Long-term Treatment Failure Research Articles

Unveiling the correlation between in vivo endodontic reciprocate instrumentation and crack formation

IntroductionDentinal microcracks have been supposedly associated with unrestorable vertical root fractures and consequently long-term treatment failure. This study aimed to investigate whether in vivo root canal instrumentation in mandibular incisors with vital pulps causes dentinal microcracks using two different irrigating solutions. MethodsFive patients with four vital mandibular incisors indicated for extraction were included. In vivo root canal preparation was performed using Reciproc R40 (tip #40 and taper 0.06). From these, two teeth were randomly assigned for root canal instrumentation irrigated with 5.25 % sodium hypochlorite irrigation (n = 10) or 2 % chlorhexidine gel with saline solution irrigation (n = 10). In sequence, all teeth were carefully extracted, stored in saline solution until microtomography (µCT) scan. Images were reconstructed and assessed for the presence or absence of dentinal microcracks where microcracks originating from the root canal lumen would be considered. All reconstructed samples were analysed dynamically and rendered in videos through the entire extension of the teeth, evaluating the axial cuts considering each third separately from the apex to the enamel-dentinal junction. Teeth were analysed using the DataViewer software at 100 % magnification without filters by three examiners blinded to the condition allocation. ResultsNo complete dentinal microcracks were observed after root canal instrumentation of mandibular incisors with vital pulps using Reciproc R40 regardless the irrigating solutions, 5.25 % sodium hypochlorite or 2 % chlorhexidine gel. ConclusionsIn vivo root canal instrumentation of mandibular incisors with vital pulps and bone/periodontal insertion does not cause dentinal microcracks and the irrigating solutions tested did not influence this occurrence. Microcrack evaluation must be performed in vivo conditions of dental tissue moist and periodontal support to avoid dryness dentinal alterations after extraction provoking false positive results. Clinical relevanceReciprocating instrumentation performed in vivo is safe and do not induce dentinal microcracks in mandibular incisors.

Preventing antimalarial drug resistance with triple artemisinin-based combination therapies

Increasing levels of artemisinin and partner drug resistance threaten malaria control and elimination globally. Triple artemisinin-based combination therapies (TACTs) which combine artemisinin derivatives with two partner drugs are efficacious and well tolerated in clinical trials, including in areas of multidrug-resistant malaria. Whether early TACT adoption could delay the emergence and spread of antimalarial drug resistance is a question of vital importance. Using two independent individual-based models of Plasmodium falciparum epidemiology and evolution, we evaluated whether introduction of either artesunate-mefloquine-piperaquine or artemether-lumefantrine-amodiaquine resulted in lower long-term artemisinin-resistance levels and treatment failure rates compared with continued ACT use. We show that introduction of TACTs could significantly delay the emergence and spread of artemisinin resistance and treatment failure, extending the useful therapeutic life of current antimalarial drugs, and improving the chances of malaria elimination. We conclude that immediate introduction of TACTs should be considered by policy makers in areas of emerging artemisinin resistance.

P441 Long-term CD treatment failure and dose modification rates with vedolizumab and other biologics: Results from a large prospective observational study

Abstract Background Durable treatment effectiveness is an important consideration in the long-term management of patients with Crohn’s disease (CD) receiving biologic therapy. The aim of this analysis was to evaluate rates of failure and dose modification for biologic treatment over time in patients with CD using data from a large long-term observational study evaluating secondary outcomes in patients initiating treatment on vedolizumab (VDZ) and other biologics. Methods We analysed data from a multicentre, prospective, observational, post-authorisation safety study (PASS; NCT02674308, EUPAS6469) following VDZ or other biologic treatment cohorts under routine standard of care. Longitudinal data on treatment failure (including biologic discontinuation†, IBD non-surgical hospitalization, primary IBD surgery and corticosteroid initiation) up to 36 months and dose modification at any time during the study were analysed in biologic-naïve and biologic-experienced patients with CD in the treatment cohorts. Results The cohort comprised 1338 biologic-naïve patients (pts) (VDZ, n=312; other biologics, n=1026) and 1543 biologic-experienced pts (VDZ, n=829; other biologics, n=714). Baseline pt characteristics (Table 1) were broadly similar across different treatment cohorts, although there were some notable differences with respect to fistulising disease and age at CD diagnosis. Treatment failure rates for biologic-naïve and biologic-experienced pts cumulatively over time at specific time points are shown in Table 2. The proportion of pts continuing biologic treatment with dose modification at any time during the study period for biologic-naïve pts was 13/312 (4.2%) in VDZ-treated pts vs 502/1026 (48.9%) in the group treated with other biologics and 34/829 (4.1%) vs 433/714 (60.6%), respectively for biologic-experienced pts. Conclusion This large observational study reported rates of treatment failure, hospitalization, and IBD-related surgeries during long-term follow-up of biologic-naïve and biologic-experienced pts with CD. Dose modification occurred less frequently in biologic-naïve and biologic-experienced pts treated with VDZ compared with pts receiving other biologic treatments during the study.

