Selective atrial vagal denervation guided by spectral mapping to treat advanced atrioventricular block.

AIMS: Asymptomatic nocturnal long ventricular pauses are usually detected accidentally and it has been suggested that they may lead to sudden death. Identification of predisposing factors could prevent cardiovascular events. METHODS AND RESULTS: We report the case of a patient with frequent asymptomatic nocturnal ventricular pauses of 3-11 s, characteristic of a vagally mediated atrioventricular (AV) block. Echocardiography, treadmill test, thyroid function test levels, and polysomnogram were normal. In an attempt to reduce the risk, it was decided that an atrial vagal denervation induced by radiofrequency (RF) ablation (cardioneuroablation) could be useful. Spectral mapping was used to localize endocardial vagal innervation in the right and left aspects of the inter-atrial septum, responsible for the sinus node and AV node modulation, and RF pulses were applied in those sites only. After finishing the procedure, significant changes were observed in the heart rate (66-90 b.p.m.), atrial-His interval (115-74 ms), Wenckebach cycle length (820-570 ms), and sinus node recovery time (1100-760 ms). Follow-up Holter recording demonstrated that the number of ventricular pauses had reduced from 438 to 0. Heart rate and time domain characteristics were compatible with vagal denervation. CONCLUSION: Ablation of the endocardial vagal innervation sites seems to be safe and efficient in reducing the frequency and the length of the ventricular pauses. It was possible by identifying certain spectral components of the atrial electrogram, resulting in a conservative approach.

Selenoprotein and antioxidant genes and the risk of high-grade prostate cancer and prostate cancer recurrence.

BACKGROUND: Observational studies suggest an inverse association between selenium and risk of prostate cancer. However, randomized controlled trials of selenium supplementation have reported conflicting results. Thus, we examined plasma selenium and selenium-related genes in relation to risk of high-grade prostate cancer and prostate cancer recurrence among men initially diagnosed with non-metastatic disease. METHODS: We measured plasma selenium and genotyped 73 single nucleotide polymorphisms in TXNRD1, TXNRD2, GPX1, GPX3, GPX4, SEP15, SEPP1, SELENBP1, OGG1, and CAT among 568 men with non-metastatic prostate cancer who underwent radical prostatectomy. We examined associations between plasma selenium, genotypes, and risk of high-grade prostate cancer (Gleason grade ≥8 or 7 with primary score ≥4; n = 111) using logistic regression, and risk of prostate cancer recurrence (61 events; 3.8 y median follow-up) using Cox proportional hazards regression. RESULTS: Plasma selenium was not associated with risk of high-grade prostate cancer or prostate cancer recurrence. Less common alleles of rs11913319 in TXNRD2 and rs125701 in OGG1 were associated with an increased risk of high-grade prostate cancer. We observed associations between the risk of prostate cancer recurrence and multiple SNPs in TXNRD1, TXNRD2, GPX3, and SEP15. These associations were no longer statistically significant after adjustment for multiple comparisons. CONCLUSIONS: Among men with non-metastatic prostate cancer, there is suggestive evidence that genetic variation in selenoproteins and related antioxidant enzymes may be associated with risk of high-grade disease at diagnosis and prostate cancer recurrence.

Physical activity and prostate gene expression in men with low-risk prostate cancer.

