Late Endpoints Research Articles

Cytokine Levels in Saliva Are Associated with Salivary Gland Fibrosis and Hyposalivation in Mice after Fractionated Radiotherapy of the Head and Neck.

Cytokines are mediators of inflammation that could lead to fibrosis. The aim was to monitor cytokine levels in saliva and serum after locally fractionated radiotherapy of the head and neck in mice and investigate associations with salivary gland fibrosis and hyposalivation. C57BL/6 mice were randomized to sham or X-ray irradiation of 66 Gy in 10 fractions over 5 days. Blood and saliva were collected on days -7, 5, 35, 80, and 105 following cytokine analysis. The harvested submandibular salivary gland was assessed for the presence of fibrosis. Decision tree regression analysis was used to investigate whether cytokine levels could predict late endpoints in terms of hyposalivation or fibrosis. Significant formation of fibrosis in gland tissue and reduced saliva production was found after irradiation. The pro-inflammatory cytokines IL-1α, TNF, TIMP1, G-CSF, KC, and MIP-1α showed increased levels in saliva in irradiated mice and a strong correlation with late endpoints. The decision tree analysis largely separated controls from irradiated animals, with IL-1α being the strongest predictor. Pro-inflammatory cytokines in saliva, but not in serum, were associated with late endpoints. This indicates that cytokine expression in saliva is a good biomarker for local salivary gland damage with IL-1α as the strongest single predictor.

Toxicity profile of patients treated with proton and carbon-ion therapy for primary nasopharyngeal carcinoma: A systematic review and meta-analysis.

Proton and carbon-ion therapy may spare normal tissues in regions with many critical structures surrounding the target volume. As toxicity outcome data are emerging, we aimed to synthesize the published data for the toxicity outcomes of proton or carbon-ion therapy (together known as particle beam therapy [PBT]) for primary nasopharyngeal carcinoma (NPC). We searched PubMed and Scopus electronic databases to identify original studies reporting toxicity outcomes following PBT of primary NPC. Quality assessment was performed using NIH's Quality Assessment Tool. Reports were extracted for information on demographics, main results, and clinical and dose factors correlates. Meta-analysis was performed using the random-effects model. Twelve studies were selected (six using mixed particle-photon beams, five performed comparisons to photon-based therapy). The pooled event rates for acute grade ≥2 toxicities mucositis, dermatitis, xerostomia weight loss are 46% (95% confidence interval [95% CI]-29%-64%, I2=87%), 47% (95% CI-28%-67%, I2=87%), 16% (95% CI-9%-29%, I2=76%), and 36% (95% CI-27%-47%, I2=45%), respectively. Only one late endpoint (xerostomia grade ≥2) has sufficient data for analysis with pooled event rate of 9% (95% CI-3%-29%, I2=77%), lower than intensity-modulated radiotherapy 27% (95% CI-10%-54%, I2=95%). For most endpoints with significant differences between the PBT and photon-based therapies, PBT resulted in better outcomes. In two studies where dose distribution was studied, doses to the organs at risk were independent risk factors for toxicities. PBT may reduce the risk of acute toxicities for patients treated for primary NPC, likely due to dose reduction to critical structures. The pooled event rate for toxicities derived in this study can be a guide for patient counseling.

Outcomes of “Anterior Versus Posterior Divisional Branches of the Hypogastric Artery as Distal Landing Zone for Iliac Branch Devices”: The International Multicentric R3OYAL Registry

Objective: The aim of this multicentric registry was to assess the outcomes of “anteRior versus posteRior divisional bRanches Of the hYpogastric artery as distAl landing zone for iLiac branch devices (R3OYAL).” Methods: The main exposure of interest for the purpose of this study was the internal iliac artery (IIA) divisional branch (anterior vs posterior) that was used as distal landing zone. Early endpoints included technical success and adverse events. Late endpoints included survival, primary/secondary IIA patency, and IIA branch instability. Results: A total of 171 patients were included in the study, of which 50 received bilateral implantation of iliac branch devices (IBDs). This resulted in a total of 221 incorporated IIAs included in the final analysis, of which 40 were anterior divisional branches and 181 were posterior divisional branches. Technical success was high in both groups (anterior division: 98% vs posterior division: 100%, P = .18). Occurrence of any adverse event was noted in 14% of patients in both groups (P = 1.0). The overall rate of freedom from the composite IBD branch instability did not show significant differences between patients receiving distal landing in the anterior or posterior division of the IIA at 3 years (79% vs 87%, log-rank test = .215). The 3-year estimates of IBD patency were significantly lower in patients who received distal landing in the anterior divisional branch than those who received distal landing in the posterior divisional branch (primary patency: 81% vs 96%, log-rank test = .009; secondary patency: 81% vs 97%, log-rank test < .001). Conclusions: The use of the anterior or posterior divisional branches of the IIA as distal landing zone for IBD implantation shows comparable profiles in terms of immediate technical success, perioperative safety, and side-branch instability up to 3 years. However, IBD patency at 3 years was higher when the distal landing zone was achieved within the posterior divisional branch of the IIA. Clinical Impact The results from this large multicentric registry confirm that use of the anterior or posterior divisional branches of the internal iliac artery (IIA) as distal landing zone for implantation of iliac branch devices (IBD) shows comparable profiles of safety and feasibility, thereby allowing to extend the indications for endovascular repair of aorto-iliac aneurysms to cases with unsuitable anatomy within the IIA main trunk. Although mid-term rates of device durability and branch instability seem to be similar, the rates of primary and secondary IBD patency at three years was favored when the distal landing zone was achieved in the posterior divisional branch of the IIA.

