Durability In Patients Research Articles

Clinical and echocardiographic predictors of the anterior mitral leaflet repair failure

Anterior mitral leaflet prolapse repair is a highly effective procedure, but despite excellent operative results still has an inferior long-term durability when compared to posterior leaflet repair. We analysed mitral repair durability in 74 consecutive patients operated for anterior leaflet prolapse between 2010 and 2021. Their pre- and postoperative clinical, echocardiographic data and repair durability as well, were compared with74 randomly assigned posterior leaflet prolapse patients who underwent valve repair during the same period. While groups were of similar age, patients with anterior leaflet prolapse had an inferior preoperative status in terms of functional reserve, atrial fibrillation, operative risk, ejection fraction and had more dilated left heart chambers as well. 1, 5, and 10-year freedom from repair failure was 87.1 ± 4.6%, 79.8 ± 6.5% and 50.7 ± 12.5% in the anterior, and 98.5 ± 1.5% respectively in the posterior leaflet group. Atrial fibrilation (hazard ratio [HR]5.365; 95%; confidence interval[CI] 1.093-26.324 p = .038) and left ventricle end-systolic diameter (HR 1.160 95%; CI 1.037-1.299 p = .010) independently predicted anterior leaflet repair failure. Receiver Operating Curve analysis established left ventricle end-systolic diameter ≤42 mm as a cut-off value associated with improved anterior leaflet repair durability. Accordingly, 10-year repair durability in a subset of patients, with preserved left ventricle end-systolic diameter (≤42 mm) was 86.4 ± 7.8%. Better long-term repair durability in patients with anterior mitral leaflet prolapse and preserved sinus rhytm and left-ventricle diameters justifies early reconstructive approach.

A comprehensive nutritional support perspective in patients with COVID-19: a review

PurposeCoronavirus disease-2019 (COVID-19) is becoming a crucial health problem worldwide. Continued and high-speed mutations of this virus result in the appearance of new manifestations, making the control of this disease difficult. It has been shown that well-nourished patients have strong immune systems who mostly have short-term hospitalization compared to others. The purpose of this study is to review the major nutrients involved in the immune system reinforcement and to explain nutritional aspects during the recovery of COVID-19.Design/methodology/approachIn this review paper, the mechanistic role of nutrients in boosting the immune system and the nutritional aspects during the recovery of COVID-19 patients were discussed. Papers indexed in scientific databases were searched using antioxidants, COVID-19, inflammation, immune system, macronutrient, micronutrient and probiotic as keywords from 2000 to 2022.FindingsBecause of the adverse effects of drugs like thrombosis, pulmonary embolism and hypercholesterolemia, a balanced diet with enough concentrations of energy and macronutrients could increase the patient's durability. The inflammatory cytokines in a vicious cycle delay patients’ rehabilitation. The main mechanistic roles of micronutrients are attributed to the downregulation of virus replication and are involved in energy homeostasis. Dysbiosis is defined as another disturbance among COVID-19 patients, and supplementation with beneficial strains of probiotics helps to exert anti-inflammatory effects in this regard. Being on a well-planned diet with anti-inflammatory properties could reverse cytokine storms as the major feature of COVID-19. Future studies are needed to determine the safe and effective dose of dietary factors to control the COVID-19 patients.Originality/valueBeing on a well-planned diet with anti-inflammatory properties could reverse cytokine storms as the major feature of COVID-19. Future studies are needed to determine the safe and effective dose of dietary factors to control the COVID-19 patients.

Durable pulmonary vein isolation with diffuse posterior left atrial ablation using low-flow, median power, short-duration strategy.