Factors associated with successful median arcuate ligament release in an international, multi-institutional cohort

ObjectivePrior research on median arcuate ligament syndrome has been limited to institutional case series, making the optimal approach to median arcuate ligament release (MALR) and resulting outcomes unclear. In the present study, we compared the outcomes of different approaches to MALR and determined the predictors of long-term treatment failure. MethodsThe Vascular Low Frequency Disease Consortium is an international, multi-institutional research consortium. Data on open, laparoscopic, and robotic MALR performed from 2000 to 2020 were gathered. The primary outcome was treatment failure, defined as no improvement in median arcuate ligament syndrome symptoms after MALR or symptom recurrence between MALR and the last clinical follow-up. ResultsFor 516 patients treated at 24 institutions, open, laparoscopic, and robotic MALR had been performed in 227 (44.0%), 235 (45.5%), and 54 (10.5%) patients, respectively. Perioperative complications (ileus, cardiac, and wound complications; readmissions; unplanned procedures) occurred in 19.2% (open, 30.0%; laparoscopic, 8.9%; robotic, 18.5%; P < .001). The median follow-up was 1.59 years (interquartile range, 0.38-4.35 years). For the 488 patients with follow-up data available, 287 (58.8%) had had full relief, 119 (24.4%) had had partial relief, and 82 (16.8%) had derived no benefit from MALR. The 1- and 3-year freedom from treatment failure for the overall cohort was 63.8% (95% confidence interval [CI], 59.0%-68.3%) and 51.9% (95% CI, 46.1%-57.3%), respectively. The factors associated with an increased hazard of treatment failure on multivariable analysis included robotic MALR (hazard ratio [HR], 1.73; 95% CI, 1.16-2.59; P = .007), a history of gastroparesis (HR, 1.83; 95% CI, 1.09-3.09; P = .023), abdominal cancer (HR, 10.3; 95% CI, 3.06-34.6; P < .001), dysphagia and/or odynophagia (HR, 2.44; 95% CI, 1.27-4.69; P = .008), no relief from a celiac plexus block (HR, 2.18; 95% CI, 1.00-4.72; P = .049), and an increasing number of preoperative pain locations (HR, 1.12 per location; 95% CI, 1.00-1.25; P = .042). The factors associated with a lower hazard included increasing age (HR, 0.99 per increasing year; 95% CI, 0.98-1.0; P = .012) and an increasing number of preoperative diagnostic gastrointestinal studies (HR, 0.84 per study; 95% CI, 0.74-0.96; P = .012) Open and laparoscopic MALR resulted in similar long-term freedom from treatment failure. No radiographic parameters were associated with differences in treatment failure. ConclusionsNo difference was found in long-term failure after open vs laparoscopic MALR; however, open release was associated with higher perioperative morbidity. These results support the use of a preoperative celiac plexus block to aid in patient selection. Operative candidates for MALR should be counseled regarding the factors associated with treatment failure and the relatively high overall rate of treatment failure.

Acquired HIV drug resistance among adults living with HIV receiving first-line antiretroviral therapy in Rwanda: A cross-sectional nationally representative survey.