PURPOSE: Vigorous physical activity after diagnosis of localized prostate cancer may reduce the risk of disease progression and prostate cancer-specific mortality. The molecular mechanisms by which physical activity may exert protective effects in the prostate remain unknown. METHODS: We examined the associations between self-reported physical activity and gene expression patterns in morphologically normal prostate tissue of 71 men with low-risk prostate cancer on active surveillance. Differential gene expression, gene set, and pathway analyses were conducted comparing dichotomous groups defined by type, intensity, and amount of physical activity reported. RESULTS: Cell cycling and DNA repair pathways were up-regulated in men who participated in ≥ 3 h/week vigorous activity compared with men who did not. In addition, canonical pathways involved in cell signaling and metabolism, the cellular effects of sildenafil (Viagra), and the Nrf2-mediated oxidative stress response were modulated in men who reported ≥ 3 h/week of vigorous activity. Differential expression analysis at the individual gene level revealed modest differences between men who performed vigorous activity for ≥ 3 h/week and those who did not. There were no differences in prostate gene expression in comparisons with exercise groupings that did not consider both duration and intensity of activity. CONCLUSIONS: Prostate gene expression and pathway analyses revealed sets of transcripts that may be modulated in normal prostate tissue by participating in ≥ 3 h/week of vigorous activity after diagnosis of low-risk prostate cancer. These findings suggest potential biological mechanisms by which vigorous activity may reduce risk of prostate cancer progression and warrant further study and validation.

Coexistence of Wolff-Parkinson-white and Brugada syndrome: mere curiosity?

The association between Brugada syndrome (BS) and ventricular preexcitation is a rare condition, with sporadic cases already reported. We report the case of a 29-year-old man, with palpitation unrelated to physical or emotional stress. The electrocardiogram of the first visit revealed a ventricular preexcitation pattern and an end-conduction delay, with negative T wave in V1 and intraventricular conduction disturbance in V2 (atypical for BS). The typical aspect of BS occurred after introduction of propafenone for the prevention of atrioventricular tachycardia. We discuss the recognition of this rare association, the proarrhythmic effects of some drugs, treatment options, and prognosis.

Antioxidant and vitamin E transport genes and risk of high-grade prostate cancer and prostate cancer recurrence.

BACKGROUND: Observational studies suggest an inverse association between vitamin E and risk of prostate cancer, particularly aggressive tumors. However, three large randomized controlled trials have reported conflicting results. Thus, we examined circulating vitamin E and vitamin E-related genes in relation to risk of high-grade prostate cancer and prostate cancer recurrence among men initially diagnosed with clinically organ-confined disease. METHODS: We measured circulating α- and γ-tocopherol and genotyped 30 SNPs in SOD1, SOD2, SOD3, TTPA, and SEC14L2 among 573 men with organ-confined prostate cancer who underwent radical prostatectomy. We examined associations between circulating vitamin E, genotypes, and risk of high-grade prostate cancer (Gleason grade ≥ 8 or 7 with primary score ≥ 4; n = 117) using logistic regression, and risk of recurrence (56 events; 3.7 years median follow-up) using Cox proportional hazards regression. RESULTS: Circulating γ-tocopherol was associated with an increased risk of high-grade prostate cancer (Q4 v. Q1 odds ratio [OR] = 1.87; 95% confidence intervals [CI]: 0.97-3.58; P trend =0.02). The less common allele in SOD3 rs699473 was associated with an increased risk of high-grade disease (T > C: OR = 1.40, 95% CI: 1.04-1.89). Two independent SNPs in SOD1 were inversely associated with prostate cancer recurrence in additive models (rs17884057 hazard ratio [HR] = 0.49, 95%CI: 0.25-0.96; rs9967983 HR = 0.62, 95% CI: 0.40-0.95). CONCLUSIONS: Among men with clinically organ-confined prostate cancer, genetic variation in SOD may be associated with risk of high-grade disease at diagnosis and disease recurrence. Circulating γ-tocopherol levels may also be associated with an increased risk of high-grade disease at diagnosis.

Experimental evaluation of impact-resistant gloves using surrogate hands.

Injuries to the hand and fingers with varying degrees of severity are widespread in industries such as mining and oil and gas production. This study presents the results of tests carried out to measure the impact performance for commonly used impact-resistant gloves (metacarpal gloves). Sets of surrogate hands made out of a 3D-printed skeletal structure and soft tissues represented by synthetic gel were manufactured and subjected to controlled impact tests. The calibration and validation of the surrogates were based on impact response data reported previously for cadaveric specimens. Calibrated surrogate hand specimens were tested to assess the impact protection of typical metacarpal gloves. Each type of metacarpal glove provided different levels of protection measured by the decrease in the peak impact reaction force and the fractures detected after the impacts. Results indicated that surrogate specimens suffered fractures in 77% and 33% of the impacts for unprotected and protected hands, respectively.