To target posterior wall isolation (PWI) in atrial fibrillation (AF) ablation, diffuse ablation theoretically confers a lower risk of conduction recovery compared to box set. We sought to assess the safety and efficacy of diffuse PWI with low-flow, medium-power, and short-duration (LF-MPSD) ablation, and evaluate the durability of pulmonary vein isolation (PVI) and PWI among patients undergoing repeat ablations. We retrospectively studied patients undergoing LF-MPSD ablation for AF (PVI + diffuse PWI) between August 2017 and December 2019. Clinical characteristics were collected. Kaplan-Meier survival analysis was performed to study AF/atrial flutter (AFL) recurrence. Ablation data were analyzed in patients who underwent a repeat AF/AFL ablation. Of the 463 patients undergoing LF-MPSD AF ablation (PVI alone, or PVI + diffuse PWI), 137 patients had PVI + diffuse PWI. Acute PWI with complete electrocardiogram elimination was achieved in 134 (97.8%) patients. Among the 126 patients with consistent follow-up, 38 (30.2%) patients had AF/AFL recurrence during a median duration of 14 months. Eighteen patients underwent a repeat AF/AFL ablation after PVI + diffuse PWI, and 16 (88.9%) patients had durable PVI, in contrast to 10 of 45 (23.9%) patients who had redo ablation after LF-MPSD PVI alone. Seven patients (38.9%) had durable PWI, while 11 patients had partial electrical recovery at the posterior wall. The median percentage of area without electrical activity at the posterior wall was 70.7%. Conduction block across the posterior wall was maintained in 16 (88.9%) patients. There was a high rate of PVI durability in patients undergoing diffuse PWI and PVI. Partial posterior wall electrical recovery was common but conduction block across the posterior wall was maintained in most patients.

Effectiveness and Durability of mRNA Vaccine-Induced SARS-CoV-2-Specific Humoral and Cellular Immunity in Severe Asthma Patients on Biological Therapy.

Coronavirus disease 2019 (COVID-19) vaccines effectively elicit humoral and cellular immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in healthy populations. This immunity decreases several months after vaccination. However, the efficacy of vaccine-induced immunity and its durability in patients with severe asthma on biological therapy are unknown. In this study, we evaluated the effectiveness and durability of mRNA vaccine-induced SARS-CoV-2-specific humoral and cellular immunity in severe asthma patients on biological therapy. The study included 34 patients with severe asthma treated with anti-IgE (omalizumab, n=17), anti-IL5 (mepolizumab, n=13; reslizumab, n=3), or anti-IL5R (benralizumab, n=1) biological therapy. All patients were vaccinated with two doses of the BNT162b2 mRNA vaccine with a 6-week interval between the doses. We found that this COVID-19 vaccination regimen elicited SARS-CoV-2-specific humoral and cellular immunity, which had significantly declined 6 months after receipt of the second dose of the vaccine. The type of biological treatment did not affect vaccine-elicited immunity. However, patient age negatively impacted the vaccine-induced humoral response. On the other hand, no such age-related impact on vaccine-elicited cellular immunity was observed. Our findings show that treatment of patients with severe asthma with biological therapy does not compromise the effectiveness or durability of COVID-19 vaccine-induced immunity.

Impact of a time-to-effect-guided ablation protocol in cryoballoon ablation on the durability of pulmonary vein isolation.

Cryoballoon (CB)-based pulmonary vein isolation (PVI) has proven to be as effective as radiofrequency-based ablation. Different ablation protocols took the individual time-to-isolation (TTI) into account aiming at shorter but equally or even more effective freeze cycles. The current study sought to assess the impact of the TTI on PVI durability in patients undergoing a repeat procedure for recurrence of atrial tachyarrhythmia (ATA). In 205 patients with ATA recurrence after previous CB-based PVI, a total of 806 pulmonary veins (PVs) were identified. A total of 126out of 806 PVs (16%) were previously treated with a TTI-guided ablation (Protocol #1; TTI + 120 s), in 92/806 (11%) PVs TTI was only monitored (m) but fixed freeze cycles were applied (Protocol #2; mTTI) and in 588/806 (73%) a fixed freeze cycle was applied without mTTI. There was no difference in the PV-reconduction rate between the groups (p = .23). The right inferior pulmonary vein (RIPV) showed overall significantly higher reconduction rates compared to the other PVs (RIPV-left inferior PVp < .003, -left superior PVp < .001, -right superior PVp < .013). Twenty-one patients (10%) were demonstrated to have only electrical reconduction of the RIPV, while all other PVs were still electrically isolated. The TTI-based CB ablationprotocol did not show significant differences regarding PV-reconduction rates compared to the other ablation protocols.

