several lines of evidence that COX-2 produced in breast cancer cells is important for bone metastasis in this model including (1) COX-2 transfection enhanced the bone metastasis of MDA-435S cells and (2) breast cancer cells isolated and cultured from the bone metastases produced significantly more prostaglandin E(2) (an important mediator of COX-2) than the parental injected cell populations of breast cancer cells. Next, we found that a COX-2 inhibitor, MF-tricyclic, inhibited bone metastasis caused by a bone-seeking clone both in prevention regimen (in which case mice started receiving MF-tricyclic 1 week before the injection of cancer cells) and in treatment regimen (in which case mice received MF-tricyclic after the development of bone metastasis). These studies indicate that COX-2 produced in breast cancer cells may be vital to the development of osteolytic bone metastases in patients with breast cancer, and that COX-2 inhibitors may be useful in halting this process.

Study of the media's potential influence on prospective research participants' understanding of and motivations for participation in a high-profile phase I trial.

PURPOSE: To describe prospective participants' initial source of information about, understanding of, and motivation to participate in a phase I clinical trial of the antiangiogenesis agent human recombinant endostatin. PATIENTS AND METHODS: We surveyed 100 of 130 persons referred to the endostatin trial between October 1999 and November 2000 and analyzed media coverage of the agent from 1997 to 2000. RESULTS: Forty-seven percent of survey respondents first heard about the trial from media reports. Fifty-one percent of these subsequently contacted their physicians. Thirty-three percent of respondents correctly understood the purpose of the trial. Seventy-nine respondents were interviewed before they met trial investigators to discuss the trial. Of these, those who first heard about endostatin from the media were five times more likely to understand correctly the trial's purpose than those who first heard from other sources. Seventy-four percent (70 of 95) of respondents cited hope for personal benefit as the main reason for their willingness to enroll. Those who first heard about endostatin from the media were no more motivated by hope of personal benefit (77%) than those who first heard from other sources (71%) (P =.46). Ninety-nine percent of all respondents cited "joining the study gives me hope" as a contributing factor in their decision making about the trial. CONCLUSION: Media coverage prompted prospective participants to contact their physicians but did not seem to hinder understanding nor could it be shown to heighten their hope for personal benefit.

Nonfunctioning islet cell carcinoma of the pancreas: survival results in a contemporary series of 163 patients.

BACKGROUND: The natural history of nonfunctioning islet cell carcinoma of the pancreas is poorly defined. We therefore reviewed our institutional experience during a period of 12 years to define more clearly the natural history of this disease as a basis for individual therapeutic recommendations. METHODS: The records of all patients who had histologically or cytologically confirmed nonfunctioning islet cell carcinoma of the pancreas were retrospectively reviewed. Patients were grouped by extent of disease at diagnosis and by initial treatment. Survival distributions were estimated by Kaplan-Meier analysis. RESULTS: One hundred sixty-three patients with nonfunctioning islet cell carcinoma of the pancreas were identified. The overall median survival duration was 3.2 years. The median survival was 7.1 years in patients with localized disease who underwent a potentially curative resection and 5.2 years in those with locally advanced, unresectable, nonmetastatic disease (P = .04). Patients with metastatic disease that could not be resected had a median survival of 2.1 years. CONCLUSIONS: Patients with completely resected localized disease had a long median survival. Patients with nonmetastatic but unresectable locally advanced disease also had a surprisingly long median survival; major treatment-related morbidity may be hard to justify in this subgroup. The short median survival in patients with metastatic disease suggests that the frequent practice of observation in this patient subgroup needs to be reexamined and that continued investigation of regional and systemic therapies with novel agents is warranted.

Reversible impairment of left and right ventricular systolic and diastolic function during short-lasting atrial fibrillation in patients with an implantable atrial defibrillator: a tissue Doppler imaging study.

