The role of immunotherapy in early-stage and metastatic NSCLC.

In the past decade we have seen new advances and thus remarkable progress in the therapeutic options for non-small cell lung cancer (NSCLC). Among cytostatic therapies with new approaches in molecularly targeted therapies, we see new developments in a wide range of applications for immunotherapies. In this review we discuss the new potential modalities for the use of immune checkpoint inhibitors (ICIs) in the frontlines, including in early-stage (perioperative) and metastatic settings. The perioperative use of ICIs in both neoadjuvant and adjuvant settings may show benefits for patients. In early-stage NSCLC (from stage IIB and above) a multimodality approach is recommended as the gold standard for the treatment. After surgical resection platinum-based adjuvant chemotherapy has been the standard of care for many years. Based on the benefit of disease-free survival, the approval of adjuvant atezolizumab and adjuvant pembrolizumab was a significant breakthrough. In the metastatic setting, the use of immune checkpoint inhibitors with chemotherapy, regardless of PD-L1 expression or ICI alone (PD-L1 expression equal to or greater than 50%) also improves overall survival and progression-free survival.

Immune-related adverse events of anti-PD-1 immune checkpoint inhibitors: a single center experience.

Objectives: Immune checkpoint inhibitors (ICIs) stimulate antitumor immune responses and, in parallel, they might trigger autoimmune and other immunopathological mechanisms eventually leading to immune-related adverse events (irAE). In our study, we assessed patients with malignancies who underwent anti-PD-1 treatment at the University of Debrecen, Clinical Center. Patients and methods: Between June 2017 and May 2021, 207 patients started ICI treatment at our university. A total of 157 patients received nivolumab and 50 were treated with pembrolizumab. We looked for factors associated with the development of irAEs. In addition to correlation studies, we performed binary logistic regression analysis to determine, which factors were associated with irAEs. We also performed Forward Likelihood Ratio (LR) analysis to determine independent prognostic factors. Results: At the time of data analysis, the mean duration of treatment was 2.03 ± 0.69 years. ROC analysis determined that 9 or more treatment cycles were associated with a significantly higher risk of irAEs. A total of 125 patients received ≥9 treatment cycles. Three times more patients were treated with nivolumab than pembrolizumab. Of the 207 patients, 66 (32%) developed irAEs. Among the 66 patients who developed irAEs, 36 patients (55%) developed one, 23 (35%) developed two, while 7 (10%) developed three irAEs in the same patient. The most common irAEs were thyroid (33 cases), dermatological (25 cases), pneumonia (14 cases) and gastrointestinal complications (13 cases). Patients who developed irAEs received significantly more treatment cycles (21.8 ± 18.7 versus 15.8 ± 17.4; p=0.002) and were younger at the start of treatment (60.7 ± 10.8 versus 63.4 ± 10.1 years; p=0.042) compared to patients without irAEs. Pembrolizumab-treated patients developed more but less severe irAEs compared to those receiving nivolumab. Conclusion: ICI treatment is very effective, however, irAEs may develop. These irAEs might be related to the number of treatment cycles and the type of treated malignancy.

A head-to-head comparison of laser vs. powered mechanical sheaths as first choice and second line extraction tools.

AIMS: During transvenous lead extraction (TLE) longer dwelling time often requires the use of powered sheaths. This study aimed to compare outcomes with the laser and powered mechanical tools. METHODS AND RESULTS: Single-centre data from consecutive patients undergoing TLE between 2012 and 2021 were retrospectively analysed. Efficacy and safety of the primary extraction tool were compared. Procedures requiring crossover between powered sheaths were also analysed. Moreover, we examined the efficacy of each level of the stepwise approach. Out of 166 patients, 142 (age 65.4 ± 13.7 years) underwent TLE requiring advanced techniques with 245 leads (dwelling time 9.4 ± 6.3 years). Laser sheaths were used in 64.9%, powered mechanical sheaths in 35.1% of the procedures as primary extraction tools. Procedural success rate was 85.5% with laser and 82.5% with mechanical sheaths (P = 0.552). Minor and major complications were observed in similar rate. Procedural mortality occurred only in the laser group in the case of three patients. Crossover was needed in 19.5% after laser and in 12.8% after mechanical extractions (P = 0.187). Among crossover procedures, only clinical success favoured the secondary mechanical arm (87.1 vs. 54.5%, aOR: 0.09, 95% CI: 0.01-0.79, P = 0.030). After step-by-step efficacy analysis, procedural success was 64.9% with the first-line extraction tool, 75.1% after crossover, 84.5% with bailout femoral snare, and 91.8% by non-emergency surgery. CONCLUSION: The efficacy and safety of laser and mechanical sheaths were similar, however in the subgroup of crossover procedures mechanical tools had better performance regarding clinical success. Device diversity seems to help improving outcomes, especially in the most complicated cases.