Induction EGFR tyrosine kinase inhibitors prior to definitive chemoradiotherapy in unresectable stage III EGFR-mutated non-small cell lung cancer

IntroductionIncreasing evidence suggests that consolidation durvalumab confers limited benefits for patients with stage III EGFR-mutated NSCLC. Induction or maintenance EGFR tyrosine kinase inhibitors (TKIs) added to concurrent chemoradiotherapy (CRT) may optimize definitive treatment, but there are limited data supporting an induction TKI strategy. MethodsWe evaluated the efficacy and safety of induction EGFR TKIs administered before concurrent CRT in a retrospective series of patients with unresectable locally advanced EGFR-mutated NSCLC. Circulating tumor DNA (ctDNA) analysis was performed on a patient subset using CAPP-seq and correlated with outcomes. ResultsOf six patients, three received erlotinib and three osimertinib as induction therapy before CRT. Induction TKIs were administered for a median of 2.5 months. The objective response rate after induction TKI was 83%. One patient had a complete response to induction erlotinib and continued erlotinib for 4 years until local progression, which was treated with CRT. Two patients completed maintenance erlotinib after CRT, and another received consolidation durvalumab. After a median follow-up of 20.5 months, only one patient developed disease recurrence, with rising ctDNA coinciding with recurrence. ctDNA remained undetectable in patients without recurrence, or low-level in a patient receiving maintenance erlotinib. Adverse events were mild and expected, and none developed pneumonitis. ConclusionInduction EGFR TKI before CRT may achieve high disease control rates with promising signs of durability in patients with locally advanced EGFR-mutated NSCLC. ctDNA analysis after CRT can correlate well with clinical outcomes. Prospective studies are needed to define the role of induction EGFR TKIs in this setting.

Abstract 13439: Long-Term Outcomes From Continuous Rhythm Monitoring After Hybrid Convergent Procedure in Longstanding Persistent Atrial Fibrillation Patients

Introduction: Endocardial catheter ablation has suboptimal effectiveness and durability in patients with longstanding persistent atrial fibrillation (LSPAF). Hybrid convergent ablation combines epicardial and endocardial ablation to create a transmural lesion set that isolates the left atrial posterior wall and pulmonary veins. The study objective was to evaluate long-term outcomes assessed by continuous rhythm monitoring in LSPAF patients who received hybrid convergent ablation. Methods: This was a single-center IRB-approved, observational study. Eligible patients were identified by retrospective chart review and included patients who received hybrid convergent procedures between September 2011 and November 2017. Patients were consented for prospective long-term follow-up visits and continuous cardiac monitoring (7-day ePatch). Baseline characteristics, procedural outcomes, and follow-up data were entered into the TRAC-AF registry. This analysis focused on the patient subgroup with pre-operative LSPAF (AF duration &gt;1 year). Results: Of 77 consented patients, 60 had pre-operative LSPAF. Mean age was 66.1 ± 7.9 years, 70% were male, and duration of AF was 6.8 ± 4.8 years. Mean CHA2DS2-VASc score was 2.6 ± 1.4; mean BMI was 32.1 ± 5.9, and 55% (33/60) of patients had previous catheter ablation. Thirty-day major adverse event rate was 5% (3/60) and included 2 inflammatory pericardial effusions and one major bleeding. On continuous monitoring, 71% (41/58) of patients had 0% AF burden at mean follow-up of 61.7 ± 18.9 months. Eight patients (13%) had repeat catheter ablation at mean 21.6 ± 16.3 months since index procedure. Comparison of baseline and follow-up left ventricular ejection fraction (LVEF) from echocardiography revealed a trend of 12.4 ± 13.0 units improvement at mean follow-up of 18.2 ± 23.7 months since baseline in 5 patients with severely reduced (&lt;40%) baseline ejection fraction (p=0.063). Conclusions: Long-term follow-up with continuous monitoring revealed a majority of patients with pre-operative LSPAF had 0% AF burden after a mean 61.7 months since the hybrid convergent procedure. These results are aligned with published studies and the CONVERGE trial on the effectiveness of hybrid convergent ablation in LSPAF.

