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Accurate anti-drug antibody (ADA) measurements in patient sera requires dissociation of ADA-drug complexes combined with sensitive and specific ADA detection. Bridging type immunoassays are often used despite several disadvantages associated with this approach. A good drug-tolerant alternative is the acid-dissociation radioimmunoassay (ARIA), but this method is not easily implemented in most labs as specialized facilities are required for working with radioactive materials. We describe an innovative method for ADA detection that combines the advantages of antigen binding tests like the ARIA with the convenience of regular immunoassays. This acid-dissociation lanthanide-fluorescence immunoassay (ALFIA) involves dissociation of ADA-drug complexes, followed by binding to an europium-labeled drug derivative and subsequently an IgG pulldown on Sepharose beads. After europium elution, detection is achieved by measuring time-resolved fluorescence originating from europium chelate complexes. We measured anti-adalimumab ADA levels in sera of 94 rheumatoid arthritis patients using the ALFIA and showed this method to be highly drug tolerant, sensitive and specific for anti-adalimumab ADAs., Competing Interests: Declaration of Competing Interest TR received funding for research from Genmab and consultancy fees from Novartis., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Ursodeoxycholic acid (UDCA) reduces symptomatic gallstone disease after Roux-en-Y gastric bypass (RYGB). The beneficial effect of UDCA is reduced by poor adherence., Objectives: We aimed to identify factors associated with poor adherence to UDCA or placebo after bariatric surgery., Setting: Outpatient clinic and department for bariatric surgery in three hospitals in the Netherlands., Methods: Patients in the multicenter, double-blind, randomized, placebo-controlled UPGRADE trial were assessed for adherence to 900 mg UDCA or placebo for 6 months through a pill count, inquiries during follow-up, and a questionnaire. Poor adherence was defined as the usage of <300 of 364 pills within a maximum of 8 months postoperatively. Multivariable logistic regression analysis was used to identify factors contributing to poor adherence., Results: In total, 967 patients were included (mean age [standard deviation (SD)]: 45.1 [11.1] years; female: 772 [80%]; RYGB: 889 [92%]; sleeve gastrectomy: 78 [8%]), of whom 357 (37%) were poor adherers. Factors associated with poor adherence were age (OR .97; 95% confidence interval [CI] .96-.98, a decrease in age increases the odds for poor adherence), foreign origin (odds ratio [OR] 2.07; 95%CI 1.50-2.84), unemployment (OR 1.73; 95%CI 1.28-2.34), and sleeve gastrectomy (OR 1.79; 95%CI 1.06-3.01). Furthermore, a difference in adherence status was also noted for the centers of surgery., Conclusions: The adherence rate to UDCA and placebo in the UPGRADE trial was suboptimal. Several factors were independently associated with poor adherence. Our findings can help to identify patients who may benefit from extra guidance to improve adherence., (Copyright © 2022. Published by Elsevier Inc.)

Background: Immune checkpoint inhibitors have improved survival outcome of advanced non-small-cell lung cancer (NSCLC). However, most patients do not benefit. Therefore, biomarkers are needed that accurately predict response. We hypothesized that molecular profiling of exhaled air may capture the inflammatory milieu related to the individual responsiveness to anti-programmed death ligand 1 (PD-1) therapy. This study aimed to determine the accuracy of exhaled breath analysis at baseline for assessing nonresponders versus responders to anti-PD-1 therapy in NSCLC patients., Methods: This was a prospective observational study in patients receiving checkpoint inhibitor therapy using both a training and validation set of NSCLC patients. At baseline, breath profiles were collected in duplicate by a metal oxide semiconductor electronic nose (eNose) positioned at the rear end of a pneumotachograph. Patients received nivolumab or pembrolizumab of which the efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at 3-month follow-up. Data analysis involved advanced signal-processing and statistics based on independent t-tests followed by linear discriminant and receiver operating characteristic (ROC) analysis., Results: Exhaled breath data of 143 NSCLC patients (training: 92, validation: 51) were available at baseline. ENose sensors contributed significantly (P < 0.05) at baseline in differentiating between patients with different responses at 3 months of anti-PD-1 treatment. The eNose sensors were combined into a single biomarker with an ROC-area under the curve (AUC) of 0.89 [confidence interval (CI) 0.82-0.96]. This AUC was confirmed in the validation set: 0.85 (CI 0.75-0.96)., Conclusion: ENose assessment was effective in the noninvasive prediction of individual patient responses to immunotherapy. The predictive accuracy and efficacy of the eNose for discrimination of immunotherapy responder types were replicated in an independent validation set op patients. This finding can potentially avoid application of ineffective treatment in identified probable nonresponders., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Anti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction., Patients and Methods: We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation., Results: We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n = 271), EGFR (n = 125), BRAF (n = 43), MET (n = 36), HER2 (n = 29), ALK (n = 23), RET (n = 16), ROS1 (n = 7), and multiple