Background:We assessed the prevalence of acquired HIV drug resistance (HIVDR) and associated factors among patients receiving first-line antiretroviral therapy (ART) in Rwanda.Methods:This cross-sectional study included 702 patients receiving first-line ART for at least 6 months with last viral load (VL) results ≥1000 copies/mL. Blood plasma samples were subjected to VL testing; specimens with unsuppressed VL were genotyped to identify HIVDR-associated mutations. Data were analysed using STATA/SE.Results:Median time on ART was 86.4 months (interquartile range [IQR], 44.8–130.2 months), and median CD4 count at ART initiation was 311 cells/mm3 (IQR, 197–484 cells/mm3). Of 414 (68.2%) samples with unsuppressed VL, 378 (88.3%) were genotyped. HIVDR included 347 (90.4%) non-nucleoside reverse transcriptase inhibitor- (NNRTI), 291 (75.5%) nucleoside reverse transcriptase inhibitor- (NRTI) and 13 (3.5%) protease inhibitor (PI) resistance-associated mutations. The most common HIVDR mutations were K65R (22.7%), M184V (15.4%) and D67N (9.8%) for NRTIs and K103N (34.4%) and Y181C/I/V/YC (7%) for NNRTIs. Independent predictors of acquired HIVDR included current ART regimen of zidovudine + lamivudine + nevirapine (adjusted odds ratio [aOR], 3.333 [95% confidence interval (CI): 1.022–10.870]; p = 0.046) for NRTI resistance and current ART regimen of tenofovir + emtricitabine + nevirapine (aOR, 0.148 [95% CI: 0.028–0.779]; p = 0.025), zidovudine + lamivudine + efavirenz (aOR, 0.105 [95% CI: 0.016–0.693]; p = 0.020) and zidovudine + lamivudine + nevirapine (aOR, 0.259 [95% CI: 0.084–0.793]; p = 0.019) for NNRTI resistance. History of ever switching ART regimen was associated with NRTI resistance (aOR, 2.53 [95% CI: 1.198–5.356]; p = 0.016) and NNRTI resistance (aOR, 3.23 [95% CI: 1.435–7.278], p = 0.005).Conclusion:The prevalence of acquired HIV drug resistance (HIVDR) was high among patient failing to re-suppress VL and was associated with current ART regimen and ever switching ART regimen. The findings of this study support the current WHO guidelines recommending that patients on an NNRTI-based regimen should be switched based on a single viral load test and suggests that national HIV VL monitoring of patients receiving ART has prevented long-term treatment failure that would result in the accumulation of TAMs and potential loss of efficacy of all NRTI used in second-line ART as the backbone in combination with either dolutegravir or boosted PIs.

Angiomyomatous hamartoma of subglottic tracheal wall in a 12-year-old adolescent: a case report

BackgroundAllergic rhinitis is the most common allergic disease encountered in a primary care setting. Diagnosis is often made clinically based on response to empiric therapy. However, with long-term treatment failure and/or atypical disease presentation, a differential diagnosis should be considered. The following is a report of an unusual and rare presentation of a subglottic tracheal angiomyomatous hamartoma in an adolescent, treated for many years as allergic rhinoconjunctivitis and asthma.Case presentationA 12-year-old Caucasian was referred to the allergy clinic with a lifetime history of bronchospasms and rhinoconjunctivitis symptoms, treated for many years for asthma and environmental allergies. Cough, posterior nasal drainage, self-described “choking on phlegm,” and a sensation of “a flap in the throat,”, worsened 5 months prior to the initial evaluation. Puncture skin testing for common environmental allergens was negative. Spirometry, performed due to history of chronic cough, showed blunting of the forced expiratory phase. A chest X-ray, immediately ordered to rule out possible extrapulmonary obstruction, showed bilateral bibasilar infiltrates. A noncontrast computerized tomographic scan of the chest, ordered to further elucidate X-ray findings, revealed a subglottic tracheal mass. Following a subsequent transfer and admission to a tertiary hospital center, microlaryngoscopy, bronchoscopy, and microsuspension laryngoscopy were performed to remove the tracheal mass. Pathology confirmed squamous mucosa with polypoid angiomyomatous changes and chronic inflammatory features consistent with angiomyomatous hamartoma. Surgical intervention was successful, and follow-up 1 year postoperatively revealed a healthy, asymptomatic adolescent child with normal lung function.ConclusionsAlthough posterior nasal drainage and cough are typical presenting symptoms in the general patient population, they may be clinically impactful as they could disguise more serious medical conditions. A detailed history and careful physical examination may provide a high index of suspicion of disease, and can help work the differential diagnosis. This case presentation is the first documentation of subglottic hamartoma reported in the pediatric literature with clinical manifestation of environmental allergy and asthma symptoms.

Risk factors for failure of long-term dutasteride add-on treatment to alpha-adrenergic antagonist for patients with lower urinary tract symptoms and benign prostatic enlargement.