Is prophylactic ablation of the cavotricuspid and peri-incisional isthmus justified in patients with postoperative atrial flutter after right atriotomy?

BACKGROUND: The two most common postoperative atrial flutter (AFL) circuits after right atriotomy are the cavotricuspid isthmus (CTI) dependent and the lateral, peri-incisional. We investigated whether radiofrequency ablation (RFA) of both circuits results in more favorable long-term outcomes. METHODS: Single-center retrospective cohort study of consecutive patients who underwent RFA of AFL after open-heart surgery. The effect of surgery type and RFA strategy on AFL recurrence was evaluated. RESULTS: One hundred and forty-two patients (mean age 64.5 ± 12.7 years, 65.% male) were enrolled. Patients with right atrial (RA) flutter (n = 124) were divided into two groups based on the index RFA procedure: only one RA circuit was ablated (Group 1, n = 84, 67.7%) or both the CTI and the peri-incisional circuit ablated (Group 2, n = 40, 32.3%). The previous open-heart surgery was categorized based on the extension of the RA incision: limited (Type A) or extended (Type B) atriotomy. After a mean follow-up of 36 ± 28 months, flutter recurrence was not different among patients with limited RA atriotomy (25% vs. 22% in Groups 1A and 2A, respectively, p = 1.0). However, after type B surgery, ablation of both AFL circuits was associated with a reduced recurrence rate (63% vs. 26% in Groups 1B and 2B, respectively, p = .002). CONCLUSIONS: In patients with postoperative RA flutter after extended right atriotomy, ablation of both the CTI and the peri-incisional isthmus significantly reduces the AFL recurrence rate. Prophylactic ablation of both isthmi, even if not proven to support reentry, is reasonable in this population.

Randomized trial of intracardiac echocardiography-guided slow pathway ablation.

PURPOSE: Radiofrequency (RF) catheter ablation of the slow pathway (SP) in atrioventricular nodal reentry tachycardia (AVNRT) is highly effective; however, it may require prolonged fluoroscopy and RF time. We postulated that visualization of the SP region with intracardiac echocardiography (ICE) could decrease ablation time, minimize radiation exposure, and facilitate SP ablation compared to the standard, fluoroscopy-guided approach. METHODS: In our study, we randomized 91 patients undergoing electrophysiologic study and SP ablation for AVNRT into 2 groups: fluoroscopy-only (n = 48) or ICE-guided (n = 43) group. Crossover to ICE-guidance was allowed after 8 unsuccessful RF applications. RESULTS: Mapping plus ablation time (mean ± standard deviation: 18.8 ± 16.1 min vs 11.6 ± 15.0 min, p = 0.031), fluoroscopy time (median [interquartile range]: 4.9 [2.93-8.13] min vs. 1.8 [1.2-2.8] min, p < 0.001), and total ablation time (144 [104-196] s vs. 81 [60-159] s, p = 0.001) were significantly shorter in the ICE group. ICE-guidance was associated with reduced radiation exposure (13.2 [8.2-13.4] mGy vs. 3.7 [1.5-5.8] mGy, p < 0.001). The sum of delivered RF energy (3866 [2786-5656] Ws vs. 2283 [1694-4284] Ws, p = 0.002) and number of RF applications (8 [4.25-12.75] vs. 4 [2-7], p = 0.001) were also lower with ICE-guidance. Twelve (25%) patients crossed over to the ICE-guided group. All were treated successfully thereafter with similar number, time, and cumulative energy of RF applications compared to the ICE group. No recurrence occurred during the follow-up. CONCLUSIONS: ICE-guidance during SP ablation significantly reduces mapping and ablation time, radiation exposure, and RF delivery in comparison to fluoroscopy-only procedures. Moreover, early switching to ICE-guided ablation seems to be an optimal choice in challenging cases.

