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Purpose: The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT;NCT03122522) investigated adaptive ipilimumab discontinuation in melanoma based on early radiographic assessment. Initial findings indicated similar effectiveness compared with conventional nivolumab-ipilimumab (nivo-ipi). Exploratory biomarker analyses and final clinical results are now reported., Patients and Methods: Patients with unresectable melanoma received two doses of nivo-ipi. Radiographic assessment at Week 6 informed continuation of ipilimumab before nivolumab maintenance. The primary endpoint was overall response rate at Week 12. Plasma was assayed for circulating tumor DNA and 10 cytokines using a multiplex immunoassay. Flow cytometry of peripheral blood mononuclear cells was performed with an 11-color panel., Results: Among the treated patients, expansion of proliferating T-cell populations was observed in responders and nonresponders. Baseline IL6 levels were low in patients achieving an objective radiographic response (median 1.30 vs. 2.86 pg/mL; P = 0.025). High baseline IL6 levels were associated with short progression-free survival [PFS; HR = 1.24, 95% confidence interval (CI), 1.01-1.52; P = 0.041]. At Week 6, patients with response had lower average tumor variant allele fractions than nonresponders (median 0.000 vs. 0.019; P = 0.014). Greater increases in average variant allele fractions from baseline to Week 6 correlated with short PFS (HR = 1.11, 95% CI, 1.01-1.21; P = 0.023). Week 12 overall response rate was 47% (95% CI, 35%-59%) with a median follow-up of 34 months among survivors. Median PFS was 21 months (95% CI, 10-not reached); 76% of responses (95% CI, 64%-91%) persisted at 36 months., Conclusions: Adaptively dosed nivo-ipi responses are durable and resemble historical data for conventional nivo-ipi. Baseline IL6 and circulating tumor DNA changes during treatment warrant further study as biomarkers of nivo-ipi response., (©2024 American Association for Cancer Research.)

The feasibility and safety of same-day discharge after transvenous implantable cardioverter-defibrillator implantation is well-established. However, subcutaneous ICDs (S-ICDs) are now increasingly being implanted, and the feasibility, safety, and potential cost savings associated with same-day discharge after S-ICD placement has not been widely investigated. In a small cohort of patients (n = 24) who underwent S-ICD implantation at our institution, 54% were successfully discharged on the same day as their implant procedure. Procedure-related complications were not apparent in this sampling and the reduction in health care costs was high, suggesting this protocol has immense benefit in today's health care environment. As such, same-day discharge of S-ICD patients is appropriate to consider and should receive further attention., Competing Interests: The authors report no conflicts of interest for the published content. A poster of this study was previously presented at the Heart Rhythm Congress, Birmingham, UK in October 2019., (Copyright: © 2020 Innovations in Cardiac Rhythm Management.)

Survivin is a mitotic spindle-associated protein involved in linking mitotic spindle function to activation of apoptosis in mammalian cells. The structure of the full-length human survivin has been determined by X-ray crystallography to 2.7 A. Strikingly, the structure forms a very unusual bow tie-shaped dimer. It does not dimerize through a C-terminal coiled-coil, contrary to sequence analysis prediction. The C-terminal helices contain hydrophobic clusters with the potential for protein-protein interactions. The unusual shape and dimensions of survivin suggest it serves an adaptor function through its alpha-helical extensions.

Collagens V and XI are thought to form a core around which the major interstitial collagens, I and II, respectively, are organized during fibrillogenesis. We previously reported the presence of a heterotypic form of collagens V and XI, [alpha 1(XI)]2 alpha 2(V), in cultures of A204 rhabdomyosarcoma cells [Kleman, J.-P., Hartmann, D. J., Ramirez, F., & van der Rest, M. (1992) Eur. J. Biochem. 210, 329-335]. This collagen forms a matrix which remains highly insoluble, even when cells were cultured in the presence of beta-aminopropionitrile, an inhibitor of lysyl oxidase and thereby of "classical" collagen cross-linking. When the cells were cultured in the presence of putrescine, a competitive inhibitor of transglutaminase-catalyzed protein cross-linking, a drastic increase in collagen solubility was observed. This result indicates that a transglutaminase contributes to the covalent stabilization of the collagen matrix of these cells. A204 rhabdomyosarcoma cells express tissue transglutaminase as revealed by specific antibodies, and enzyme activity was detected in the cell layer during culture and in cell extracts. Both collagens V and XI are specific glutaminyl substrates for tissue transglutaminase in vitro, as shown by incorporation of [3H]putrescine. The highly homologous alpha 1 chains of collagens V and XI were the major targets for the cross-linking. Trypsin cleaved the [3H] label from the alpha 1 chain of collagen V, demonstrating that the cross-linking occurs in the non triple helical propeptide domains.