To identify the clinical factors resulting in the failure of dutasteride add-on treatment to alpha-adrenergic antagonist for patients with lower urinary tract symptoms and benign prostatic enlargement (BPE). We retrospectively surveyed the patient cohort who had been enrolled in the study of dutasteride add-on treatment to alpha-adrenergic antagonist from December 2009 to November 2011. Treatment failure was defined as receiving surgery for BPE or requiring intermittent catheterization or permanent bladder catheter for urinary retention or huge postvoid residual urine. Clinical parameters before dutasteride treatment were compared between the successful and failed group. Of 92 patients, 23 (25%) were defined as treatment failure at 7-109months (mean: 38months) after dutasteride add-on treatment. In the failed group, the patient' age was younger (71.6 ± 6.8 vs 75.4 ± 8.4, p = 0.033), prostatic volume (PV) was larger (76 ± 41 vs 49 ± 26ml, p = 0.005), voiding efficiency was lower (54 ± 27 vs 68 ± 24%, p = 0.045) and bladder outlet obstruction index was higher (73 ± 30 vs 48 ± 30, p = 0.015). The cox proportional-hazards model indicated that only intravesical prostatic protrusion (IPP) was associated with treatment failure. Non-failure rate at 3years after dutasteride add-on treatment was 89% with patients of IPP < 13mm versus 51% with those of IPP ≥ 13mm (p < 0.001). IPP ≥ 13mm is the risk factor resulting in the failure of dutasteride add-on treatment to alpha-adrenergic antagonist. This kind of information should be provided to the patients early in the clinical practice so that they could consider the necessity of BPE surgery in the long run.

18F]-Fluorodeoxyglucose Positron Emission Tomography/CT to Assess the Early Metabolic Response in Patients with Hormone Receptor-Positive HER2-Negative Metastasized Breast Cancer Treated with Cyclin-Dependent 4/6 Kinase Inhibitors

Introduction: Addition of cyclin-dependent 4/6 kinase (CDK4/6) inhibitors to endocrine therapy is standard of care in the treatment of women with advanced hormone receptor-positive HER2-negative breast cancer. However, the predictive factors for the treatment response to CDK4/6 inhibitor therapy are poorly elucidated. Early changes in the by [¹⁸F]-fluorodeoxyglucose positron emission tomography (FDG-PET) uptake of tumors receiving different kinds of therapy have proven to reliably predict treatment outcomes in a variety of malignancies. Therefore, the feasibility of early metabolic response assessment to predict the long-term treatment response to CDK4/6 inhibitor therapy was evaluated in the present study. Methods: Eight patients underwent FDG-PET/CT before and after the initiation of CDK4/6 inhibitor therapy (ribociclib, palbociclib or abemcaciclib). CDK4/6 inhibitor therapy was combined with either aromatase inhibition or fulvestrant. The median interval between the treatment start (including baseline PET) and the follow-up PET examination was 14 days. Conventional radiographic staging was performed 3 months after the start of CDK4/6 inhibitor therapy. The percentual changes in molecular tumor volume, SUV_peak, the summed SUV_peak of up to 5 metastases (PERCIST-5), and total lesion glycolysis (TLG) were calculated for each patient. Results: Three patients showed progressive disease after 3 months of CDK4/6 inhibitor therapy, whereas 5 patients showed disease control (3 stable disease and 2 partial remission). Disease control was maintained in these patients (follow-up range 7–22 months). Patients with disease control had a significantly greater decline in TLG (–55.3 vs. 16.7%; p < 0.05). The same was true for the PERCIST-5 (–21.9 vs. 11.3%, p < 0.05). All patients with progressive TLG showed treatment failure and/or a poor outcome. Conclusion: Elevated TLG on early FDG-PET seems to be associated with long-term treatment failure and a poor outcome in patients undergoing CDK4/6 inhibitor therapy for metastatic breast cancer. Early findings indicate a potential prognostic value of early FDG-PET in this setting and warrant a prospective evaluation.

Prevalence of insufficient weight loss 5 years after Roux-en-Y gastric bypass: metabolic consequences and prediction estimates: a prospective registry study

ObjectiveThe study aimed to investigate the heterogeneity of weight loss 5 years after Roux-en-Y gastric bypass (RYGB) and the association with cardiometabolic health as well as to model prediction estimates...

Elevated mucus interleukin-17A levels are associated with increased prior sinus surgery for chronic rhinosinusitis.