Simulation of low-energy impacts on the human hand for prediction of peak reaction forces and bone fracture.

Hands of workers in extractive and heavy-duty industries are susceptible to suffering injuries of varying severity. Improved safety procedures and new technologies for production and maintenance tasks have contributed to reducing the severity of injuries. However, manual tasks with high-risk factors can still lead to hand injuries. Hand bone fractures and dislocations can be caused by relatively small objects impacting a region of the hand at velocities in the range of 1.3 to 1.6 m per second. This impact can produce significant functional, physical, and psychological consequences in those affected and result in high costs derived from medical care. This study presents the results of a finite element simulation study conducted to reproduce impacts with energies in the range of 7 to 10 Joules of an object on the dorsal region of the hand. Simulation results are compared to previous experimental results obtained from controlled impact tests performed using cadaveric hand specimens. The vertical peak reaction force (PRF) as a function of the impact position was used as a primary outcome for comparisons. Simulation results for all impact positions were within the standard deviation measured experimentally, with differences in the PRF values in the range of -5.3% to 4.9%. Bone stress analyses at the position of impacts showed the locations where the maximum principal stress exceeded the bone strength, as well as the variability in the correspondence between the stress distribution predicted by the FE models and the fracture rate distribution observed experimentally.

Isolation and genomic analysis of circulating tumor cells from castration resistant metastatic prostate cancer.

BACKGROUND: The number of circulating tumor cells (CTCs) in metastatic prostate cancer patients provides prognostic and predictive information. However, it is the molecular characterization of CTCs that offers insight into the biology of these tumor cells in the context of personalized treatment. METHODS: We developed a novel approach to isolate CTCs away from hematopoietic cells with high purity, enabling genomic analysis of these cells. The isolation protocol involves immunomagnetic enrichment followed by fluorescence activated cell sorting (IE/FACS). To evaluate the feasibility of isolation of CTCs by IE/FACS and downstream genomic profiling, we conducted a pilot study in patients with metastatic castration resistant prostate cancer (CRPC). Twenty (20) sequential CRPC patients were assayed using CellSearch™. Twelve (12) patients positive for CTCs were subjected to immunomagnetic enrichment and fluorescence activated cell sorting (IE/FACS) to isolate CTCs. Genomic DNA of CTCs was subjected to whole genome amplification (WGA) followed by gene copy number analysis via array comparative genomic hybridization (aCGH). RESULTS: CTCs from nine (9) patients successfully profiled were observed to have multiple copy number aberrations including those previously reported in primary prostate tumors such as gains in 8q and losses in 8p. High-level copy number gains at the androgen receptor (AR) locus were observed in 7 (78%) cases. Comparison of genomic profiles between CTCs and archival primary tumors from the same patients revealed common lineage. However, high-level copy number gains in the AR locus were observed in CTCs, but not in the matched archival primary tumors. CONCLUSIONS: We developed a new approach to isolate prostate CTCs without significant leukocyte admixture, and to subject them to genome-wide copy number analysis. Our assay may be utilized to explore genomic events involved in cancer progression, e.g. development of castration resistance and to monitor therapeutic efficacy of targeted therapies in clinical trials in a relatively non-invasive manner.

Mechanical Characterization of Synthetic Gels for Creation of Surrogate Hands Subjected to Low-Velocity Impacts.