Unlabelled: Implantable cardioverter defibrillators (ICDs) are increasingly being implanted without the need for thoracotomy. Long-term lead performance and stability were evaluated in 150 consecutive patients in whom 1 of 3 nonthoracotomy ICD lead systems was implanted over a 3-year period from September 1990., Results: Twelve (8%) patients (7 males, 5 females) experienced 13 lead complications during a follow-up period of 12 +/- 10 months. Complications were related to intracardiac leads in 7 (4 dislodgments, 2 fractures, 1 right ventricular perforation) and patch leads in 6 (2 folding, 1 fracture, 1 erosion, and 2 hematomas) cases. Freedom from lead related complications at 1 year was 92% (95% confidence interval, 86%-95%). A significant difference in freedom from lead complications between the two most frequently implanted lead systems was observed (P = 0.02). Complication rates were similar in the initial 75 and the more recent 75 implants (P = 0.5). The median time between lead implant and detection of complications was 37 days (range 3-1,147). Complications were diagnosed before hospital discharge in only two cases. In five patients, complications were asymptomatic and in three of these, reoperation was required due to inadequate defibrillation thresholds. Reoperation was necessary in 9 of 12 patients., Conclusions: Nonthoracotomy ICD lead systems are associated with a low complication rate. Complications may or may not cause symptoms, usually occur after hospital discharge, and require reoperation. Complications are not related to a "learning curve." There is a significant difference in performance between different lead systems.

To minimize procedural and fluoroscopic times and avoid the risks of vascular injury and pneumothorax, some investigators have advocated elimination of routine placement of a coronary sinus (CS) catheter during electrophysiological procedures. We hypothesized that expedient and reproducible CS catheterization could be performed with minimal patient risk by utilizing a femoral vein approach. Fifty consecutive patients referred for radiofrequency ablative procedures underwent attempted CS catheterization using a 6-French steerable, quadripolar catheter via a femoral vein. Procedures were performed utilizing single-plane fluoroscopy without contrast angiographic aid by operators experienced in the technique. Successful catheterization was defined by the attainment, in < 15 minutes, of a stable catheter position with the distal electrode at or beyond the lateral margin of the heart. Successful catheterization of the CS was achieved in 47 (94%) patients. Selective pacing of the left atrium without patient discomfort was possible in all, eliminating the need for a right atrial pacing catheter. The median time to successful catheterization was 1.4 minutes (range 0.3-14.7). Only six patients required > 5 minutes. The median fluoroscopic time required was 1.2 minutes (range 0.3-12.7). No clinical variable was predictive of catheterization failure or time to successful catheterization. No complications were observed as a result of this technique. This prospective evaluation demonstrates that catheterization of the CS via a femoral vein approach is highly successful, expedient, and safe. The ability to selectively pace the left atrium may eliminate the requirement for a right atrial catheter.