Rituximab in Mucous Membrane Pemphigoid: A Monocentric Retrospective Study in 10 Patients with Severe/Refractory Disease.

Rituximab (RTX) is a monoclonal antibody directed against CD20 antigen indicated in an increasing number of immune-mediated diseases. While its efficacy in pemphigus vulgaris has been widely investigated, only a few data about its possible role in pemphigoid diseases have been reported in the literature. Accordingly, herein we evaluated a case series of patients with mucous membrane pemphigoid (MMP) treated with RTX. We included patients with a history of severe/refractory MMP who received at least one cycle of intravenous RTX between May 2018 and December 2021 and had 6 months of follow-up time. Disease control (DC) was our early endpoint, while complete remission (CR) and partial remission (PR) were late endpoints. CR off-therapy, relapses, and adverse events were evaluated as well. Our population included 10 MMP patients. Eight out of ten patients (80%) achieved DC in a mean of 8 weeks, while two patients with ocular MMP were non-responders. Among the eight patients who achieved DC, two reached CR off therapy, two CR on minimal therapy, and two achieved PR on minimal therapy. In our case series, the addition of RTX to conventional therapies was demonstrated to be safe and effective in reaching rapid disease control in the majority of refractory MMP patients.

MO-0557 Estimates of α/β ratios for individual late urinary toxicity endpoints: analysis of a cohort trial

MO-0557 Estimates of α/β ratios for individual late urinary toxicity endpoints: analysis of a cohort trial

OSPred Tool: A Digital Health Aid for Rapid Predictive Analysis of Correlations Between Early End Points and Overall Survival in Non–Small-Cell Lung Cancer Clinical Trials

PURPOSEOverall survival (OS) is the gold standard end point for establishing clinical benefits in phase III oncology trials. However, these trials are associated with low success rates, largely driven by failure to meet the primary end point. Surrogate end points such as progression-free survival (PFS) are increasingly being used as indicators of biologic drug activity and to inform early go/no-go decisions in oncology drug development. We developed OSPred, a digital health aid that combines actual clinical data and machine intelligence approaches to visualize correlation trends between early (PFS-based) and late (OS) end points and provide support for shared decision making in the drug development pipeline.METHODSOSPred is based on a trial-level data set of 81 reports (35 anticancer drugs with various mechanisms of action; 156 observations) in non–small-cell lung cancer (NSCLC). OSPred was developed using R Shiny, with packages ggplot2, metafor, boot, dplyr, and mvtnorm, to analyze and visualize correlation results and predict OS hazard ratio (HR OS) on the basis of user-inputted PFS-based data, namely, HR PFS, or the odds ratio of PFS at 4 (OR PFS4) or 6 (OR PFS6) months.RESULTSThe three main features of the tool are as follows: prediction of HR OS on the basis of user-inputted early end point values; visualization of comparisons of the user's investigational drug with other drugs in the NSCLC setting, including by specific MoA; and creation of a probability density chart, providing point prediction and CIs for HR OS. A working version of the tool for download is linked.CONCLUSIONThe OSPred tool offers interactive visualization of clinical trial end point correlations with reference to a large pool of historical NSCLC studies. Its focused capability has the potential to digitally transform and accelerate data-driven decision making as part of the drug development process.

Correlation Between Early Endpoints and Overall Survival in Non-Small-Cell Lung Cancer: A Trial-Level Meta-Analysis.