Automated procedure assessing the accuracy of HRCT-PET registration applied in functional virtual bronchoscopy.

BACKGROUND: Bronchoscopy serves as direct visualisation of the airway. Virtual bronchoscopy provides similar visual information using a non-invasive imaging procedure(s). Early and accurate image-guided diagnosis requires the possible highest performance, which might be approximated by combining anatomical and functional imaging. This communication describes an advanced functional virtual bronchoscopic (fVB) method based on the registration of PET images to high-resolution diagnostic CT images instead of low-dose CT images of lower resolution obtained from PET/CT scans. PET/CT and diagnostic CT data were collected from 22 oncological patients to develop a computer-aided high-precision fVB. Registration of segmented images was performed using elastix. RESULTS: For virtual bronchoscopy, we used an in-house developed segmentation method. The quality of low- and high-dose CT image registrations was characterised by expert's scoring the spatial distance of manually paired corresponding points and by eight voxel intensity-based (dis)similarity parameters. The distribution of (dis)similarity parameter correlating best with anatomic scoring was bootstrapped, and 95% confidence intervals were calculated separately for acceptable and insufficient registrations. We showed that mutual information (MI) of the eight investigated (dis)similarity parameters displayed the closest correlation with the anatomy-based distance metrics used to characterise the quality of image registrations. The 95% confidence intervals of the bootstrapped MI distribution were [0.15, 0.22] and [0.28, 0.37] for insufficient and acceptable registrations, respectively. In case of any new patient, a calculated MI value of registered low- and high-dose CT image pair within the [0.28, 0.37] or the [0.15, 0.22] interval would suggest acceptance or rejection, respectively, serving as an aid for the radiologist. CONCLUSION: A computer-aided solution was proposed in order to reduce reliance on radiologist's contribution for the approval of acceptable image registrations.

Effect of the replacement of tripodal 4N donors by two 2N chelators on the redox and cytotoxic activity of maltolato and deferipronato containing Co(III) complexes.

Fourteen novel CoIII ternary complexes with the general formula [Co(4N)(2O)]X2 or [Co(2N)2(2O)]X2 where 4N = tris(2-aminoethyl)amine (tren) or tris(2-pyridylmethyl)amine (tpa); 2N = 1,10-phenantroline (phen), 2,2'-bipyridine (bipy), 1,2-diaminoethane (en) or 2-(aminomethyl)pyridine (ampy) and 2O = 1,2-dimethyl-3-hydroxy-4(1H)-pyridinone (dhpH), 3-hydroxy-2-methyl-4-pyrone (maltH) or 2-ethyl-3-hydroxy-4H-pyran-4-one (etmaltH) were synthesized, characterized and their redox features explored. Molecular structure of some selected [Co(2N)2(2O)](ClO4)2 (2N = phen, bipy, en; 2O = dhp, malt) or [Co(4N)(2O)](ClO4)2 (4N = tpa; 2O = etmalt) type complexes were assessed by X-ray diffraction and showed the expected octahedral geometry. Replacement of the 4N donor ligands by two 2N donor ligands resulted in the decrease of the cathodic peak potential of the complexes indicating easier reduction and allowing therefore the tailoring of the redox properties of the complexes. Screening of selected compounds against a human derived cancer cell line, HeLa, showed that, unlike the [Co(4N)(2O)]X2 derivatives, the complexes containing 2N = bipy or phen ligands have better anticancer activity than cisplatin or carboplatin.

Characterization of a rare bla VIM-4 metallo-ß-lactamase-producing Serratia marcescens clinical isolate in Hungary.