AF with a fast ventricular response may cause ventricular mechanical impairment, though whether short-lasting AF with satisfactory rate control may affect ventricular function is unknown. This study investigated if prompt cardioversion by an implantable atrial defibrillator (IAD) may prevent left (LV) and right ventricular (RV) systolic and diastolic dysfunction. Ten patients (mean age 61 +/- 9 years, 8 men) with paroxysmal AF without structural heart disease who received an IAD were studied by echocardiography and tissue Doppler imaging (TDI) for both ventricles. Measurements were made during baseline sinus rhythm and at 1-minute, 20-minute, 4-hour, and 1-week postcardioversion of an episode of spontaneous AF. The occurrence of AF and the ventricular rate were monitored at 2-hour intervals by the device. There were 50 episodes of AF with a mean duration of 8.8 +/- 8.9 days (2 hours to 37 days). There was no difference in M-mode measured LV fractional shortening and ejection fraction between baseline sinus rhythm and after cardioversion. However, the TDI derived myocardial systolic velocity (TDI-S) was significantly lower at 1-minute postcardioversion and was normalized at 1 week in both LVs (baseline: 5.7 +/- 1.8, 1 minute: 4.2 +/- 1.0, 20 minutes: 4.3 +/- 0.9, 4 hours: 4.8 +/- 1.0, 1 week: 5.5 +/- 1.8 cm/s; P < 0.005 when comparing 1 minute and 20 minutes to baseline; P < 0.05 when comparing 4 hour to baseline) and RV (baseline: 10.4 +/- 2.1, 1 minute: 7.8 +/- 1.4, 20 minutes: 8.1 +/- 1.2, 4 hours: 9.2 +/- 1.5, 1 week: 10.0 +/- 2.0 cm/s; P < 0.005 when comparing 1 minute, 20 minutes, and 4 hours to baseline). For diastolic function, transmitral Doppler study showed a decrease in early filling velocity at 1 minute (P < 0.05) and 20 minutes (P < 0.005), which was normalized at 4 hours. There was no change in transtricuspid Doppler flow. However, TDI derived myocardial early filling velocity was decreased in the LV (baseline: 6.0 +/- 2.8, 1 minute: 5.4 +/- 2.3, 20 minutes: 5.4 +/- 2.1, 4 hours: 6.1 +/- 2.2, 1 week: 5.8 +/- 1.7 cm/s; P < 0.05 when comparing 1 minute and 20 minutes to baseline) and RV (baseline: 8.9 +/- 3.5, 1 minute: 7.9 +/- 3.3, 20 minutes: 8.1 +/- 3.3, 4 hours: 8.5 +/- 2.9, 1 week: 8.4 +/- 3.5 cm/s; P < 0.05 when comparing 1 minute to baseline). AF of a longer duration (> 48 hours) resulted in a more depressed TDI-S in LV (> 48 hours: 4.2 +/- 1.0, < or = 48 hours: 5.3 +/- 1.3 cm/s; P < 0.01). Shocks in sinus rhythm did not affect any of the above echocardiographic parameters. Therefore, despite adequate rate control, short-lasting AF impairs systolic and diastolic function in both ventricles, which improves gradually after cardioversion. Early restoration of sinus rhythm by an IAD minimizes ventricular dysfunction. TDI is a sensitive tool to assess early systolic and diastolic dysfunction.

Effect of verapamil on prevention of atrial fibrillation in patients implanted with an implantable atrial defibrillator.

BACKGROUND: The role of verapamil in the prevention of atrial fibrillation (AF) in patients with recurrent AF is unknown. HYPOTHESIS: The aim of this study was to evaluate the effect of verapamil on the prevention of AF in patients implanted with an implantable atrial defibrillator (IAD). METHODS: The effects of verapamil (240 mg/day) on the total duration of AF, number of AF recurrences, and number of cardioversions were prospectively evaluated in a randomized, crossover fashion over an 8-week period in 11 patients (9 men, 2 women; mean age: 60 +/- 6 years) implanted with an IAD. RESULTS: Implantable atrial defibrillators successfully converted 13 of 14 (93%) spontaneous episodes of AF. There was no significant difference in the efficacy of cardioversion (86 vs. 100%, p = 0.8), the total duration of AF (173 +/- 198 vs. 270 +/- 241 h, p = 0.5), the number of AF episodes (8.5 +/- 9.0 vs. 9.3 +/- 10.2, p = 0.3), and the number of cardioversions (1.7 +/- 2.4 vs. 1.8 +/- 2.1 p = 0.7) with or without treatment with verapamil. CONCLUSIONS: The results of the present study suggest that treatment with verapamil has no significant effect on the prevention of AF in patients treated with an LAD.

Determining the amount of physical activity needed for long-term weight control.