Early endpoints, such as progression-free survival (PFS), are increasingly used as surrogates for overall survival (OS) to accelerate approval of novel oncology agents. Compiling trial-level data from randomized controlled trials (RCTs) could help to develop a predictive framework to ascertain correlation trends between treatment effects for early and late endpoints. Through trial-level correlation and random-effects meta-regression analysis, we assessed the relationship between hazard ratio (HR) OS and (1) HR PFS and (2) odds ratio (OR) PFS at 4 and 6 months, stratified according to the mechanism of action of the investigational product. Using multiple source databases, we compiled a data set including 81 phase II–IV RCTs (35 drugs and 156 observations) of patients with non-small-cell lung cancer. Low-to-moderate correlations were generally observed between treatment effects for early endpoints (based on PFS) and HR OS across trials of agents with different mechanisms of action. Moderate correlations were seen between treatment effects for HR PFS and HR OS across all trials, and in the programmed cell death-1/programmed cell death ligand-1 and epidermal growth factor receptor trial subsets. Although these results constitute an important step, caution is advised, as there are some limitations to our evaluation, and an additional patient-level analysis would be needed to establish true surrogacy.

Rituximab Therapy for Treatment of Pemphigus in Southeast Asians.

BackgroundRituximab provides more effective and less adverse effects than the standard dose of corticosteroids, but evidence on its efficacy and safety in the Thai population is lacking.ObjectiveTo evaluate the efficacy and safety of rituximab in the treatment of pemphigus and also to determine prognostic factors linked to the treatment outcomes.MethodsPemphigus patients who received rituximab from November 2017 to December 2020 were retrospectively reviewed. The outcome was evaluated by using early (end of consolidation phase [ECP]) and late endpoints (complete remission [CR] on/off therapy, immunological remission [IR], and relapse). Adverse events were noted. Prognostic factors associated with remission and relapse were analyzed.ResultsOf 53 pemphigus patients, all attained ECP within 1.61 months. Almost 80% achieved CR on therapy within a median time of 6.36 months, while 33.9% reached CR off therapy in 19.74 months. Nearly half had IR within a median time of 6.88 months. Relapse occurred in 33.3% with a median time of 14 months. In multivariate analysis, receiving rituximab within 12 months of disease duration was more likely to achieve CR off therapy and IR (hazard ratio [HR] 3.79; 95% confidence interval [CI] 1.38, 10.42; P = 0.01 and HR 2.74; 95% CI 1.12, 6.69; P = 0.027, respectively), whereas older patients and positive anti-desmoglein 1 levels at the time of CR were predictive indicators for relapse (HR 1.07; 95% CI 1.01, 1.13; P = 0.036 and HR 4.38; 95% CI 1.24, 15.46; P = 0.022, respectively). The treatment-related adverse effects occurred in 33.9%.ConclusionRituximab is effective and safe in Thai pemphigus patients. Early administration of rituximab was a predictor of clinical and immunological remission. Older age and persistently positive anti-Dsg1 were correlated with disease relapse.

Multi-institutional registry study evaluating the feasibility and toxicity of accelerated partial breast irradiation using noninvasive image-guided breast brachytherapy

PurposeThe noninvasive image-guided breast brachytherapy (NIBB) technique is a novel noninvasive yet targeted method for accelerated partial breast irradiation. We established a multi-institutional registry to evaluate the toxicity and efficacy of this technique across various practice settings. Methods and MaterialsInstitutions using the NIBB technique were invited to participate. Data for acute/late toxicity, cosmetic outcome, and tumor recurrence were collected. Toxicity and cosmetic outcome were graded based on the Common Terminology Criteria for Adverse Events version 3.0 and NRG/Radiation Therapy Oncology Group scale, respectively. Treatment variables were analyzed for association with outcomes. ResultsA total of 252 patients from eight institutions were analyzed. The median age was 69 years. The mean tumor size was 1.1 cm (0.1–4.0 cm). Treatment was delivered 10 fractions (34–36 Gy) in 75% and five fractions (28.5 Gy) in 22%. B.i.d. fractionation was used in 9%. Acute radiation dermatitis was Grade 0–1, 2, and 3 in 77%, 19%, and 4%, respectively. One hundred ninety-one patients with a median followup of 18 months (4–72 months) were evaluable for late outcomes. Late toxicity Grades 2 and 3 were observed in 8.8% and 1%, respectively. Cosmetic outcome was excellent, good, and fair/poor in 62%, 36%, and 2%, respectively. B.i.d. fractionation was associated with higher acute and late toxicity. Second-generation applicators were associated with lower late toxicity and better cosmetic outcome. Actuarial freedom from ipsilateral breast tumor recurrence and true recurrence were 98.3% and 98.3% at 2 years and 90.9% and 95.4% at 5 years, respectively. ConclusionsAccelerated partial breast irradiation using NIBB was well tolerated with a low rate of acute and late toxicity across various practice settings. Ipsilateral breast tumor recurrence and cosmetic outcomes were favorable. b.i.d. fractionation was associated with higher toxicity. Longer followup is needed to confirm late endpoints.

Concordance of Early and Late End Points for Community-acquired Bacterial Pneumonia Trials.