Recent advances in molecular biology have enabled the identification of potential inflammatory endotypes of chronic rhinosinusitis (CRS), with prior work suggesting differential short-term surgical outcome trajectories based on cytokine signatures. However, there is a paucity of data assessing long-term treatment failure and need for revision surgery based on inflammatory biomarkers. Retrospective analysis of prospectively collected cross-sectional data from 231 patients electing surgical therapy for CRS. Intraoperative mucus specimens were quantitatively sampled for inflammatory cytokines using a multiplex flow cytometric bead assay. Univariate Spearman correlations between cytokine levels and prior number of surgeries were assessed. A stepwise adjusted multivariate Poisson regression analysis was used to model patient-reported prior sinus surgery counts as a function of cytokine levels. Several cytokines (interleukin [IL]-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IL-17A, tumor necrosis factor α [TNF-α], interferon γ [IFN-γ], and eotaxin) demonstrated significant positive correlations with number of prior surgeries. However, only higher IL-17A levels were independently associated with a higher number of prior sinus surgeries (β = 0.345, p = 0.0003) after adjusting for the significant covariates of age (β = 0.018, p = 0.0036), Lund-Mackay score (β = -0.046, p = 0.02), history of aspirin-exacerbated respiratory disease (β = 1.01, p < 0.0001) and allergic fungal rhinosinusitis (β = 1.08, p < 0.0001). Higher levels of regulated on activation, normal T-cell expressed and secreted (RANTES) were conversely associated with a lower number of prior surgeries (β = -0.17, p = 0.048). An IL-17A-predominant cytokine profile is linked to an increased number of prior sinus surgeries. Thus, type 3 inflammatory markers may indicate a particularly difficult-to-treat, recalcitrant CRS endotype.

Surgical debridement of corneal shield ulcers in pediatric patients: two case reports and a review of the literature

BackgroundOcular allergy is a common disease, especially in the pediatric population, with unpleasant and long-term consequences, including corneal complications and decreased visual acuity. This study reports two cases of corneal shield ulcer due to vernal keratoconjunctivitis, with good results of surgical debridement performed after failure of long-term clinical treatment. Furthermore, this study highlights that this therapeutic approach, although less common, is efficient in treating refractory cases that cause suffering in pediatric patients.Case presentationThe first patient was a 7-year-old Caucasian boy with chronic ocular allergy, especially photophobia, who had been treated with eye drops, antihistamine, and corticosteroids for 60 days without success. Biomicroscopy of the right eye showed the presence of gelatinous limbus, giant papillae in the tarsal conjunctiva, and a shield ulcer measuring 6.0 mm vertically and 2.7 mm horizontally. Surgical debridement was performed, and the ulcer did not recur. The second patient was a 4-year-old Caucasian boy with chronic ocular allergy, especially itching and photophobia, who had been treated with eye drops for 1 year without success. Biomicroscopy of the left eye showed a shield ulcer, with a dense central corneal plaque, measuring 8 mm vertically and 3.5 mm horizontally. Surgical debridement of the ulcer was performed immediately because of the chronicity of the case and severity of the lesion, and the treatment was effective.ConclusionsThe treatment of shield ulcers caused by vernal keratoconjunctivitis in the two reported cases was curative and definitive by surgical debridement in the 7-month follow-up period. Therefore, the early debridement of shield ulcers refractory to drug treatment can considerably reduce the time of disease evolution and the probability of ocular complications caused by clinical treatment or disease chronicity. However, this approach is rarely described in the literature and needs to be included in the ophthalmologist’s therapeutic arsenal.

Prevalence of HIV-1 Drug-Resistance Genotypes Among Unique Recombinant Forms from Yunnan Province, China in 2016-2017.

To investigate the prevalence and characteristics of drug-resistance genotypes among unique recombinant forms (URFs) in HIV-1 infected people under long-term antiretroviral treatment failure from Yunnan Province. The plasma samples were collected from antiretroviral therapy (ART)-failure experienced individuals from 2016 to 2017 in Yunnan Province, China. The genotyping drug resistance of HIV-1 pol gene fragments was implemented using in-house assay. According to the analysis of RIP and MEGA 7.0, the HIV-1 strains related to URFs were screened for recombinant identification and drug resistance analysis. A total of 130 pol sequences of HIV-1 URF strains were obtained from 1,121 samples. The proportion of HIV-1 URF strains was 11.6% among the ART-failure individuals from 2016 to 2017 in Yunnan. The overall drug-resistance rate of HIV-1 URF strains was 56.9%. Meanwhile, the percentage of protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) resistance was 3.8% (5/130), 36.2% (47/130), and 53.8% (70/130), respectively. Mutations such as M184V/I (35.4%) in NRTIs and K103N/R/S/T (25.4%), V179D/E/T/Y (18.9%), G190A/E/R/S (13.8%), and Y181C (9.2%) in NNRTIs were common among the HIV-1 URF strains relative to other mutations. Factors such as male, sexual transmission pathway, and source of the year 2017 were significantly correlated with the development of HIV-1 URF drug resistance. The emergence of the multiple recombinant forms identified in Yunnan indicates active transmission networks of HIV-1 of different HIV-1 subtype/circulating recombinant forms cross-infection in this region. Therefore, it is necessary to further monitor the molecular epidemiology and drug resistance of HIV-1 in Yunnan.