OBJECTIVE: To evaluate prospectively the influence of habitual physical activity on body weight of men and women and to develop a model that defines the role of physical activity on longitudinal weight change. DESIGN AND SETTING: Occupational cohort study conducted for a mean of 5.5 y. SUBJECTS: A total of 496 (341 male and 155 female) NASA/Johnson Space Center employees who completed the 3 month education component of the employee health-related fitness program and remained involved for a minimum of 2 y. MEASUREMENTS: Body weights were measured at baseline (T1) and follow-up (T2), and habitual physical activity was obtained from the mean of multiple ratings of the 11-point (0-10) NASA Activity Scale (NAS) recorded quarterly between T1 and T2. Other measures included age, gender, VO(2 max) obtained from maximal treadmill testing, body mass index (BMI), and body fat percentage. RESULTS: Multiple regression demonstrated that mean NAS, T1 weight, aging and gender all influence long-term T2 weight. T1 age was significant for the men only. Independently, each increase in mean NAS significantly (P<0.01) reduced T2 weight in men (b=-0.91 kg; 95% CI:-1.4 to-0.42 kg) and women (b=-2.14 kg; 95% CI:-2.93 to-1.35 kg). Mean NAS had a greater effect on T2 weight as T1 weight increased, and the relationship was dose-dependent. CONCLUSIONS: Habitual physical activity is a significant source of long-term weight change. The use of self-reported activity level is helpful in predicting long-term weight changes and may be used by health care professionals when counseling patients about the value of physical activity for weight control.

Time course of recovery of left atrial mechanical dysfunction after cardioversion of spontaneous atrial fibrillation with the implantable atrial defibrillator.

The effect of the timing of cardioversion of atrial fibrillation on left atrial mechanical function was studied in 11 patients treated with the implantable atrial defibrillator. Results of this study suggested that prompt cardioversion of spontaneous episodes of atrial fibrillation within 48 hours after onset was associated with early resolution of left atrial mechanical dysfunction seen after cardioversion.

The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy.

OBJECTIVES: We sought to assess the impact of intermittent atrial fibrillation (AF) on health-related quality of life (QoL). BACKGROUND: Intermittent AF is a common condition with little data on health-related QoL questionnaires to guide investigational therapies. METHODS: Outpatients from four centers, with documented AF (n = 152), completed validated QoL questionnaires (Medical Outcomes Study Short Form 36 [SF-36], Specific Activity, Symptom Checklist, Illness Intrusiveness and University of Toronto AF Severity Scales). Comparison groups were made up of healthy individuals (n = 47) and four cardiac control groups: published (n = 78) and created for study (n = 69) percutaneous transluminal coronary angioplasty (PTCA); published heart failure (n = 216) and published postmyocardial infarction (MI) (n = 107). RESULTS: Across all domains of the SF-36, AF patients reported substantially worse QoL than healthy controls (1.3 to 2.0 standard deviation units), with scores of 24%, 23%, 16% and 30% lower than healthy individuals on measures of physical and social functioning, mental and general health, respectively (all p < 0.001). Patients with AF were either significantly worse (p < 0.05, published controls) or as impaired (study controls) as either PTCA or post-MI patients on all domains of the SF-36 and the same as heart failure controls on SF-36 psychological subscales. Patients with AF were as impaired or worse than study PTCA controls on measures of illness intrusiveness, activity limitations and symptoms. Associations between objective disease indexes and subjective QoL measures had poor correlations and accounted for <6% of the total variability in QoL scores. CONCLUSIONS: Quality of life is as impaired in patients with intermittent AF as in patients with significant structural heart disease. Patients' perception of QoL is not dependent on the objective measures of disease severity that are usually employed.

Initial clinical experience with ambulatory use of an implantable atrial defibrillator for conversion of atrial fibrillation. Metrix Investigators.

BACKGROUND: A recent study has shown that the implantable atrial defibrillator can restore sinus rhythm in patients with recurrent atrial fibrillation when therapy was delivered under physician observation. The objective of this study was to evaluate the safety and efficacy of ambulatory use of the implantable atrial defibrillator. METHODS AND RESULTS: An atrial defibrillator was implanted in 105 patients (75 men; mean age, 59+/-12 years) with recurrent, symptomatic, drug-refractory atrial fibrillation. After successful 3-month testing, patients could transition to ambulatory delivery of shock therapy. Patients completed questionnaires regarding shock therapy discomfort and therapy satisfaction using a 10-point visual-analog scale (1 represented "not at all," 10 represented "extremely") after each treated episode of atrial fibrillation. During a mean follow-up of 11.7 months, 48 of 105 patients satisfied criteria for transition and received therapy for 275 episodes of atrial fibrillation. Overall shock therapy efficacy was 90% with 1.6+/-1.2 shocks delivered per episode (median, 1). Patients rated shock discomfort as 5.2+/-2.4 for successful therapy and 4.2+/-2.2 for unsuccessful therapy (P:>0.05). The satisfaction score was higher for successful versus unsuccessful therapy (3.4+/-3. 3 versus 8.7+/-1.3, P:<0.05). There was no ventricular proarrhythmia observed throughout the course of this study. CONCLUSIONS: Ambulatory use of an implantable atrial defibrillator can safely and successfully convert most episodes of atrial fibrillation, often requiring only a single shock. Successful therapy is associated with high satisfaction and only moderate discomfort.