While there are ongoing regulatory convergence efforts, differences remain in primary end points recommended for community-acquired bacterial pneumonia (CABP) trials. The US Food and Drug Administration (FDA) recommends assessing CABP symptom resolution at an early time point (3-5 days after randomization). Other regulatory agencies recommend assessing overall clinical response at a later time point (5-10 days after therapy ends). We analyzed participant-level data from 6 recent CABP trials submitted to the FDA (n = 4645 participants) to evaluate concordance between early and late end-point outcomes. We used multivariate logistic regression to identify factors associated with discordance. Early and late end-point outcomes were concordant for 85.6% of participants. The proportions of early end-point responders that ultimately failed and early end-point nonresponders that ultimately succeeded were similar (6.0% vs 8.4%, respectively). Early end-point response was highly predictive of late end-point success (positive predictive value, 92.9%). Multivariate logistic regression identified early end-point responders/late end-point failures as less likely to be obese and more likely to be infected with Chlamydophila pneumoniae or Staphylococcus aureus, have received antibacterial drug therapy prior to randomization, and have severe chest pain at baseline. The most common investigator-provided reasons for failure among early end-point responders/late end-point failures were receipt of nonstudy antibacterial drug therapy and loss to follow-up. Early and late end-point outcomes were highly concordant. These data may be useful in the continuing efforts to reach international regulatory convergence on CABP clinical trial design recommendations.

Pyphe, a python toolbox for assessing microbial growth and cell viability in high-throughput colony screens.

Microbial fitness screens are a key technique in functional genomics. We present an all-in-one solution, pyphe, for automating and improving data analysis pipelines associated with large-scale fitness screens, including image acquisition and quantification, data normalisation, and statistical analysis. Pyphe is versatile and processes fitness data from colony sizes, viability scores from phloxine B staining or colony growth curves, all obtained with inexpensive transilluminating flatbed scanners. We apply pyphe to show that the fitness information contained in late endpoint measurements of colony sizes is similar to maximum growth slopes from time series. We phenotype gene-deletion strains of fission yeast in 59,350 individual fitness assays in 70 conditions, revealing that colony size and viability provide complementary, independent information. Viability scores obtained from quantifying the redness of phloxine-stained colonies accurately reflect the fraction of live cells within colonies. Pyphe is user-friendly, open-source and fully documented, illustrated by applications to diverse fitness analysis scenarios.

Outcomes after Standalone Use of Gore Excluder Iliac Branch Endoprosthesis for Endovascular Repair of Isolated Iliac Artery Aneurysms

The aim of our study was to describe outcomes of stand-alone use (i.e., without concomitant implantation of an aortic stent graft) of the Gore Excluder iliac branch endoprosthesis (IBE) for elective endovascular repair of isolated iliac artery aneurysms. We evaluated all consecutive patients electively treated for isolated iliac artery aneurysms using standalone Gore Excluder IBE (January 2014-December 2018). Early (i.e., 30-day) endpoints were technical success, mortality, major adverse events (MAEs), and major access-site complications. Late endpoints were survival, freedom from aortic-related mortality (ARM), internal iliac artery (IIA) primary patency, IIA branch instability, graft-related adverse events (GRAEs), secondary interventions, endoleaks (ELs), aneurysm sac behavior, and new-onset buttock claudication (BC). A total of 11 consecutive patients (10 men; median age 75years) were included. The technical success rate was 100%. At 30days, mortality, MAEs, and major access-site complications were all 0%. Survival and freedom from ARM were 91% and 100%, respectively; only one nonaortic related death was recorded during follow-up. At a median follow-up of 14months, IIA primary patency, IIA branch instability, and GRAEs were 100%, 0%, and 0%, respectively. No instances of graft migration ≥10mm were detected. No graft-related secondary interventions were recorded, and 2 patients required a procedure-related secondary intervention 3months after the index procedure (1 common femoral artery endarterectomy and 1 external iliac artery stenting). Although new-onset type 1 or type 3 ELs were never noted, one patient developed a new-onset type 2 EL. Aneurysm sac regression ≥5mm was noted in 6 patients (55%), whereas in the remaining ones, the sac size was stable. No instances of new-onset BC were noted. Use of standalone Gore Excluder IBE for elective endovascular repair of isolated iliac artery aneurysms is a safe, feasible, and effective treatment option. These results may support use of the technique as an effective means of endovascular reconstruction in patients with suitable anatomy.