The development of human body simulators that can be used as surrogates for testing protective devices and measures requires selecting synthetic materials with mechanical properties closely representative of the human tissues under consideration. For impact tests, gelatinous materials are often used to represent the soft tissues as a whole without distinguishing layers such as skin, fat, or muscles. This research focuses on the mechanical characterization of medical-grade synthetic gels that can be implemented to represent the soft tissues of the hand. Six grades of commercially available gels are selected for quasi-static hardness and firmness tests as well as for controlled low-velocity impact tests, which are not routinely conducted by gel manufacturers and require additional considerations such as energy level and specimen sizes relevant to the specific application. Specimens subject to impacts represent the hand thicknesses at the fingers, knuckles, and mid-metacarpal regions. Two impact test configurations are considered: one with the gel specimens including a solid insert representing a bone and one without this insert. The impact behavior of the candidate gels is evaluated by the coefficient of restitution, the energy loss percentage, and the peak reaction force at the time of impact. The resulting values are compared with similar indicators reported for experiments with cadaveric hands. Relatively softer gels, characterized by Shore OOO hardness in the range of 32.6 ± 0.9 to 34.4 ± 2.0, closely matched the impact behavior of cadaveric specimens. These results show that softer gels would be the most suitable gels to represent soft tissues in the creation of surrogate hands that can be used for extensive impact testing, thus, minimizing the need for cadaveric specimens.

Nutritional supplements, COX-2 and IGF-1 expression in men on active surveillance for prostate cancer.

BACKGROUND: Nutritional factors are associated with reduced risk of prostate cancer progression, yet mechanisms remain unclear. We examined the effects of lycopene and fish oil supplements versus placebo on the normal prostate microenvironment, among men pursuing active surveillance for low-burden prostate cancer. We hypothesized that lycopene or fish oil supplements would down-regulate insulin-like growth factor-1 (IGF-1) and cyclooxygenase 2 (COX-2) gene expression, respectively, reflecting putative proliferation (IGF-1) and inflammatory (COX-2) pathways relevant to carcinogenesis. METHODS: We conducted a 3-month randomized, double-blinded, clinical trial comparing prostate tissue gene expression profiles (assessed by qRT-PCR) among men with favorable-risk prostate cancer receiving either 30 mg/day lycopene, 3 g/day fish oil (including 1,098 mg eicosapentaenoic and 549 mg docosahexaenoic fatty acids) or placebo. RESULTS: Among 69 men (22 assigned to lycopene, 21 to fish, and 26 to placebo), there was no difference in the change from baseline to the 3 months in IGF-1 expression level between the placebo and lycopene arms (p = 0.93) nor in COX-2 expression between the placebo and fish arms (p = 0.99). CONCLUSION: Compared to placebo, 3-month intervention with lycopene or fish oil did not significantly change IGF-1 and COX-2 gene expression in the normal prostate microenvironment in men with low-burden prostate cancer. Further analysis of global gene expression profiles may shed light on the bioactivity and relevance of these nutrients in prostate cancer.

Spectral characteristics of atrial electrograms in sinus rhythm correlates with sites of ganglionated plexuses in patients with paroxysmal atrial fibrillation.

AIMS: To verify whether spectral components of atrial electrograms (AE) during sinus rhythm (SR) correlate with cardiac ganglionated plexus (GP) sites. METHODS AND RESULTS: Thirteen patients undergoing atrial fibrillation (AF) ablation were prospectively enrolled. Prior to radio frequency application, endocardial AE were recorded with a sequential point-by-point approach. Electrical stimuli were delivered at 20 Hz, amplitude 100 V, and pulse width of 4 ms. A vagal response was defined as a high-frequency stimulation (HFS) evoked atrioventricular block or a prolongation of RR interval. Spectral analysis was performed on single AE during SR, sampling rate of 1000 Hz, Hanning window. Overall, 1488 SR electrograms were analysed from 186 different left atrium sites, 129 of them corresponding to negative vagal response sites, and 57 to positive response sites. The electrogram duration and the number of deflections were similar in positive and negative response sites. Spectral power density of sites with vagal response was lower between 26 and 83 Hz and higher between 107 and 200 Hz compared with negative response sites. The area between 120 and 170 Hz normalized to the total spectrum area was tested as a diagnostic parameter. Receiver operating characteristic curve analysis demonstrated that an area 120-170/area(total) value >0.14 identified vagal sites with 70.9% sensitivity and 72.1% specificity. CONCLUSION: Spectral analysis of AE during SR in sites that correspond to the anatomical location of the GP is feasible and may be a simpler method of mapping the cardiac autonomic nervous system, compared with the HFS technique.