drivers (n = 1). Median age was 60 years, gender ratio was 1 : 1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS = 26%, BRAF = 24%, ROS1 = 17%, MET = 16%, EGFR = 12%, HER2 = 7%, RET = 6%, and ALK = 0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2)., Conclusions: : ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Malignant pleural mesothelioma (MPM) has limited treatment options and a poor outcome. Programmed death 1/programmed death ligand 1 (PD-L1) checkpoint inhibitors have proven efficacious in several cancer types. Nivolumab is a fully humanized monoclonal antibody against programmed death 1 with a favorable toxicity profile. In MPM, the immune system is considered to play an important role. We therefore tested nivolumab in recurrent MPM., Methods: In this single-center trial, patients with MPM received nivolumab 3 mg/kg intravenously every 2 weeks. Primary endpoint was the disease control rate at 12 weeks. Pre- and on-treatment biopsy specimens were obtained to analyze biomarkers for response., Results: Of the 34 patients included, 8 patients (24%) had a partial response at 12 weeks and another 8 had stable disease resulting in a disease control rate at 12 weeks of 47%. One reached a partial response at 18 weeks. In 4 patients with stable disease, the tumor remained stable for more than 6 months. Treatment-related adverse events of any grade occurred in 26 patients (76%), most commonly fatigue (29%) and pruritus (15%). Grades 3 and 4 treatment-related adverse events were reported in 9 patients (26%), with pneumonitis, gastrointestinal disorders, and laboratory disorders mostly seen. One treatment-related death was due to pneumonitis and probably initiated by concurrent amiodarone therapy. PD-L1 was expressed on tumor cells in nine samples (27%), but did not correlate with outcome., Conclusions: Single-agent nivolumab has meaningful clinical efficacy and a manageable safety profile in pre-treated patients with mesothelioma. PD-L1 expression does not predict for response in this population., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

The genotypes of 36 Y-chromosomal short tandem repeat (Y-STR) marker units were analysed in a Dutch population sample of 2085 males. Profiling results were compared for several partially overlapping kits, i.e. PowerPlex Y, Yfiler, PowerPlex Y23, and two in-house designed multiplexes with rapidly mutating Y-STRs. Nineteen Y-STR marker units, of which two are rapidly mutating, reside in at least two of these multiplexes, and for these markers concordance testing was performed. Two samples showed discordant genotyping results and the probable causative base change was revealed by Sanger sequencing. In addition, we encountered concordant, but aberrant genotyping results including one allele with low peak height and several null alleles. For 12 samples, this involved a null allele in two adjacent loci suggesting a large and recurrent deletion as the samples represent three distinct haplogroups. For each marker unit, the allele counts and frequencies are presented, as are the haplotype counts and haplotype diversities for several combinations of markers., (Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: Laparoscopic adjustable gastric banding (LAGB) is a standard restrictive bariatric procedure. Previous studies have shown that patients lost to follow-up do worse than patients who remain in follow-up. However, it is unknown if this is purely because of a lack of band adjustments. The aim of this study was to study the relation between number of adjustments and results., Methods: Patients who underwent primary LAGB from October 2006 until March 2009 were included. The following parameters were collected: demographic characteristics, preoperative and postoperative weight, preoperative and postoperative status of co-morbidities, type of band, short- and long-term complications, reoperations, date, number and volume of adjustments, total amount of inserted volume, and last measured volume., Results: One hundred seventy-four patients underwent primary LAGB. Twelve patients did not attend follow-up visits after 24 months (8.1%). Mean follow-up was 46 months, and excess weight loss, 47%. Eleven patients (8.1%) developed long-term complications, and 12 patients (8.8%) underwent revisional surgery. Patients underwent a mean number of 5 adjustments with a range of 0 to 18. The mean volume of totally inserted milliliters was 8 mL, with a range of 0 to 14 mL. There was a strong positive relation between number of adjustments and weight loss as well as reduction in obesity-related co-morbidities (r = .22; P<.01). There was no significant relation between number of adjustments and complications or revisional surgery., Conclusion: There is a strong relation between the number of band adjustments and weight loss, whereas complications and reoperations seem to be independent of the number of adjustments. A continual and lifelong follow-up of LAGB patients, including regular band volume adjustments, is necessary., (Copyright © 2013 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB) are frequently used bariatric procedures. With both techniques, LAGB more than RYGB, failures occur. After years of experience with both techniques, we present a series of patients who underwent RYGB after failed LAGB. The band was kept in place. Our objective was to evaluate the safety and short-term effectiveness of RYGB after failed LAGB, without removing the band. The setting was a large teaching hospital in Heerlen, The Netherlands., Methods: We first retrospectively considered the efficacy and complication rate of adding an