Outcomes of the Gore Excluder Iliac Branch Endoprosthesis Using Division Branches of the Internal Iliac Artery as Distal Landing Zones

Purpose: To evaluate the outcomes of the Gore Excluder Iliac Branch Endoprosthesis (IBE) using division branches of the internal iliac artery (IIA) as distal landing zones. Materials and Methods: Between January 1, 2014, and December 31, 2018, 74 patients (mean age 74±7 years; 72 men) treated for aortoiliac or common iliac artery aneurysms had an IBE deployed with distal landing of the side branch within the main trunk (n=60) of the internal iliac artery (IIA) vs within a division branch (n=25). Thirteen (17%) patients received bilateral IBE implantations for a total of 85 vessels evaluated. Early endpoints were technical success, 30-day mortality, 30-day major adverse events (MAEs), and 30-day major access complications. Late endpoints were survival, primary and secondary IIA patency, freedom from IIA branch instability, freedom from new-onset buttock claudication, and aneurysm sac diameter changes. Time-dependent outcomes were reported as Kaplan-Meier curves with differences assessed using the log-rank test. Estimates are presented with the 95% confidence interval (CI). Results: The overall technical success rate was 97%, with 1 technical failure per group (p=0.43). Two patients, one from each group, died within 30 days (p=0.43). No significant differences were seen in the rates of 30-day MAEs (7% vs 17%, p=0.35) or major access complications (9% vs 11%, p>0.99) for patients receiving distal landing in the main trunk vs a division branch, respectively. The mean follow-up for the entire cohort was 19±12 months. The overall 1-year survival rate was 94% (95% CI 74% to 99%). The primary and secondary patency rates at 1 year were 98% (95% CI 88% to 99%) vs 95% (95% CI 72% to 99%, p=0.72) and 98% (95% CI 88% to 99%) vs 100% (p=0.41) for the main trunk vs division branch groups, respectively. Freedom from IIA branch instability estimates were also similar at 1-year follow-up [93% (95% CI 82% to 97%) vs 90% (95% CI 66% to 97%), p=0.29], as were the freedom from new-onset buttock claudication estimates [98% (95% CI 86% to 99%) and 94% (95% CI 67% to 99%), respectively; p=0.62]. Mean sac diameter change was 5.4±5.3 mm, not significantly different between the groups (p=0.85). Conclusion: Use of the posterior or anterior division of the IIA as a distal landing zone for the Gore Excluder IBE was safe and efficacious in the midterm. This technique may permit extending indications for endovascular repair of aortoiliac aneurysms to cases with unsuitable anatomy within the IIA main trunk. Long-term assessment is needed to affirm the efficacy of this technique.

A Comparison of Azathioprine and Mycophenolate Mofetil as Adjuvant Drugs in Patients with Pemphigus: A Retrospective Cohort Study.

IntroductionAzathioprine (AZA) and mycophenolate mofetil (MMF) are both first-line steroid-sparing agents used for the treatment of pemphigus in combination with a corticosteroid, but few studies to date have directly compared these two combination treatment modalities. The aim of this study was to compare the efficacy and safety of each of these agents as adjuvant therapy with the corticosteroid prednisolone for the treatment of pemphigus, using standardized outcome parameters.MethodsThis was a retrospective study of patients with pemphigus who received corticosteroid therapy in combination with either AZA or MMF at the Autoimmune Blistering Skin Diseases Clinic of Ramathibodi Hospital (Bangkok) between January 2007 and July 2017. The treatment response was evaluated using early [end of the consolidation phase (ECP)] and late endpoints [complete remission (CR) on therapy, CR off therapy and immunological remission]. Cumulative steroid use, relapse rate and adverse events in each treatment group were also compared.ResultsOf the 62 patients with pemphigus included in the study, 37 were treated with prednisolone plus AZA as adjuvant (AZA group) and 25 patients were treated with prednisolone plus MMF as adjuvant (MMF group). The majority of patients in both treatment groups reached the ECP (AZA group 88.2%; MMF group 71.4%; between-group difference not statistically significant at p = 0.156); the median time required to achieve this early endpoint was also comparable (p = 0.362). A high percentage of patients in both the AZA and MMF groups attained CR on therapy (AZA 73%; MMF 72%). The total number of patients who achieved CR on and off therapy were comparable in the two groups (p = 0.933 and p = 0.690, respectively). However, the median time for patients to achieve CR on therapy was significantly shorter for those on MMF than for those on AZA (7.3 vs. 12.5 months; p = 0.019), and the cumulative steroid dose required for patients to achieve CR both on and off therapy was significantly lower in the MMF group than in the AZA group (p = 0.007 and p = 0.043, respectively).ConclusionWhile corticosteroid in combination with either AZA or MMF is an effective therapeutic regimen for the treatment of pemphigus, MMF demonstrates a shorter time to achieve CR on therapy and has a significantly higher steroid-sparing effect.