The Degree of Ulcerative Colitis Burden of Luminal Inflammation score is superior to predicting medium- to long-term prognosis in patients with active ulcerative colitis.

Aims:The endoscopic evaluation is crucial for the management and treatment of ulcerative colitis (UC). Currently, the Mayo Endoscopic Score (MES) and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) are two major endoscopic score systems to evaluate the status of mucosal inflammation and disease activity. However, in both MES and UCEIS systems, the disease extent is not included. The Degree of Ulcerative Colitis Burden of Luminal Inflammation (DUBLIN) score is a simple clinical score which is calculated as a product of the MES (0–3) and the extent of disease (E1–E3). The objective of this study was to compare the correlation among DUBLIN, UCEIS and MES, and also investigate the clinical characteristics for predicting treatment failure in patients with active UC.Methods:Between March 2015 and April 2019, 172 patients who were previously diagnosed with UC and had undergone colonoscopy were recruited in this study. We retrospectively reviewed the endoscopic scores and clinical characteristics at the time of the colonoscopy and assessed the prognosis of the patients. Endoscopic response was defined as the decrease in MES ⩾1 grade.Results:DUBLIN showed significant correlation with MES (r = 0.748) and partial Mayo score (pMayo) (r = 0.707), and moderately correlated with CRP (r = 0.590). UCEIS also showed strong correlation with MES (r = 0.712) but moderate correlation with pMayo (r = 0.609) and CRP (r = 0.588). Compared with the UCEIS (cut-off value: 4; sensitivity: 75.73%), DUBLIN score (cut-off value: 4; sensitivity: 86.41%) showed higher diagnostic sensitivity than UCEIS score (McNemar test, p < 0.05). Furthermore, a multivariate analysis also revealed that DUBLIN ⩾4 was the independent factor for predicting treatment failure for UC (p < 0.001, odds ratio: 1.547; 95% confidence interval: 1.32–1.88).Conclusion:The DUBLIN score shows superior diagnostic performances in terms of sensitivity value compared with the UCEIS. Moreover, multivariate analysis indicates that DUBLIN ⩾4 is an independent factor for predicting medium- to long-term treatment failure in active UC patients.

Analysis of Linear Relations Between Branch Vessel Catheterisation and Procedure Complexity in Fenestrated and Branched Endovascular Aneurysm Repair

Introduction - The use of fenestrated endovascular aneurysm repair (FEVAR) and branched endovascular aneurysm repair (BEVAR) for the treatment of complex abdominal aortic aneurysms (AAA) is rapidly increasing.1 Successful aneurysm exclusion and prevention of long-term treatment failure need to be balanced against the increased technical complexity and operative risks of more extensive procedures.2 The aim of this study was to analyse the linear relationships between the number of catheterised vessels and various procedural variables for endovascular treatments of complex aortic aneurysms using FEVAR and BEVAR, as compared to conventional endovascular aneurysm repair (EVAR).

ID1 Is Critical for Tumorigenesis and Regulates Chemoresistance in Glioblastoma.

Glioblastoma is the most common primary brain tumor in adults. While the introduction of temozolomide chemotherapy has increased long-term survivorship, treatment failure and rapid tumor recurrence remains universal. The transcriptional regulatory protein, inhibitor of DNA-binding-1 (ID1), is a key regulator of cell phenotype in cancer. We show that CRISPR-mediated knockout of ID1 in glioblastoma cells, breast adenocarcinoma cells, and melanoma cells dramatically reduced tumor progression in all three cancer systems through transcriptional downregulation of EGF, which resulted in decreased EGFR phosphorylation. Moreover, ID1-positive cells were enriched by chemotherapy and drove tumor recurrence in glioblastoma. Addition of the neuroleptic drug pimozide to inhibit ID1 expression enhanced the cytotoxic effects of temozolomide therapy on glioma cells and significantly prolonged time to tumor recurrence. Conclusively, these data suggest ID1 could be a promising therapeutic target in patients with glioblastoma. SIGNIFICANCE: These findings show that the transcriptional regulator ID1 is critical for glioblastoma initiation and chemoresistance and that inhibition of ID1 enhances the effect of temozolomide, delays tumor recurrence, and prolongs survival.