adjustable band to RYGB. This was safe and effective. The patients lost a median of 7.6 kg within a median period of 21 months. The complication rate was low. Observing the positive results in this group, we began to leave the band in place when converting patients from LAGB to RYGB., Results: A total of 12 patients underwent revision of LAGB to RYGB. There was no mortality. The complication rate and severity were low. During a median period of 16 months, the patients lost a median of 23 kg or 8 points in the body mass index. Also, additional improvement in co-morbidities was observed., Conclusion: Our results suggest that performing RYGB after LAGB and leaving the band in place is feasible, safe, and effective in the short term., (Copyright © 2012 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: After Roux-en-Y gastric bypass (RYGB), a substantial number of patients do not achieve successful long-term weight loss. In cases of loss of restriction, the application of an adjustable gastric band ("salvage banding") over the gastric pouch, or gastrojejunostomy, could prevent weight regain or increase weight loss. The objective of this literature review is to provide an overview of the studies that report the effect of salvage banding after failed RYGB., Methods: A systemic literature search was conducted in PubMed, Google Scholar, Medline, the Cochrane Library, and the online websites of specific bariatric surgery journals to identify all relevant studies describing salvage banding after failed RYGB., Results: Seven studies, with a total of 94 patients, were included for a systemic literature review. Inclusion criteria for salvage banding varied from unsuccessful weight loss to technical pouch failure. After salvage banding, all studies reported further weight loss, varying from 55.9%-94.2% excess body mass index loss (EBMIL) after 12-42 months of follow-up. In the included study group, 18% (17/94) of the patients developed long-term complications requiring a re-revision in 17% (16/94) of the cases., Conclusion: The results of all 9 studies that were included in this review report a further increase in weight loss after salvage banding for failed RYGB. In case of insufficient weight loss or technical pouch failure after RYGB, all reports suggest that salvage banding is a safe and feasible revisional procedure. Prospective studies are necessary to determine to the success of direct application of an adjustable gastric band in primary RYGB., (Copyright © 2012 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Cryosurgery is a relatively new treatment option for vein stripping in case of insufficiency of the great saphenous vein (GSV). A prospective randomized trial was performed to compare operation time, extracted vein length, and postoperative outcomes of cryosurgery with conventional short stripping. Forty patients with one-sided, duplex-proven insufficiency of the GSV were included. Operation time was shorter with cryosurgery, 17.6 +/- 1.11 vs. 20 +/- 0.80 min. Extracted vein length was significantly longer with conventional stripping, 40 +/- 1.45 vs. 28 +/- 1.46 cm. After the operation, all symptoms of venous insufficiency decreased significantly in both groups. In the first 2 weeks after operation, pain scores were higher in the cryosurgery group, but the difference was only significant on the fifth postoperative day. Postoperative mobility, hematoma formation, and complications were not significantly different. Cryosurgery has comparable postoperative results with conventional short stripping. Operation time is reduced with cryosurgery, but postoperative pain scores are higher. Patients favor cryosurgery because of better cosmetic results.

Recombination can result in genetic instability, and thus constitutes an important factor in the carcinogenic conversion of mammalian cells. Here we describe the occurrence of UV-stimulated recombination called enhanced recombination (EREC), measured with the use of Herpes Simplex Viruses type 1 mutants. In normal diploid human cells, EREC is induced by UV-C, mitomycin C and ENU, but not by X-ray or MMS. The kinetics of induction of EREC is similar to that of other SOS-like responses such as enhanced reactivation (ER) and enhanced mutagenesis (EM). In contrast to the latter responses, EREC is induced to higher levels and persists for longer periods in DNA repair deficient fibroblasts derived from xeroderma pigmentosum (XP), Cockayne syndrome (CS) and Trichothiodystrophy (TTD) patients. This observation indicates that EREC is a distinct SOS-like response. Apparently, the presence of unrepaired DNA lesions in the host genome is a strongly inducing signal for EREC. On the other hand, in cells derived from patients suffering from Bloom, Werner or Rothmund-Thomson syndrome (RTS) the EREC response is absent. These data indicate that determining EREC is a useful assay to investigate diploid human fibroblasts for abnormalities in UV-stimulated recombination.

The stabilization of p53 protein was studied after UV exposure of normal human skin fibroblasts and cells derived from patients suffering from xeroderma pigmentosum (XP) and trichothiodystrophy (TTD). The data show that p53 is transiently stabilized both in UV-irradiated normal and repair deficient cells. However, particularly at later times after UV irradiation, stabilization of p53 persists much longer in repair deficient XP and TTD cells than in normal cells. The stabilization of p53 was found to be dose-dependent in normal and XP cells. These results indicate that unremoved DNA damage could possibly be responsible for the induction of transient stabilization of p53.