The impact of valve selection on haemodynamics in patients with small annuli undergoing contemporary transcatheter aortic valve implantation

Abstract Background/Introduction The use of smaller THVs in transcatheter aortic valve implantation (TAVI) can result in suboptimal haemodynamics with long-term implications on valve durability in patients with smaller aortic annuli. Purpose The objective of this study was to examine the predictive value of aortic annulus size on THV haemodynamics in patients with small annuli undergoing contemporary TAVI. Methods This was a retrospective, observational study of 857 patients who underwent TAVR using either the intra-annular SAPIEN 3 THV or the supra-annular CoreValve Evolut PRO THV at our institution between 2015–2020. Patients were dichotomized based on a native aortic annulus size above or below 430mm2. We then examined 30-day hemodynamics and outcomes in each subgroup and based on THV selection. Results The majority of patients with an annular area &amp;lt;430mm2 were females (82.5%). Of the 857 patients screened, 542 had an annular area &amp;gt;430mm2 and the remaining 315 had an annular area &amp;lt;430mm2. In patients with small aortic annuli, mean gradients were lower at 30 days if they received a supra-annular THV (8.1mmHg vs. 13.8mmHg; p&amp;lt;0.001) which led to lower rates of moderate or severe patient prosthesis mismatch (36.7% vs. 85.4%; p&amp;lt;0.001) (Table 1). All-cause mortality was similar in small annuli between THV groups at 1 year (Table 2). Conclusions The majority of patients with small aortic annuli (&amp;lt;430mm2) undergoing TAVI with contemporary THVs were females. Those that received a supra-annular THV saw superior haemodynamics at 30-days with similar mortality at 1 year. Funding Acknowledgement Type of funding sources: None.

Native Aortic Valve Disease Progression and Bioprosthetic Valve Degeneration in Patients With Transcatheter Aortic Valve Implantation.

Major uncertainties remain regarding disease activity within the retained native aortic valve, and regarding bioprosthetic valve durability, after transcatheter aortic valve implantation (TAVI). We aimed to assess native aortic valve disease activity and bioprosthetic valve durability in patients with TAVI in comparison with subjects with bioprosthetic surgical aortic valve replacement (SAVR). In a multicenter cross-sectional observational cohort study, patients with TAVI or bioprosthetic SAVR underwent baseline echocardiography, computed tomography angiography, and 18F-sodium fluoride (18F-NaF) positron emission tomography. Participants (n=47) were imaged once with 18F-NaF positron emission tomography/computed tomography either at 1 month (n=9, 19%), 2 years (n=22, 47%), or 5 years (16, 34%) after valve implantation. Patients subsequently underwent serial echocardiography to assess for changes in valve hemodynamic performance (change in peak aortic velocity) and evidence of structural valve dysfunction. Comparisons were made with matched patients with bioprosthetic SAVR (n=51) who had undergone the same imaging protocol. In patients with TAVI, native aortic valves demonstrated 18F-NaF uptake around the outside of the bioprostheses that showed a modest correlation with the time from TAVI (r=0.36, P=0.023). 18F-NaF uptake in the bioprosthetic leaflets was comparable between the SAVR and TAVI groups (target-to-background ratio, 1.3 [1.2-1.7] versus 1.3 [1.2-1.5], respectively; P=0.27). The frequencies of imaging evidence of bioprosthetic valve degeneration at baseline were similar on echocardiography (6% versus 8%, respectively; P=0.78), computed tomography (15% versus 14%, respectively; P=0.87), and positron emission tomography (15% versus 29%, respectively; P=0.09). Baseline 18F-NaF uptake was associated with a subsequent change in peak aortic velocity for both TAVI (r=0.7, P<0.001) and SAVR (r=0.7, P<0.001). On multivariable analysis, 18F-NaF uptake was the only predictor of peak velocity progression (P<0.001). In patients with TAVI, native aortic valves demonstrate evidence of ongoing active disease. Across imaging modalities, TAVI degeneration is of similar magnitude to bioprosthetic SAVR, suggesting comparable midterm durability. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02304276.

Outcome and durability of mitral valve annuloplasty in atrial secondary mitral regurgitation

ObjectivesAtrial secondary mitral regurgitation (ASMR) is a clinically distinct form of Carpentier type I mitral regurgitation (MR), rooted in excessive atrial and mitral annular dilation in the absence of left...