A carbapenem-resistant S. marcescens isolate was recovered from a patient with an inflammed pacemaker inplantation pocket from a Cardiac Surgery ward in a Hungarian University Hospital. Phenotypic tests and polymerase chain reaction (PCR) confirmed a very rare gene responsible for production of a carbapenemase ( bla VIM-4 ), which was further characterized by Sanger-sequencing. The characterization of this S. marcescens strain emphasizes the ongoing emergence of novel or rare carbapenemases. Strains expressing a weak carbapenemase like this strain might go unrecognized by routine diagnostics due to low minimum inhibitory concentrations (MICs) for the bacterial strains producing such enzymes.

Is adenosine useful for the identification of atrial fibrillation triggers?

INTRODUCTION: Both isoproterenol (Iso) and adenosine (Ado) are used to induce atrial fibrillation (AF) in the electrophysiology lab. However, the utility of Ado has not been systematically established. OBJECTIVE: The purpose of this study was to compare Ado to Iso for the induction of paroxysmal AF. METHODS: Forty patients (16 women; mean age, 60 ± 12 years) with paroxysmal AF, presenting for ablation were prospectively included of whom 36 (90%) received Ado (18-36 mg) and/or Iso (3-20 µg/min incremental dose) in a randomized order (26 [72%] received both drugs). RESULTS: AF was induced with Iso in 15 of 32 (47%) and with Ado in 12 of 30 (40%) patients (P = 0.9). Iso-triggered AF started from the left pulmonary veins (PVs) in 11 of 15 (73%), from the right PVs in 3 of 15 (20%), and from the coronary sinus (CS) in 1 of 15 (7%) cases. Ado-induced AF episodes originated from the left PVs in 6 of 12 (50%), from the right atrium (RA) in 4 of 12 (33%), and from the CS in 2 of 12 (17%) cases. Altogether, Iso-induced AF was more likely initiated from the PVs (93%) compared with Ado (50%) ( P = 0.02). Ado-induced non-PV triggers were not predictive of arrhythmia recurrence after PV isolation. CONCLUSION: Ado much more frequently induces non-PV triggers, especially from the RA. The clinical significance of these foci, however, is questionable.

Primary cardiac angiosarcoma: A case report.

Cardiac angiosarcomas are the most common primary malignant cardiac tumors in adults. The diagnosis is often delayed due to nonspecific clinical symptoms at presentation. The cornerstones of diagnosis are echocardiography and the histological evaluation of the cardiac biopsy. The knowledge on the treatment is limited; the outcomes of chemotherapy, radiotherapy, complete surgical removal, and heart transplantation are controversial. We report a 38-year-old woman with a primary heart tumor which infiltrated the right atrial wall and the pericardium and caused pericardial effusion. Angiosarcoma was verified histologically. The surgical excision could not be radical, and the patient died 3 months from diagnosis.

Surgical technique and the mechanism of atrial tachycardia late after open heart surgery.

INTRODUCTION: Diverse atrial tachycardias (ATs) can develop after open heart surgery. The aim of our study was to examine the determinants of the mechanism of postoperative AT. METHODS AND RESULTS: One hundred patients with AT occurring at least 3 months after open heart surgery were studied. Patients were grouped according to the atrial incision applied at the time of surgery. During 127 electrophysiology procedures, 151 ATs were studied. Eighty-eight patients had cavotricuspid isthmus (CTI)-dependent atrial flutter (AFL), 49 patients had at least one non-CTI-dependent AFL and 11 patients had focal AT. While CTI-dependent AFL was equally prevalent across groups, the finding of a non-CTI-dependent AFL was progressively more common as more extensive atriotomy was applied (p < 0.001). Among patients who had right atrial (RA) operations, RA incisional tachycardia was the most common non-CTI-dependent circuit, while the finding of perimitral or left atrial (LA) roof-dependent AFL was associated with LA atriotomy (p = 0.002 and p = 0.041, respectively). After adjustment for possible confounders, surgical group remained independent predictor of non-CTI-dependent AFLs (p < 0.001). No predictor was identified for focal AT, which originated from typical predilection sites and in 36% from the vicinity of surgical scar. Radiofrequency ablation was highly effective for all ATs, but the recurrence rate of AFL and atrial fibrillation was high at 22% and 27%, respectively, during 19 ± 15 months of follow-up. CONCLUSION: While CTI-dependent AFL is the most common AT late after open heart surgery, atypical AFL becomes progressively more common with more extensive atriotomy. Right atrial incisional tachycardia is the dominant non-CTI-dependent AFL after opening of the RA, while a perimitral or roof-dependent LA circuit can be expected after LA operations.