Experimental evaluation of protected and unprotected hands under impact loading.

Hand injuries are a significant problem in many industries with relatively high incidence rates and injury severity. Many workers are required to wear impact protective gloves to protect their hands from impact-related hazards. This research presents the results of an experimental quantification of metacarpal gloves performance subjected to controlled impacts. Thirteen cadaveric hands were used to conduct a set of controlled impact tests on protected and unprotected hands. The controlled impacts targeted the proximal interphalangeal (PIP) joints, the metacarpophalangeal (MCP) joints, and the middle section of the metacarpal bones. Two types of metacarpal gloves commonly used in mining and oil and gas operations were selected for the tests. These gloves include different material and protection configurations on the dorsal side of the hand. The performance of selected gloves was quantified using the maximum reaction force to the impact and number of bone fractures. A total of 191 impacts produced 108 fractures, from which 71% corresponded to the unprotected hands and 40% to the protected hands. Depending on the impact position and type of glove used, the effect of protection ranged from no change up to a 23% reduction in peak reaction force.

Effects of wearing of metacarpal gloves on hand dexterity, function, and perceived comfort: A pilot study.

Metacarpal gloves are commonly used in heavy-duty industries such as mining and are typically thicker and bulkier than manufacturing or assembly industrial gloves. This pilot study investigates the impact of wearing metacarpal gloves on hand dexterity, functional capabilities, and perceived comfort. Four types of commercially available metacarpal gloves were selected for evaluation in a randomized controlled trial. Evaluations included turning and placing tests, also grip, pinch, and screwdriver tests, and rating of the perceived level of effort. Dexterity test results showed that metacarpal gloves significantly reduced the ability to perform motor tasks requiring coordination compared to bare hands. Hand functions such as gripping, pinching, and forearm rotations were not significantly affected. However, the perceived level of effort needed to complete those hand functions increased as the metacarpal glove's bulkiness increased. High levels of mechanical protection typically offered by metacarpal gloves can inversely affect hand dexterity and hand exertion.

Selective vagal denervation of the sinus and atrioventricular nodes, guided by vagal reflexes induced by high frequency stimulation, to treat refractory neurally mediated syncope.

A 15-year-old female patient presented with frequent episodes of vasovagal syncope refractory to non-pharmacological and pharmacological measures. Two tilt-table tests performed before and after conventional therapy were positive and reproduced the patient's clinical symptoms. Selective vagal denervation, guided by HFS, was performed. Six radiofrequency pulses were applied on the left and right sides of the interatrial septum, abolishing vagal responses at these locations. Basal sinus node and Wenckebach cycle lengths changed significantly following ablation. A tilt test performed after denervation was negative and revealed autonomic tone modification. The patient reported significant improvement in quality of life and remained asymptomatic for 9 months after denervation. After this period, three episodes of NMS occurred during a 4-month interval and a tilt test performed 11 months after the procedure demonstrated vagal activity recovery.

Ninfoplastia o Labioplastia: Técnica quirúrgica y tratamiento de sus complicaciones / Nymphoplasty or Labioplasty: Surgical Technique and Treatment of its Complications

Se describe la técnica quirúrgica denominada ninfoplastia o labioplastia. Es la reducción del tamaño de los labios menores de la vulva hipertróficos, requerida además por razones estéticas. Se realiza una reseña de sus técnicas quirúrgicas y el detalle que nosotros realizamos en la resección, con el fin de respetar la zona clitoriana. Se señalan además las complicaciones presentadas y cómo resolverlas

The surgical technique called nymphoplasty or labiaplasty is described. It is the reduction in the size of the hypertrophic labia minora of the vulva, furthermore, required for aesthetic reasons. A review is made of their surgical techniques and the detail that we carry out in the resection, in order to respect the clitoral area. The complications presented and how to resolve them are also pointed out

Gastric hypomotility following epicardial vagal denervation ablation to treat atrial fibrillation.