Long-Term Outcomes for Cementless Anatomic Femoral Components, Compared by Area of Porous Coating, in Patients Younger Than 50 Years Treated for Hip Dysplasia

BackgroundWe investigated whether the proximal circumferential porous coating of cementless stems would make implant survival of >20 years possible in young patients. MethodsData for patients younger than 50 years with hip dysplasia who had an anatomic stem implanted with a proximal porous coating with hydroxyapatite/tricalcium phosphate were reviewed. Noncircumferential porous (non-C-type) stems were used in 17 hips (13 cases), and circumferential porous (C-type) stems were used in 87 hips (68 cases). Acetabular components with conventional polyethylene were used for all hips. The mean ages at surgery for patients with non-C-type stems and those with C-type stems were 43.3 and 44.7 years, respectively. Stems that had not loosened were retained at the time of acetabular revision. The average duration of follow-up for patients with non-C-type stems was 26.9 years and was 22.3 years for those with C-type stems. ResultsMean survival rates as determined by the Kaplan-Meier method were 74.9% at 20 years and 59.9% at 25 years for non-C-type stems and were 100% at 20 years and 94.0% at 25 years for C-type stems. The survivorship for C-type stems was significantly higher than that for non-C-type stems (P < .01). Focal osteolysis in the shoulder of 37 hips with C-type stems suppressed the spread of osteolysis to the distal femur. ConclusionAnatomic femoral stems with a circumferential porous coating provide excellent durability in patients with hip dysplasia who are 50 years of age or younger. Level of EvidenceTherapeutic Level IV.

A randomized controlled trial of comparative effectiveness between the 2 dose and 3 dose regimens of hepatitis a vaccine in kidney transplant recipients

Hepatitis A virus (HAV) is able to cause a spectrum of illnesses ranging from no symptom to fulminant hepatitis which may lead to acute kidney injury. Although hepatitis A vaccine is recommended in non-immune solid organ transplant recipients who live in or travel to endemic areas, the standard 2-dose vaccination regimen demonstrated less favorable immunogenicity among these population. The 3-dose regimen showed higher response rate and immune durability in patients with human immunodeficiency virus. However, this strategy has never been studied in solid organ transplant recipients. A single-center, open-labeled, computer-based randomized controlled trial (RCT) with a 2:1 allocation ratio was conducted from August 2017 to December 2018. The study compared the seroconversion rate after receiving 2- or 3-dose regimen of hepatitis A vaccine at 0, 6 and 0, 1, 6 months, respectively, in non-immune kidney transplant recipients. A total of 401 adult kidney transplant recipients were screened for anti-HAV IgG and 285 subjects had positive results so the seroprevalence was 71.1%. Of 116 seronegative recipients, 93 (80.2%) completed vaccination; 60 and 33 participants completed 2- and 3-dose vaccination, respectively. The baseline characteristics were comparable between both groups. The seroconversion rate at 1 month after vaccination was 51.7% in the standard 2-dose regimen and 48.5% in the 3-dose regimen (p = 0.769). Overall, the seroconversion rate appeared to be associated with high estimated glomerular infiltration rate, high serum albumin, and low intensity immunosuppressive regimen. Seroconversion rate after hepatitis A vaccination in kidney transplant recipients was less favorable than healthy population. Three-dose regimen did not show superior benefit over the standard 2-dose regimen. Other strategies of immunization may increase immunogenicity among kidney transplant recipients.

Aortic valve-sparing root replacement in patients with bicuspid aortic valve: long-term outcome with the David I procedure over 20 years.

Aortic valve-sparing root replacement is an excellent treatment option for patients with intact tricuspid aortic valves. However, the durability in patients with bicuspid aortic valves is still a matter of debate. The aim of this study was to analyse the short- and long-term outcomes in patients with bicuspid aortic valves. Between July 1993 and October 2015, a total of 582 patients underwent the David I procedure, 50 of whom had a bicuspid aortic valve. In these patients, the mean age was 46 ± 13 years, and 80% (n = 40) were men. Follow-up was complete for 100% of patients and comprised a total of 552 patient-years with a mean follow-up time of 11 ± 5.2 years. In addition to the David procedure, cusp plication was performed in 34% (n = 17) of patients and commissure repair in 8% (n = 4) of patients. There were no in-hospital deaths, and 1 patient (2%) had a perioperative stroke. The 1-, 5-, 10- and 20-year survival rates of patients after discharge were 98%, 94%, 88% and 84%, respectively. The rates for freedom from valve-related reoperation at 1, 5, 10 and 20 years after initial surgery were 98%, 88%, 79% and 74%, respectively. Long-term freedom from reoperation was comparable to that of patients with tricuspid aortic valves (P = 0.2). The David procedure has excellent short-term results in patients with a bicuspid aortic valve. In this study, the long-term durability of reimplanted bicuspid aortic valves was comparable to that of tricuspid valves. However, careful patient selection might have contributed to this, and further studies might be needed to definitely clarify this issue.

