The nature of localized atrial activation during atrial fibrillation was characterized in 34 patients following open heart surgery. Bipolar atrial electrograms (AEG) recorded in each patient with atrial fibrillation exhibited a myriad of sizes, shapes, polarities, amplitudes, and beat-to-beat intervals. On the basis of the AEG morphology and the nature of its baseline, we have classified the recordings into four Types. Type I was characterized by discrete AEG complexes separated by an isoelectric baseline free of perturbation, Type II by discrete AEG complexes but with perturbations of the baseline between complexes, Type III by AEGs which failed to demonstrate either discrete complexes or isoelectric intervals, and Type IV in which AEGs of Type III alternated with periods characteristic of Type I and/or Type II. In 22 patients, the AEGs were recorded a second time, and in 11 of these patients the type of atrial fibrillation changed between the first and second recording period. An atrial flutter-fibrillation pattern in the ECG was associated with a relatively ordered atrial activation pattern and a relatively slow atrial rate. Human atrial fibrillation is not an electrophysiologically homogeneous process when compared among different patients or ad seriatim in the same patient.

SUMMARY Studies were performed using bipolar atrial wire electrodes to record atrial electrograms and to pace the atria in 27 patients who developed atrial flutter after open heart surgery. Two types of atrial flutter, classic or type I atrial flutter, and type II atrial flutter, were identified. Both types of atrial flutter were characterized by uniformity of the beat-to-beat atrial cycle length, morphology, polarity, and amplitude of the recorded bipolar atrial electrogram. Both types sometimes manifested a beat-to-beat electrical alternans, which in turn was sometimes associated with an alternans in beat-to-beat cycle length. ATRIAL FLUTTER is a supraventricular arrhythmia which has long been recognized in man,' although its underlying mechanism has not been explained. Based on the ECG, it has been characterized as a regular, rapid atrial rhythm, most often with an atrial rate close to 300 beats/min, with the upper and lower limits of its range uncertain and variously stated.2-8 At our institution, at the time of open heart surgery, bipolar wire electrodes are routinely placed on the right atrial epicardium for possible diagnostic or therapeutic use in the immediate postoperative period.9-12 Since many patients develop atrial flutter spontaneously during this latter period, this was an opportunity to use these electrodes to characterize and define this rhythm better while providing patient care. Methods Twenty-seven patients who developed atrial flutter in the immediate period after open heart surgery were studied. The atrial flutter was identified initially from a standard or monitored ECG, or from bipolar atrial electrograms recorded from a pair of atrial wire electrodes placed routinely 0.5-1.0 cm apart on the epicardial surface of the superior portion of the right atrium.9 12 The atrial electrograms were used to distinguish atrial flutter from atrial fibrillation when this differentiation was not clear from the ECG recording alone.'2 After identifying atrial flutter, bipolar atrial electrograms were recorded simultaneously with ECG leads II and IIII for as long as 15 minutes with an Electronics for Medicine Model DR-12 switched beam oscilloscopic recorder. In one patient, the recordings were made using a Medical Systems Corporation Model DU-35 three-channel ECG machine and in two patients using a Hewlett-Packard Model 1151B ECG machine. Then, the atria were paced rapidly at rates up to 600 beats/min in an attempt to interrupt the atrial flutter.10 11 All data were recorded on magnetic FM tape (Honeywell Model 5600) for later playback and analysis, except in three patients. In the 24 patients in whom recordings were made using the Electronics for Medicine DR-12 machine, allECGs and atrial electrograms were recorded between a bandpass of 0