Early and Long-term Efficacy of Fenestrated Endografting in the Treatment of Juxta-renal Aortic Aneurysms

Introduction - Juxta-renal aneurysms (j-AAAs) are increasingly repaired by endovascular means with fenestrated endografts (FEVAR) worldwide, however long-term data are presently lacking. Aim of our study was therefore to evaluate late outcome of FEVAR in j-AAAs Methods - Between 2008 and 2017, all consecutive patients undergoing endovascular repair for j-AAAs (neck length ≤5mm) by FEVAR (Cook-Zenith platform) were prospectively collected. Preoperative clinical and morphological features, together with procedural and postoperative data were analyzed. Early endpoints were: technical success (TS: patency of target visceral vessels; TVVs, absence of type I-III endoleak; iliac leg stenosis/occlusion and 24-hour survival), renal function worsening (reduction of baseline GFR ≥30%) and 30-day mortality. Late endpoints were: survival, freedom from re-intervention (FFR), TVV-patency, j-AAA shrinkage (> 5mm) and renal function worsening. Results - During the study period, overall 181 cases underwent FB-EVAR repair. Sixty-six patients with j-AAA (M: 94%; age: 72±6years; ASA 3/4: 79/21%) were enrolled. The mean j-AAA diameter was 58±6mm. Endograft with 1, 2, 3 and 4 fenestrations were planned in 2 (3%), 22 (33%), 27 (41%) and 15 (23%) cases, respectively. Overall, 236 TVVs were treated by fenestrations and scallops (3.6±1 TVV/patient). Technical success was achieved in 65 cases (99%). The only failure occurred for a type III endoleak requiring renal artery relining on postoperative day 32. No TVVs were lost. Cardio and pulmonary morbidities were 5% and 6%, respectively. There were no cases of acute splanchnic ischemia. Renal function worsening occurred in 7 cases (10%): 4 returned to baseline within 30-day; 1 required hemodialysis and died within 30-day (1.5%). This was the only case of 30-day mortality. The mean follow-up was 46±32 months. Aneurysm sac shrinkage or stability was observed in 42 (64%) and 22 (33%) cases, respectively. Two patients (3%) with persistent type II endoleak had sac enlargement and required re-interventions (sac embolization by trans-limb approach). Freedom from re-interventions at 1, 3 and 5 years was 97%, 93% and 88%, respectively. An asymptomatic celiac trunk occlusion occurred at 36-month in a case with asevere pre-operative stenosis - accommodated by a scallop. No late renal arteries occlusions or type I-III endoleaks occurred. Overall, renal function worsening was reported in 5 patients (8%) during follow-up (2 persisted from post-operative period and 3 with new onset). Survival at 1, 3 and 5 years was 92%, 86% and 67%, respectively, with no j-AAA related mortality. At the univariate analysis, COPD (p:.006), BMI >31 (p:.048), preoperative chronic renal failure (p:0.44) and late renal function worsening (p:.050) were risk factors for mortality. COPD was the only independent predictor for mortality at the multivariate analysis (p:.021; OR:5.3; 95%CI, 1.3-21.9) Conclusion - FEVAR for j-AAAs is safe and effective at early and long-term follow-up. According with the results of this series, FEVAR could be proposed as the first line treatment for j-AAAs in anatomically fit cases if performed in high volume centers. Long term survival is reduced in the presence of pre-operative COPD. The results of the present series should be taken in consideration when considering alternative open surgery technique in the treatment of J-AAAs

The Italian Multi-centre Experience of Fenestrated Anacondatm Endograft for Juxta/Para-renal Aortic Aneurysms