Usefulness of Postprocedural Electrophysiological Confirmation Upon Totally Thoracoscopic Ablation in Persistent Atrial Fibrillation

Little information is available concerning the usefulness of electrophysiological confirmation followed by totally thoracoscopic ablation. This study aimed to examine whether postprocedural electrophysiological confirmation is always necessary after totally thoracoscopic ablation (TTA) in patients with isolated persistent atrial fibrillation. Forty-five patients with isolated persistent atrial fibrillation were randomized into 2 groups those who received routine electrophysiological confirmation and additional catheter ablation after totally thoracoscopic ablation (the hybrid group [n = 22]) and those who did not (the TTA group [n = 23]). Electrophysiological study was performed 4 or 5 days after surgery. No early or late mortality occurred. In the hybrid group, 5 patients (23%, 5/22) required additional ablation due to residual potential in the left atrium. At a year postoperatively, normal sinus rhythm was observed in 89% of patients (40/45) and similar in both groups (Odds ratio 0.80, 95% confidence interval 0.32 to 1.99). During follow-up, sinus rhythm was maintained in 16 patients (70%) in the TTA group without additional catheter ablation, which was similar (p = 0.920) to the results in the hybrid group (n = 15, 68.2%). Event-free survival rate at 12 months did not differ between groups (TTA group vs hybrid group, 78% vs 77%; p = 0.633). In simple Cox regression analysis, preoperative left atrium volume index was associated with atrial arrhythmia (p = 0.030, hazards ratio 1.087, 95% confidence interval 1.01-1.18). In conclusion, thoracoscopic ablation provided good 1-year durability in patients with isolated persistent AF irrespective of postprocedural electrophysiological confirmation. Seventy-percent of the TTA group did not need additional catheter ablation.

1175O - Durvalumab activity in previously treated patients who stopped durvalumab without disease progression

BackgroundA proportion of cancer patients treated with anti-programmed cell death-1 (PD-1) and its ligand (PD-L1) achieve long-lasting responses. Some of these patients stop treatment without disease progression (DP). Limited data exist on re-initiation of the same PD-1/PD-L1 inhibitor upon progression. MethodsIn NCT01693562, a phase I/II study evaluating durvalumab in advanced solid tumors, patients were treated until DP or up to 1 year. Per protocol, patients who benefited from durvalumab and stopped treatment after 1 year of therapy were eligible to be rechallenged at time of DP. Clinical outcomes analyzed were best overall response, duration of response, disease control rate (DCR), and progression-free survival (PFS), defined as time from first day of retreatment with durvalumab to DP or death. ResultsOf 1,022 patients, 160 stopped durvalumab without developing DP after 1 year of treatment. Of those, 70 (43.8%) patients across 14 different primary tumor types were rechallenged with durvalumab after DP (Table). During their first treatment with durvalumab, 5.7% and 50% had achieved complete responses (CR) and partial responses (PR), respectively. While off therapy, median time without DP was 266 days. After rechallenge with durvalumab, 66 of 70 (94.3%) were evaluable. Confirmed best overall response was 0% CR, and 11.4% had PR, 60% had stable disease (SD), and 22.9% had DP. Median duration of response was 16.5 months. DCR at≥24 weeks was 47.1%. PFS at 12 months was 34.2%, with similar rates observed regardless of tumor type.Table1175O Best overall response and 12-month PFS with durvalumab rechallengeTableTumour TypeAll Patients (N=70)NSCLC (n=21)MSI-High (n=12)Bladder (n=8)HNSCC (n=6)HCC (n=5)Other (n=18)Best overall response, n (%)CR0000000PR8 (11.4)3 (14.3)03 (37.5)01 (20.0)1 (5.6)SD42 (60)8 (38.1)11 (91.7)3 (37.5)4 (66.7)4 (80.0)1212 (66.7)DP16 (22.9)8 (38.1)1 (8.3)2 (25.0)2 (33.3)03 (16.7)Nonevaluable4 (5.7)2 (9.5)00002 (11.1)Duration of response, months16.513.4N/A16.5N/A18.7+12+CR/PR + SD (DCR ≥24 weeks), %47.133.358.350.033.340.040.0PFS at 12 months, %34.23159.462.5202572.2 ConclusionsThis is the largest cohort supporting the role of rechallenge with a PD-1/PD-L1 inhibitor in patients who have previously progressed after planned interruption. Rechallenge with durvalumab resulted in restored antitumor efficacy, high rates of disease control, and prolonged durability in patients who responded. These findings support the role of durvalumab in patients who progressed after planned treatment interruption. Clinical trial identificationNCT01693562. Legal entity responsible for the studyAstraZeneca, PLC. FundingAstraZeneca. DisclosureS. Sheth: Research grant / Funding (institution): AstraZeneca. C. Gao: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. N. Mueller: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. P. Martinez: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Soria: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca.