Early vedolizumab trough levels at induction in inflammatory bowel disease patients with treatment failure during maintenance

Vedolizumab (VDZ) is effective as an induction and maintenance treatment for Crohn's disease and ulcerative colitis, but, as observed with antitumour necrosis factor-α (anti-TNFα) agents, some patients are nonetheless experiencing loss of response. The aim of this study was to investigate the impact of the pharmacokinetics of VDZ during induction on long-term treatment response. This study focused on a single cohort of 103 inflammatory bowel disease patients treated with VDZ. VDZ trough levels (TLs) were measured by enzyme-linked immunosorbent assay (n=536 samples), and thereafter correlated to clinical, biological, endoscopic and serological data. For patients exposed previously to infliximab, antibodies to infliximab were measured at baseline. On the basis of the outcome at the end of follow-up, patients were then categorized into long-term response, optimized and treatment failure groups. During VDZ induction, at week 6, inflammatory bowel disease patients with long-term response had higher TLs compared with patients in the treatment failure group (33 vs. 24 µg/ml, P=0.02). A cut-off TL of 28 µg/ml predicted a sustained response in the follow-up with an area under curve of 0.723 (95% confidence interval=0.567-0.878, P=0.02). Patients with mucosal healing in maintenance had higher TLs at week 6 (41.65 µg/ml) compared with patients with mild (26 µg/ml) or severe endoscopic activity (20.8 µg/ml), P=0.009. Positive perinuclear antineutrophil cytoplasmic antibody serology was associated with lower TLs. Patients previously exposed to anti-TNFα had lower TLs than naive patients (22.5 vs. 36 µg/ml, P=0.03) without any impact of detectable antibodies to infliximab. Finally, the presence of an immunomodulator at induction did not impact on VDZ TLs at induction. We confirmed that a drug exposure-efficacy association was found early on at induction. This study emphasizes that previous exposure to anti-TNFα and positive perinuclear antineutrophil cytoplasmic antibody serology are important factors influencing VDZ TLs at induction.

Transobturator Tape: Over 10 Years Follow-up

ObjectivesTo assess subjective and objective outcomes in incontinent patients following “out-in” TOT, at >10-year follow-up; to evaluate effect on quality of life and other urinary symptoms, late adverse events and predictive factors for failure. MethodsThis single-centre prospective study evaluated women with “complicated” or “uncomplicated” stress urinary incontinence (SUI) following “out-i”’ TOT between 2003 and 2007.The pre-op work-up comprised: history; pelvic examination; cough stress test; urodynamic study; UDI-6; and King's Health questionnaires.Work-up was the same as pre-op plus the Patient Global Impression of Improvement scale with final follow-up in 2017. ResultsOne hundred thirty six consecutive patients underwent TOT; at final follow-up (mean 145 months) we evaluated 123. Cure rates: objective: 78.9%; subjective: 62.6%; no significant deterioration in SUI cure rates over time.Urgency and urgency urinary incontinence (UUI) significantly reduced. Voiding dysfunction increased without urodynamic obstruction. De novo urgency appeared in 7.3% and de novo UUI in 4.1%.In the 31 uncomplicated SUI patients, the objective cure rate was 87.1% and the subjective cure rate was 72.2%. De novo urgency appeared in 9.7% and de novo UUI in 3.2%.Nine King's Health questionnaires domains saw statistically significant improvements.In univariate analysis, pre-op wet OAB was associated with subjective recurrent SUI (P < .038) and parity >2 was associated with objective recurrent SUI (P = .023).We had 5 cases of partial mesh exposure. ConclusionCure rates are satisfactory, 10 years after TOT surgery, with good quality of life and few major complications. However, some postoperative symptoms may be caused by long-term treatment failure or by advancing age or another pathology.

Cervical laser vaporization for women with cervical intraepithelial neoplasia-3.