Introduction - Aim of this study is to describe the outcomes of “AnacondaTM-Fenestrated Endograft (Vascutek, Inchinnan, UK) Italian registry” for challenging abdominal aortic aneurysms (AAA), unfit for standard endovascular aortic repair (EVAR). Methods - Between 2012 and 2017, patients with proximal neck unsuitable for standard EVAR were prospectively enrolled. Clinical (demographic, cardiovascular risk factors, co-morbidities) and morphological aortic-iliac features were collected. Intra and peri-operative data were analyzed. Early endpoints were technical success (TS defined as absence of endoleaks (EL) I-III, patency of target visceral vessels (TVV) and iliac legs and 24-hour survival). Late endpoints were survival, endoleaks, TVV patency and limb occlusion/stenosis, freedom from re-interventions and AAA-related mortality during the follow-up. Results - Seventy-eight patients (male 92%(62); mean age 74±4 years, ASA III-IV:73-27%) were submitted to Fenestrated-AnacondaTM in 25 Italian Vascular Surgery Units (73 juxta/para-renal AAA, 4 Type IV TAAA and 1 EL 1A post-EVAR). The mean AAA diameter was 58mm ± 3mm (range: 50-70mm). Configuration with 1, 2, 3 and 4 fenestrations were used in 3 (4%), 40 (51%), 25 (32%) and 10 (13%) cases, respectively for a total of 198 visceral vessels, (3.6±1TVV/patient). Sixty-six (85%) bifurcated and 12 (15%) tube endograft were implanted. The endograft was repositioned during the procedure in 42% (33/78) of cases. From the brachial access, at least 1 TVV was cannulated in 54% (27/52) of cases. TS was 90% (70/78) due to 5 type I EL, 1 type III EL (between fenestration and vessel stent) and 2 renal artery occlusions. All the target visceral vessels were cannulated and stented. The 30-day mortality was 5.1% (4/78). One patient died for a multiple organ disfunction syndrome (MOF) after renal artery ligature ad nephrectomy; one patient died for sepsis after embolization of the renal artery for artery perforation, two patients died for cardiological reasons. Two of the 5 type I EL solved spontaneously at 30-day for adaptation of the sealing ring of the device to the aortic neck. Two type III endoleak detected at the completion angiography were treated by relining of renal artery. At a median follow-up of 20 months (range:1-60) there were 3 type I EL, 2 type III EL and 3 occlusions of renal artery. The reintervention free-survival was 91% and no AAA-related mortality occurred. One patients had a bilateral renal artery occlusion so he has subjected to thrombolysis combined with angioplasty. A patient with type II EL underwent to open hypogastric ligature and another to lumbar embolization. There was an aortic rupture due to a proximal progression of AAA in a patient with two fenestrations for renal arteries; the patient was treated by suprarenal extension with chimney technique for celiac trunk and upper mesenteric artery. The survivor at 36 months was 77% (no AAA-related mortality hasn’t been reported). Conclusion - AnacondaTM-Fenestrated Endograft is an effective treatment of challenging AAA. The repositionability, the brachial access and the adaptation during the follow-up of the proximal ring are useful for complex anatomies and increase the technical success of the procedure.

Secondary Endovascular Repair of Recurring Lesions and Perioperative Complications after Open Aortic Repair: The Complementary Role of Different Technical Solutions

The aim of our article was to describe the complementary role of different technical solutions for secondary endovascular repair of recurring lesions and perioperative complications after open aortic repair (OAR). We describe our clinical experience of secondary endovascular repair after OAR. We included in the analysis all consecutive patients who presented recurring lesions and perioperative complications after OAR and underwent secondary endovascular repair between January 1, 2015 and June 31, 2018. Both elective and nonelective cases were captured. Early end points were technical success, 30-day mortality, 30-day major adverse events, and 30-day vascular access complications. Late end points were survival and freedom from secondary interventions. Three different techniques were used in 6 patients: 2 cases of fenestrated-branched endovascular aortic repair (F-BEVAR), 2 cases of parallel-graft EVAR (pg-EVAR), and 2 cases of off-label use of standard devices. Technical success was 100%. One patient died within 30days from acute pulmonary embolism. One patient developed acute kidney injury not requiring renal replacement therapy, whereas the remaining 4 patients were free from 30-day major adverse events. The cumulative rate of 30-day vascular access complications was 0%. All the 5 patients who survived the index hospitalization had ≥12months of clinical and imaging follow-up. At the longest individual follow-up, they all were alive and free from secondary interventions. Computed tomography angiography showed in all cases sustained clinical success. Secondary endovascular repair of recurring lesions and perioperative complications after OAR is safe and feasible and offers a minimally invasive effective treatment option when a redo surgical operation would be associated with a considerable risk to the patient. Different solutions are available (including F-BEVAR, pg-EVAR, and off-label use of standard devices) and are complementary rather than competitive. Careful preoperative assessment and familiarity with advanced techniques are essential to achieve satisfactory outcomes.

Novel technique for the direct closure of the radial forearm flap donor site defect with a local bilobed flap.

The donor site defect remains the major disadvantage of the radial forearm free flap (RFFF). The purpose of this case series was to evaluate the effectiveness and safety of a local bilobed flap in direct closure of the RFFF donor site defect. Between February 2017 and July 2017, a prospective study was designed with 13 patients who had undergone RFFF reconstruction of the oral cavity. The primary purpose was to assess the effectiveness and safety of a bilobed flap closure of the RFFF donor site with primary healing. The late endpoint was to evaluate functional morbidity of the donor hand by comparing preoperative and postoperative outcomes. The donor site defect healed primarily in 12 of the 13 patients. A small area of skin necrosis (4%) developed in one patient, which was managed conservatively and healed by secondary intention. A significant reduction of wrist extension (mean difference [MD] = 2.64°, P = .01) and grip strength (MD = 3.68 kg, P = .04) was observed between preoperative and postoperative measurements. No statistically significant difference was observed regarding flexion, radial deviation, ulnar deviation, supination, pronation and pinch strength (P > .05). The bilobed flap is a reliable and effective method for closure of a RFFF donor site defect, ≤5 cm in greatest length. The advantages are excellent regional skin color match and avoidance of a second donor site and its inherent complications.