Modulation of Target Antigen Density Improves CAR T-cell Functionality and Persistence

Chimeric antigen receptor T-cell (CART) therapy targeting CD22 induces remission in 70% of patients with relapsed/refractory acute lymphoblastic leukemia (ALL). However, the majority of post-CD22 CART remissions are short and associated with reduction in CD22 expression. We evaluate the implications of low antigen density on the activity of CD22 CART and propose mechanisms to overcome antigen escape. Using ALL cell lines with variable CD22 expression, we evaluate the cytokine profile, cytotoxicity, and in vivo CART functionality in the setting of low CD22 expression. We develop a high-affinity CD22 chimeric antigen receptor (CAR) as an approach to improve CAR sensitivity. We also assess Bryostatin1, a therapeutically relevant agent, to upregulate CD22 and improve CAR functionality. We demonstrate that low CD22 expression negatively impacts in vitro and in vivo CD22 CART functionality and impairs in vivo CART persistence. Moreover, low antigen expression on leukemic cells increases naïve phenotype of persisting CART. Increasing CAR affinity does not improve response to low-antigen leukemia. Bryostatin1 upregulates CD22 on leukemia and lymphoma cell lines for 1 week following single-dose exposure, and improves CART functionality and in vivo persistence. While Bryostatin1 attenuates IFNγ production by CART, overall in vitro and in vivo CART cytotoxicity is not adversely affected. Finally, administration of Bryostain1 with CD22 CAR results in longer duration of in vivo response. We demonstrate that target antigen modulation is a promising strategy to improve CD22 CAR efficacy and remission durability in patients with leukemia and lymphoma.See related commentary by Guedan and Delgado, p. 5188.

Features of humoral answer in experimental animal tularemia with different sensitivity to infection

Tularemia is an anthropozoonotic infection caused by Francisella tularensis. In clinical and sanitary-epidemiological practice, traditional diagnostics methods in tularemia are based on serological assays for detecting specific antibodies, allowing to diagnose it and estimate durability of patients’ immunity after vaccination. Previously, it was shown that specific serum antibodies in patients recovered after tularemia, unlike to those vaccinated with the live tularemia vaccine F. tularensis 15 NIIEG, can interact with specific epitopes on lipopolysaccharides isolated from strains of various subspecies — F. tularensis (Ft) and F. novicida (LPS Fn), while LPS Fn-specific immunoglobulins are lacked in the blood of vaccinated individuals. A set of experiments on identifying antibodies with similar specificity in laboratory animals of various species — mice, guinea pigs and rats with differed sensitivity to tularemia, administered with live tularemia vaccine strain as well as virulent F. tularensis strains to simulate vaccine-mediated and infectious processes, respectively was conducted. A methodical approach has been developed that allows to analyze humoral response in modelled infectious process in animals highly sensitive to tularemia such as BALB/c mice and guinea pigs that consisted of preliminary immunization with live tularemia vaccine followed by infection with virulent F. tularensis strains. It was shown that induction of specific anti-LPS Ft antibodies occured in these animal species, both after vaccination and infection with virulent strains. It was noted that, unlike guinea pigs and rats, mice both during vaccination and infection were characterized by significantly lower titers of LPS Ft-specific antibodies. However, no specific interaction between mouse serum and LPS Fn might be detected. Moreover, two types of immunoglobulins with different antigen specificities to the LPS Ft and LPS Fn epitopes were detected by dot-blot analysis in guinea pigs immunized with live tularemia vaccine, followed by infection with a virulent strain. In addition, antibodies to LPS Fn were also detected in the serum of rats infected with virulent, but not vaccine-based, F. tularensis strains. Thus, previous experimental data on the production of immunoglobulins with different antigenic specificity were confirmed in an experimental tularemia modelled in rats and guinea pigs that demonstrated a diagnostic significance and feasibility of using LPS Fn to confirm tularemia infection in humans.