Our results and those of others (Table I) suggest that both anatomic and electrogram (potential) approaches are highly successful in eliminating AVNRT. The use of slow-pathway potentials appears to minimize lesion delivery and to be associated with a very small likelihood of complete AV block. Approaches aimed directly at the midseptum also appear to reduce lesion delivery. It is important, however, to understand that the fast and slow AV-nodal pathways are not always confined to anterosuperior (fast) and posteroinferior (slow) locations (at least as they are determined fluoroscopically). On occasion, the slow pathway may be ablated anteriorly and the fast pathway posteriorly. Our three inadvertent successful fast-pathway ablations support these findings. We prefer to conceptualize the AV node as having three ablation zones. Ablation in the anterosuperior zone most often affects fast-pathway conduction; ablation in the posteroinferior zone most often affects slow pathway conduction; and ablation in the midseptal region predominantly affects slow-pathway conduction. Lesions applied to the midseptum do, however, appear more likely to affect inadvertently the fast (or both) pathway(s), probably because of the anatomic convergence of the posteroinferior and anterosuperior AV-nodal approaches in this region. A preliminary report by Wu et al. supports this three-zone concept. The subsequent larger series reported by this group has raised concern that midseptal approaches may be associated with too great a risk of complete AV block. On the other hand, approaches guided exclusively by potentials may be associated with much longer procedure times. Controversy exists over the acceptable end point for ablation procedures. We have not found it necessary routinely to eliminate dual-nodal conduction to maintain a low (3.2%) overall recurrence rate. Aggressive attempts to eliminate all evidence of slow-pathway conduction must be balanced against the risk of inadvertent complete AV block. In conclusion, cumulative data and our clinical experience with ablation of AVNRT suggest that it is possible to be both pragmatic and highly successful. The key components of our approach are (1) an anatomically based, systematic, time-limited search for potentials; (2) elimination of unnecessary lesions that are too atrial or too ventricular to involve the reentrant circuit; (3) a caudocephalad approach that avoids excessively anterior initial lesions, which may result in inadvertent complete AV block; and (4) avoidance of unnecessary lesions in the most inferoposterior sector, which results in patient discomfort and low clinical efficacy. This approach is safe (with minimal risk of AV block), reproducible, and efficacious.

The processing of human collagen type-V chains was studied using anti-peptide polyclonal antibodies raised against peptide sequences at the N-terminal non-triple-helical region of pro-alpha 1(V) and pro-alpha 2(V) chains. The anti-peptide polyclonal antibody raised against positions 48-57 of the N-terminal alpha 2(V) sequence recognized the mature form of the human alpha 2(V) chain extracted without any proteolytic treatment from several tissues in the presence of a mixture of protease inhibitors. It also recognized the pro-alpha 2(V) and pN-alpha 2(V) collagen chains secreted in the cell-culture media of the rhabdomyosarcoma A204 cell line. The pN-alpha 2(V) collagen chain from this cell line migrated during electrophoresis with the alpha 2(V) chain obtained from tissues. This demonstrates that the alpha 2(V) chain in tissues is incompletely processed and is present as the pN-alpha 2(V) collagen chain which lacks the C-propeptide. In comparison, an anti-peptide polyclonal antibody raised against residues at positions 284-299 of the N-terminal alpha 1(V) human sequence failed to recognize the mature form of the alpha 1(V) chain while it reacted with the pN-alpha 1(V) collagen chain form. These results suggest that the alpha 1(V) chain undergoes a processing event in the N-terminal region that involves the removal of at least the first 284 residues. Amino acid sequence analysis was performed on cyanogen-bromide-generated or trypsin-generated peptides of the two electrophoretic bands obtained for the tissue form of collagen V. The slower-migrating band corresponding to the intact alpha 1(V) chain gave, as expected, only sequences corresponding to the alpha 1(V) chain. However, the band previously considered to be the intact alpha 2(V) chain also gave sequences for the alpha 1(V) chain in addition to the alpha 2(V) chain. This result indicates the presence in tissue extracts of a further processed form of alpha 1(V) chain which migrates with the intact alpha 2(V) chain. On further analysis, we observed that the two bands of the tissue form of collagen V occurred in a 1:1 ratio whereas, after the pepsin digestion to remove non-collagenous regions, two bands were observed with an alpha 1(V)/alpha 2(V) chain ratio of 3:1. These results indicate that the alpha 1(V) chain exists in an additional stoichiometry, different from [alpha 1(V)]2 alpha 2(V).(ABSTRACT TRUNCATED AT 400 WORDS)