Decreasing the number of leads required for an implantable atrial defibrillator: use of a new 2-lead system.

BACKGROUND: The purpose of this study was to evaluate the use of a new 2-lead system for detection of atrial fibrillation (AF) and atrial defibrillation. METHODS: In 16 patients undergoing elective cardioversion of AF, a 2-lead system was compared with the conventional 3-lead system in a randomized trial. The new 2-lead system consisted of a catheter with a distal bipolar right ventricular electrode pair and a proximal right atrial shock electrode coil and a separate decapolar defibrillation catheter in the coronary sinus. For the 3-lead system, an additional decapolar catheter was placed in the right atrium. AF and sinus rhythm signal amplitude detection and atrial defibrillation threshold (ADFT) were compared in each patient with both systems. RESULTS: Successful defibrillation was obtained in all patients. ADFT for the 2-lead system was significantly higher compared with the 3-lead system (370 +/- 112 vs 316 +/- 100 V, P < .05; 9.3 +/- 5.2 vs 6.8 +/- 4.2 J, P < .05). In contrast, there was an increase in impedance for the 3-lead system (77 +/- 16 ohms vs 68 +/- 13 ohms; P < .05). AF had a lower signal amplitude compared with sinus rhythm for both systems (P < .05), and the 2-lead system had a lower signal amplitude compared with the 3-lead system for both rhythms (P < .05). CONCLUSION: The use of a 2-lead system with this configuration is not superior to the 3-lead system regarding AF signal amplitude detection and ADFT. Further study is needed with implantable-quality leads in place of the temporary catheters used in this study.

Atrial pacing for suppression of early reinitiation of atrial fibrillation after successful internal cardioversion.

AIMS: To evaluate the efficacy of atrial pacing in the suppression of early reinitiation of atrial fibrillation after successful internal cardioversion. METHODS AND RESULTS: The efficacy of atrial pacing in suppressing early reinitiation of atrial fibrillation was studied in 12 of 45 (29%) patients with early reinitiation of atrial fibrillation after successful cardioversion. These patients were randomized to undergo either repeated defibrillation alone or repeated defibrillation followed by high right atrial pacing at 500 ms in a crossover fashion. In patients with persistent early reinitiation of atrial fibrillation despite atrial pacing at 500 ms and repeated defibrillation, atrial pacing at 300 ms was tested. Lastly, if early reinitiation of atrial fibrillation persisted, administration of intravenous sotalol (1.5 mg. kg(-1)) was tested. Atrial pacing at 500 ms after defibrillation prevented early reinitiation of atrial fibrillation in five of 12 (42%) patients, and was significantly more effective than repeated defibrillation (0/9 patients, 0%, P<0.05). During atrial pacing at 500 ms, the density of atrial premature depolarizations (APDs) was significantly decreased (2.4+/-2.4 APDs. min(-1)vs 16.4+/-9.8 APDs. min(-1), P<0. 05) and the coupling interval of atrial premature depolarization was significantly increased (420+/-32 ms vs 398+/-19 ms, P<0.05) as compared to no pacing. In the remaining seven (58%) patients, atrial pacing at 500 ms failed to prevent early reinitiation of atrial fibrillation, but significantly decreased the density of atrial premature depolarization (3.4+/-2.4 APDs. min(-1)vs 14.2+/-4.8 APDs. min(-1), P<0.05) and delayed the onset of early reinitiation of atrial fibrillation (33+/-17s vs 11+/-11 s, P<0.05). Atrial pacing at 300 ms decreased the coupling interval of atrial premature depolarization as compared to no pacing and during atrial pacing at 500 ms (P<0.05), but without early reinitiation of atrial fibrillation suppression. Administration of intravenous sotalol was effective in preventing early reinitiation of atrial fibrillation in five of seven (71%) patients where pacing failed to suppress early reinitiation of atrial fibrillation. CONCLUSION: The results of this study suggest that atrial pacing can be useful when combined with transvenous defibrillation in patients with early reinitiation of atrial fibrillation.