A Clinical Study on Microsurgical Denervation of Spermatic Cord for Refractory Chronic Orchialgia

Objectives: Microsurgical denervation of the spermatic cord (MDSC) is a treatment option for chronic orchialgia (CO) refractory to conservative treatment. Studies showed specific nerve fibers as the possible cause of CO. We aimed to present the outcomes of ligation of these nerves using targeted MDSC. Methods: We retrospectively reviewed 30 cases who underwent targeted MDSC from August 2014 to February 2018. Patients included were under strict criteria. Pain was assessed preoperatively and postoperatively using a subjective visual analog scale (VAS) and objectively with the standardized and validated Pain Impact Questionnaire-6 (PIQ-6) score. Results: Data were available on 28 cases at repercussion. During a median follow-up of 12 months (range 10–29), 25 cases (89.2%) showed a significant reduction in pain and 3 (9.8%) had no change in pain by subjective VAS scoring. Of cases with a significant reduction in pain, 15 (53.5%) had complete resolution and 19 (67.9%) had a 50% or greater reduction. Objective PIQ-6 analysis showed a significant reduction in pain in 78.6% of patients at 6 months postoperatively, in 82.1% at 1 year, in 82.1% at 2 years. Conclusions: Targeted MDSC is an effective, minimally invasive approach with potential long-term durability in patients with refractory CO.

Long-term Survival and Valve Durability in Patients Undergoing Transcatheter Aortic Valve Implantation

Long-term Survival and Valve Durability in Patients Undergoing Transcatheter Aortic Valve Implantation

Endoscopic Injection of Low Dose Triamcinolone: A Simple, Minimally Invasive, and Effective Therapy for Interstitial Cystitis With Hunner Lesions

To investigate the efficacy of low dose triamcinolone injection for effectiveness and durability in patients with interstitial cystitis/bladder pain syndrome (IC/BPS) with Hunner lesions (HL). Clinical data from patients with HL who underwent endoscopic submucosal injection of triamcinolone were reviewed. Demographics, pre- and postoperative pain and nocturia scores, and long-term clinical outcomes were assessed. Duration of response was estimated by time to repeat procedure. Kaplan-Meier estimator was used to evaluate time to repeat procedure. A total of 36 patients who received injections of triamcinolone between 2011 and 2015 were included. Median age ± standard deviation of patients was 61.5 ± 12.0 years; 28 (77.8%) were female patients and 8 (22.2%) were male patients. Twenty six patients (72.2%) received only 1 set of injections, 8 (22.2%) received 2 sets of injections, and 2 (5.56%) received 3 or more sets of injections. Average time between injections in those receiving more than 1 set of injections was 344.9 days (median: 313.5, range: 77-714). Preprocedural pain scores were 8.3 ± 1.2 (mean ± standard deviation) on Likert pain scale (0-10), and mean postprocedural pain scores at approximately 1 month were 3.8 ± 2.2, P <.001. Mean preprocedural nocturia bother scores was 7.5 ± 2.0 and mean postprocedural nocturia bother scores was 5.1 ± 2.5, P <.001. Endoscopic submucosal injection of low dose triamcinolone in patients with IC/BPS with HL is an effective and durable adjunct to existing treatment modalities. This approach is associated with low morbidity and can be performed on an outpatient basis.