Randomized trial of intracardiac echocardiography during cavotricuspid isthmus ablation.

UNLABELLED: Randomized Trial of ICE During CTI Ablation. INTRODUCTION: Despite a high success rate, radio-frequency ablation (RFA) of the cavotricuspid isthmus (CTI) can be unusually challenging in some cases. We postulated that visualization of the CTI with intracardiac echocardiography (ICE) could maximize the success rate, decrease the procedure and ablation time, and minimize the radiation exposure. METHODS AND RESULTS: In our prospective, randomized study, we included 102 patients scheduled for CTI ablation. We randomized patients in 2 groups: guided only by fluoroscopy (n = 52) or ICE-guided (n =50) group. Procedure time, fluoroscopy time, and the time spent for RFA were significantly shorter, radiation exposure (dose-area product-DAP) and the sum of delivered radio frequency energy were significantly lower in the ICE-group (68.06 ± 15.09 minutes vs 105.94 ± 36.51 minutes, P < 0.001, 5.54 ± 3.77 minutes vs 18.63 ± 10.60 minutes, P <0.001, 482.80 ± 534.12 seconds vs 779.76 ± 620.82 seconds, P = 0.001 and 397.62 ± 380.81 cGycm(2) vs 1,312.92 ± 1,129.28 cGycm(2) , P < 0.001, 10,866.84 ± 6,930.84 Ws vs 16,393.56 ± 13,995.78 Ws, P = 0.048, respectively). Seven patients (13%) from the fluoroscopy-only group crossed over to ICE-guidance because of prolonged unsuccessful RFA and were all treated successfully. Four vascular complications and 2 recurrences were equally distributed between the 2 groups. CONCLUSIONS: ICE-guided ablation of the CTI significantly shortens the procedure and fluoroscopy time, markedly decreases radiation exposure, and time spent for ablation in comparison with fluoroscopy-only procedures. At the same time, visualization with ICE allowed successful ablation in challenging cases. (J Cardiovasc Electrophysiol, Vol. 23, pp. 996-1000, September 2012).

Ventricular location of a part of the right atrial isthmus after tricuspid valve replacement for Ebstein's anomaly: a challenge for atrial flutter ablation.

We report the case of a patient with atrial flutter late after tricuspid valve replacement for Ebstein's anomaly. Computed tomographic angiography revealed that coronary sinus ostium and part of the right atrial isthmus were located on the ventricular side of the valve ring due to the specific surgical approach in this condition. Based on the results of electroanatomic mapping and entrainment, the arrhythmia was found to be cavotricuspid isthmus dependent clockwise atrial flutter. Completion of the isthmus line required ablation lesions across the artificial valve. When these were delivered the arrhythmia terminated and isthmus block was achieved. Due to arrhythmia recurrence a redo procedure was performed which demonstrated conduction recovery in the ventricular part of the cavotricuspid isthmus. Intracardiac ultrasound-guided ablation successfully eliminated conduction across the isthmus with subsequent freedom from arrhythmia on follow up.

[Wenckebach AV block, as part of vasovagal syncope]. / Vasovagalis syncope talaján kialakuló átmeneti pitvar-kamrai Wenckebach-blokk.

Vasovagal syncope or common faint is the most frequent form of syncopes. With regard to the different involvement of the efferent mechanisms, several forms of the neurally mediated syncope syndromes are recognized. The authors present a case of mixed type vasovagal syncope, diagnosed by tilt table testing. The efferent mechanisms of syncope included Wenckebach type atrioventricular block due to increased vagal tone, and sympathetic withdrawal, reflected by sudden drop in the blood pressure. The significance and interrelationship of these factors are discussed.