Results of infrainguinal revascularization with bypass surgery using a heparin-bonded graft for disabling intermittent claudication due to femoropopliteal occlusive disease

BackgroundThe purpose of this study was to analyze the results of infrainguinal revascularization for disabling intermittent claudication (IC) due to femoropopliteal occlusive disease using bypass graft (BPG) surgery with a heparin-bonded expanded polytetrafluoroethylene (HB-ePTFE) graft. MethodsBetween 2002 and 2016, we performed 1400 BPGs with HB-ePTFE interventions in patients with femoropopliteal occlusive disease, of which IC was an indication in 485 (34.6%) patients. Early major end points were in-hospital mortality and major complications; late major end points were primary patency, freedom from redo bypass, freedom from progression to critical limb ischemia, and freedom from above-knee amputation or prosthetic graft infection. ResultsWe performed 200 (41.2%) above-knee BPGs and 231 (47.6%) below-knee BPGs; 54 (11.1%) BPGs targeted a tibial artery. In-hospital death occurred in two (0.4%) patients. Overall, the major complication rate was 4.3%. The median duration of follow-up was 33 months (range, 1-150 months; interquartile range [IQR], 14-62.8 months); the cumulative follow-up index for survival was 0.75 ± 0.25. During the follow-up, 56 (11.6%) patients died. Estimated primary patency of the BPG was 86.1% ± 1.6% (95% confidence interval [CI], 82.7-88.9) at 12 months, 68.4% ± 2.4% (95% CI, 63.5-72.9) at 36 months, and 57.7% ± 2.9% (95% CI, 52.0-63.2) at 60 months. On multivariate analysis, runoff status (no or one vessel), site of the distal anastomosis (below the knee), and postoperative medical treatment (oral anticoagulants) impaired primary patency. Estimated freedom from redo bypass was 96.1% ± 0.9% (95% CI, 93.9-97.5) at 12 months, 84.8% ± 1.9% (95% CI, 80.7-88.2) at 36 months, and 76.4% ± 2.6% (95% CI, 71.0-81.1) at 60 months. Both the runoff status (no or one vessel) and the diameter of the graft (6 mm) were significantly associated with the need for redo bypass. Freedom from progression to critical limb ischemia was 86.1% ± 2.2% (95% CI, 81.2-89.9) at 60 months. During the follow-up, there were 20 (4.1%) above-knee amputations, which occurred at a median of 33 months (range, 2-107 months; IQR, 14-63 months) after the indexed BPG intervention. Prosthetic graft infection occurred in seven (1.4%) patients, with a median delay from index procedure to presentation with graft infection of 33 months (range, 1-72 months; IQR, 14-62.5 months), resulting in a freedom from prosthetic graft infection rate of 98.2% ± 2% (95% CI, 95.8-99.2) at 60 months. ConclusionsIn patients suffering from lifestyle-disabling IC with long or complex occlusive lesions of the femoropopliteal segment, open BPG surgery with Hb-ePTFE graft had an acceptably low mortality rate. A poor runoff status was a significant predictor of loss of graft patency, especially after a below-knee anastomosis, as was the need for redo bypass. Dual antiplatelet therapy had significantly better results against follow-up thrombosis, and 8-mm grafts showed better freedom from redo bypass compared with 6-mm grafts.

The Advantage of FLASH Radiotherapy Confirmed in Mini-pig and Cat-cancer Patients.

Previous studies using FLASH radiotherapy (RT) in mice showed a marked increase of the differential effect between normal tissue and tumors. To stimulate clinical transfer, we evaluated whether this effect could also occur in higher mammals. Pig skin was used to investigate a potential difference in toxicity between irradiation delivered at an ultrahigh dose rate called "FLASH-RT" and irradiation delivered at a conventional dose rate called "Conv-RT." A clinical, phase I, single-dose escalation trial (25-41 Gy) was performed in 6 cat patients with locally advanced T2/T3N0M0 squamous cell carcinoma of the nasal planum to determine the maximal tolerated dose and progression-free survival (PFS) of single-dose FLASH-RT. Using, respectively, depilation and fibronecrosis as acute and late endpoints, a protective effect of FLASH-RT was observed (≥20% dose-equivalent difference vs. Conv-RT). Three cats experienced no acute toxicity, whereas 3 exhibited moderate/mild transient mucositis, and all cats had depilation. With a median follow-up of 13.5 months, the PFS at 16 months was 84%. Our results confirmed the potential advantage of FLASH-RT and provide a strong rationale for further evaluating FLASH-RT in human patients.See related commentary by Harrington, p. 3.