This study evaluated outcomes of laser vaporization of the cervix for women with cervical intraepithelial neoplasia (CIN)-3. We retrospectively reviewed 161 consecutive patients with CIN3 who were treated with cervical laser vaporization between January 2008 and December 2012. At each follow-up visit, histologically confirmed CIN2, CIN3 and invasive carcinoma were defined as treatment failures, as were high-grade squamous intraepithelial lesion (HSIL) or atypical squamous cells that cannot exclude HSIL with subsequent treatment or lost to follow-up. Primary endpoints included long-term follow-up (at least 5 years of regular hospital visits) and treatment failure rate. Treatment failure rates were estimated by the Kaplan-Meier method. Patients' median age was 31 years old. Median follow-up period was 67 months (interquartile range: 52-74 months). Over 5 years, 70.8% continued their follow-up visits, but significantly more patients aged ≥35 years did so (86.4%) than did those aged ≤34 years (61.8%, P = 0.0009). Treatment failure was observed in 14 (8.7%) patients, 1 of whom progressed to invasive cancer (0.6%). Cumulative treatment failure rates were 1-year: 5.1%, 2-year: 6.4% and 5-year: 9.5%. Among patients who suffered treatment failures, 57.1% initial failures occurred within the first year and 71.4% within the first 2 years. Long-term oncologic outcomes of cervical vaporization in CIN3 remain at a suboptimal level. The importance of a minimum of 5 years of regular hospital visits should be emphasized to patients with CIN3 who are candidates for cervical laser vaporization, especially those aged ≤34 years.

Cognitive, Behavioral, and Situational Influences on Relapse to Smoking After Group Treatment for Tobacco Dependence.

Socioeconomic disparities in treatment failure rates for evidence-based tobacco dependence treatment are well-established. Adapted cognitive behavioral treatments are extensively tailored to meet the needs of lower socioeconomic status (SES) smokers and dramatically improve early treatment success, but there is little understanding of why treatment failure occurs after a longer period of abstinence than with standard treatment, why early treatment success is not sustained, and why long-term treatment failure rates are no different from standard treatments. We sought to understand the causes of treatment failure from the perspective of diverse participants who relapsed after receiving standard or adapted treatment in a randomized control trial. We used a qualitative approach and a cognitive-behavioral framework to examine themes in responses to a semi-structured post-relapse telephone interview. The primary causes of relapse were familiar (i.e., habit, stress, unanticipated precipitating events). The adapted treatment appeared to improve the management of habits and stress short-term, but did not adequately prepare respondents for unanticipated events. Respondents reported that they would have benefited from continued support. New therapeutic targets might include innovative methods to reduce long-term treatment failure by delivering extended relapse prevention interventions to support early treatment success.Trial Registration: Clinicaltrials.gov NCT02785536.

Drug resistance evolution in patients with human immunodeficiency virus-1 under long-term antiretroviral treatment-failure in Yunnan Province, China

BackgroundUnderstanding the prevalence and evolution of HIV-1 drug resistance (DR) and associated mutation patterns is critical to implementing free antiretroviral therapy in Yunnan, the first antiretroviral treatment location in China. Here We provide a basis for understanding the occurrence and development of HIV-1 resistance in Yunnan and a theoretical foundational for strategy to delay HIV-1 drug resistance and achieve successful individualized treatment.MethodsPlasma samples from different cities/prefectures were collected at Yunnan Provincial Hospital of Infectious Disease from January 2010 to September 2016, and those from drug-resistant individuals were genotyped using in-house assays, 88 patients were selected for the study who had been on treatment for ≥6 months (and for whom drug resistance was then measured), and each patient had at least 3 genotype resistance tests and who were enrolled to analyze mutation and evolution of HIV resistance.Results264 Pol sequences of 88 patients were obtained. Drug resistance levels to eight drugs increased to varying degrees with prolonged treatment. Resistance to efavirenz (EFV) and etravirine (ETR) showed the highest change, comparisons of resistant changes to second and first and to third and second agents showed altered level of drug resistance were 25 and 20 cases, 28 and 18 cases, respectively. The smallest change was Lopinavir/Ritonavir (LPV/r) present 2 and 3 cases; Resistance to lamivudine (3TC) and lopinavir/ritonavir (LPV/r) was high among patients detected thrice, whereas other drugs were distributed in all resistance levels. M184 V/I (26.14%), T69S (11.36%), and T215Y/I (10.23%) mutations were the most common in nucleoside reverse transcriptase inhibitors (NRTIs), and K103 N/R/S (21.59%), V179D/E (20.45%) in Non-NRTIs (NNRTIs). Furthermore, L10 V/F/I (6.82%), A71V (4.55%), and I54V (4.55%) mutations were common in protease inhibitors (PIs).ConclusionsWe found dynamic genotypic changes in HIV-1 drug-resistance in Yunnan, with prolonged treatment, and drug resistance was inevitable. However, resistance to different drugs occurred at varying times, and mutation site emergence was the main cause. These findings enhance our understanding of evolution and regulation, and are valuable for developing HIV-1 DR prevention strategies in Yunnan.