BackgroundPatients with chemotherapy refractory metastatic colorectal cancer (CRC) have a poor prognosis and limited therapeutic options. In this phase Ib/II clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) for the combination of capecitabine and ziv-aflibercept, and then we evaluated the efficacy of the combination in patients with chemotherapy refractory metastatic CRC.MethodsAll patients were required to have a Karnofsky Performance Status > 70% and adequate organ function. The phase Ib dose escalation cohort included patients with advanced solid tumors who had progressed on all standard therapies. Using a standard 3 + 3 design, we identified the MTD and RPTD for the combination. Fifty patients with metastatic CRC who had progressed on or were intolerant of a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab were then enrolled in a single-arm phase II expansion cohort, and were treated at the RPTD. Prior EGFR antibody therapy was required for subjects with RAS wildtype tumors. The primary endpoint for the expansion cohort was progression-free survival (PFS) at two months. Secondary endpoints included objective response rate (ORR) and overall survival (OS).ResultsA total of 63 patients were enrolled and evaluable for toxicity (13 dose escalation; 50 expansion). The MTD and RPTD were: capecitabine 850 mg/m2, P.O. bid, days 1–14, and ziv-aflibercept 6 mg/kg I.V., day 1, of each 21-day cycle. In the expansion cohort, 72% of patients were progression-free at two months (95% confidence interval [CI], 60–84%). Median PFS and OS were 3.9 months (95% CI, 2.3–4.5) and 7.1 months (95% CI: 5.8–10.0), respectively. Among all patients evaluable for toxicity, the most common treatment related adverse events (all grade [%]; grade ≥ 3 [%]) included palmar-plantar erythrodysesthesia (41%; 6%), hypertension (33%; 22%), and mucositis (19%; 5%). RNA was isolated from archived tumor specimens and gene expression analyses revealed no association between angiogenic biomarkers and clinical outcomes.ConclusionThe combination of capecitabine and ziv-aflibercept at the RPTD demonstrated acceptable safety and tolerability. PFS at 2 months in patients with chemotherapy refractory metastatic CRC was significantly greater than that in historical controls, indicating that this combination warrants further study.Trial registrationThis clinical trial was registered in the www.clinicaltrials.gov system as NCT01661972 on July 31, 2012.

Lessons Learned Antitumor activity was observed in the study population. Dose modifications of cabozantinib improve long‐term tolerability. Biomarkers are needed to identify patient populations most likely to benefit. Further study of cabozantinib with or without panitumumab in patients with metastatic colorectal cancer is warranted. Background The epidermal growth factor receptor (EGFR) antibody panitumumab is active in patients with RAS wild‐type (WT) metastatic colorectal cancer (mCRC), but nearly all patients experience resistance. MET amplification is a driver of panitumumab resistance. Cabozantinib is an inhibitor of multiple kinases, including vascular endothelial growth factor receptor 2 (VEGFR2) and c‐MET, and may delay or reverse anti‐EGFR resistance. Methods In this phase Ib clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of cabozantinib and panitumumab. We then treated an expansion cohort to further describe the tolerability and clinical activity of the RP2D. Eligibility included patients with KRAS WT mCRC (later amended to include only RAS WT mCRC) who had received prior treatment with a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab. Results Twenty‐five patients were enrolled and treated. The MTD/RP2D was cabozantinib 60 mg p.o. daily and panitumumab 6 mg/kg I.V. every 2 weeks. The objective response rate (ORR) was 16%. Median progression free survival (PFS) was 3.7 months (90% confidence interval [CI], 2.3–7.1). Median overall survival (OS) was 12.1 months (90% CI, 7.5–14.3). Five patients (20%) discontinued treatment due to toxicity, and 18 patients (72%) required a dose reduction of cabozantinib. Conclusion The combination of cabozantinib and panitumumab has activity. Dose reductions of cabozantinib improve tolerability.

During the second half of the 20th century, organ transplantation saved thousands of lives. This, unfortunately, also led to unforeseen consequences that need to be addressed to help extend the lives of patients who require these life-saving procedures. Secondary malignancies have been recognized as a potential consequence for decades. One of these malignancies, squamous cell carcinoma of the skin, not only appears more frequently in organ transplant recipients than the general population, but also is more aggressive in organ transplant recipients. It also shows a high propensity to nodal spread and metastasis in transplant patients. Unfortunately, there are no clear guidelines for a chemotherapy in this population, who have an increased need for alternative therapies to surgery given the high recurrence and metastasis rate. In this review, we attempt to describe the characteristics of squamous cell carcinoma of the skin in transplant recipients and discuss what chemotherapeutic options can be used to treat this aggressive malignancy.