We report a case of a 55-year-old man with vagal paroxysmal atrial fibrillation (AF) who was submitted to selective epicardial and endocardial atrial vagal denervation with the objective of treating AF. Radiofrequency pulses were applied on epicardial and endocardial surface of the left atrium close to right pulmonary veins (PVs) and also on epicardial surface close to left inferior PV. Following the procedure, patient presented with symptoms of gastroparesis, which was documented on CT scan and gastric emptying scintigraphy. Symptoms were transient and the patient recovered completely.

Genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer.

Detection of disseminated tumor cells (DTCs) in bone marrow is an established negative prognostic factor. We isolated small pools of (~20) EPCAM-positive DTCs from early breast cancer patients for genomic profiling. Genome-wide copy number profiles of DTC pools (n = 45) appeared less aberrant than the corresponding primary tumors (PT, n = 16). PIK3CA mutations were detected in 26% of DTC pools (n = 53), none of them were shared with matched PTs. Expression profiling of DTC pools (n = 30) confirmed the upregulation of EPCAM expression and certain oncogenes (e.g., MYC and CCNE1), as well as the absence of hematopoietic features. Two expression subtypes were observed: (1) luminal with dual epithelial-mesenchymal properties (high ESR1 and VIM/CAV1 expression), and (2) basal-like with proliferative/stem cell-like phenotype (low ESR1 and high MKI67/ALDH1A1 expression). We observed high discordance between ESR1 (40%) and ERRB2 (43%) expression in DTC pools vs. the clinical ER and HER2 status of the corresponding primary tumors, suggesting plasticity of biomarker status during dissemination to the bone marrow. Comparison of expression profiles of DTC pools with available data from circulating tumor cells (CTCs) of metastatic breast cancer patients revealed gene expression signatures in DTCs that were unique from those of CTCs. For example, ALDH1A1, CAV1, and VIM were upregulated in DTC pools relative to CTCs. Taken together, analysis of pooled DTCs revealed molecular heterogeneity, possible genetic divergence from corresponding primary tumor, and two distinct subpopulations. Validation in larger cohorts is needed to confirm the presence of these molecular subtypes and to evaluate their biological and clinical significance.

Expanded Genomic Profiling of Circulating Tumor Cells in Metastatic Breast Cancer Patients to Assess Biomarker Status and Biology Over Time (CALGB 40502 and CALGB 40503, Alliance).

Purpose: We profiled circulating tumor cells (CTCs) to study the biology of blood-borne metastasis and to monitor biomarker status in metastatic breast cancer (MBC).Methods: CTCs were isolated from 105 patients with MBC using EPCAM-based immunomagnetic enrichment and fluorescence-activated cells sorting (IE/FACS), 28 of whom had serial CTC analysis (74 samples, 2-5 time points). CTCs were subjected to microfluidic-based multiplex QPCR array of 64 cancer-related genes (n = 151) and genome-wide copy-number analysis by array comparative genomic hybridization (aCGH; n = 49).Results: Combined transcriptional and genomic profiling showed that CTCs were 26% ESR1-ERBB2-, 48% ESR1+ERBB2-, and 27% ERBB2+ Serial testing showed that ERBB2 status was more stable over time compared with ESR1 and proliferation (MKI67) status. While cell-to-cell heterogeneity was observed at the single-cell level, with increasingly stable expression in larger pools, patient-specific CTC expression "fingerprints" were also observed. CTC copy-number profiles clustered into three groups based on the extent of genomic aberrations and the presence of large chromosomal imbalances. Comparative analysis showed discordance in ESR1/ER (27%) and ERBB2/HER2 (23%) status between CTCs and matched primary tumors. CTCs in 65% of the patients were considered to have low proliferation potential. Patients who harbored CTCs with high proliferation (MKI67) status had significantly reduced progression-free survival (P = 0.0011) and overall survival (P = 0.0095) compared with patients with low proliferative CTCs.Conclusions: We demonstrate an approach for complete isolation of EPCAM-positive CTCs and downstream comprehensive transcriptional/genomic characterization to examine the biology and assess breast cancer biomarkers in these cells over time. Clin Cancer Res; 24(6); 1486-99. ©2018 AACR.

Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation.

BACKGROUND: The aim of this study was to evaluate whether selective radiofrequency (RF) catheter ablation of the atrial sites in which high-frequency stimulation induces vagal reflexes prevents paroxysmal atrial fibrillation (AF). METHODS AND RESULTS: Ten patients with episodes suggestive of vagal-induced paroxysmal AF and no heart disease were selected for percutaneous epicardial and endocardial mapping of the atria to search for sites in which high-frequency transcatheter stimulation (20 Hz,) induced vagal reflexes. A vagal response defined as AV block of > 2 seconds was elicited in 7 of 10 patients (70%) with an average of 5 +/- 2.4 (range, 2 to 9) sites per patient, and RF pulses (21.0 +/- 12.0 per patient) were applied at those sites to eliminate all evoked vagal reflexes. The 3 patients in whom evoked vagal reflexes were not obtained underwent circumferential pulmonary vein ablation with an average of 58.0 +/- 13.9 RF pulses per patient (P = 0.022). Autonomic evaluation was performed before and 48 hours and 3 months after the procedure and was consistent with vagal withdrawal in all patients. Two of the 7 patients who underwent denervation remained asymptomatic without the use of antiarrhythmic medication at a mean follow-up of 8.3 +/- 2.8 months (range, 5 to 15 months); 4 had frequent recurrences and were referred for circumferential pulmonary vein ablation; and 1 had few AF episodes without antiarrhythmic medication. The 3 patients without evoked vagal reflexes who underwent circumferential pulmonary vein ablation remained asymptomatic without antiarrhythmic medication. One patient had acute delayed gastric emptying after atrial vagal denervation. CONCLUSIONS: RF catheter ablation of selected atrial sites in which high-frequency stimulation induced vagal reflexes may prevent AF recurrences in selected patients with apparently vagal-induced paroxysmal AF.

Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC.

We explored the association between liver metastases, tumor CD8+ T-cell count, and response in patients with melanoma or lung cancer treated with the anti-PD-1 antibody, pembrolizumab. The melanoma discovery cohort was drawn from the phase I Keynote 001 trial, whereas the melanoma validation cohort was drawn from Keynote 002, 006, and EAP trials and the non-small cell lung cancer (NSCLC) cohort from Keynote 001. Liver metastasis was associated with reduced response and shortened progression-free survival [PFS; objective response rate (ORR), 30.6%; median PFS, 5.1 months] compared with patients without liver metastasis (ORR, 56.3%; median PFS, 20.1 months) P ≤ 0.0001, and confirmed in the validation cohort (P = 0.0006). The presence of liver metastasis significantly increased the likelihood of progression (OR, 1.852; P < 0.0001). In a subset of biopsied patients (n = 62), liver metastasis was associated with reduced CD8+ T-cell density at the invasive tumor margin (liver metastasis+ group, n = 547 ± 164.8; liver metastasis- group, n = 1,441 ± 250.7; P < 0.016). A reduced response rate and shortened PFS was also observed in NSCLC patients with liver metastasis [median PFS, 1.8 months; 95% confidence interval (CI), 1.4-2.0], compared with those without liver metastasis (n = 119, median PFS, 4.0 months; 95% CI, 2.1-5.1), P = 0.0094. Thus, liver metastatic patients with melanoma or NSCLC that had been treated with pembrolizumab were associated with reduced responses and PFS, and liver metastases were associated with reduced marginal CD8+ T-cell infiltration, providing a potential mechanism for this outcome. Cancer Immunol Res; 5(5); 417-24. ©2017 AACR.