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Abstract Background 15-20% of all patients initially diagnosed with colorectal cancer develop metastatic disease and surgical resection remains the only potentially curative treatment available. Current 5-year survival following R0-resection of liver metastases is 28-39%, but recurrence eventually occurs in up to 70%. To date, adjuvant chemotherapy has not improved clinical outcomes significantly. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer patients following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from colorectal cancer. In a phase IIB trial, L-BLP25 has shown acceptable tolerability and a trend towards longer survival in patients with stage IIIB locoregional NSCLC. Methods/Design This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 patients from 20 centers in 3 countries. Patients with stage IV colorectal adenocarcinoma limited to liver metastases are included. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous metastases, eligible patients are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with s.c. L-BLP25 930 μg once weekly for 8 weeks, followed by s.c. L-BLP25 930 μg maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals unless recurrence occurs. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint is the comparison of recurrence-free survival (RFS) time between groups. Secondary endpoints are overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. The primary endpoint will be assessed in Q3 2016. Follow-up will end Q3 2017. Interim analyses are not planned. Discussion The design and implementation of such a vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion. Trial Registration EudraCT Number 2011-000218-20

Abstract Background As myocardial oxygenation may serve as a marker for ischemia and microvascular dysfunction, it could be clinically useful to have a non-invasive measure of changes in myocardial oxygenation. However, the impact of induced blood flow changes on oxygenation is not well understood. We used oxygenation-sensitive CMR to assess the relations between myocardial oxygenation and coronary sinus blood oxygen saturation (SvO2) and coronary blood flow in a dog model in which hyperemia was induced by intracoronary administration of vasodilators. Results During administration of acetylcholine and adenosine, CMR signal intensity correlated linearly with simultaneously measured SvO2 (r2 = 0.74, P < 0.001). Both SvO2 and CMR signal intensity were exponentially related to coronary blood flow, with SvO2 approaching 87%. Conclusions Myocardial oxygenation as assessed with oxygenation-sensitive CMR imaging is linearly related to SvO2 and is exponentially related to vasodilator-induced increases of blood flow. Oxygenation-sensitive CMR may be useful to assess ischemia and microvascular function in patients. Its clinical utility should be evaluated.

Background: In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available., Methods: GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0-2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m 2 , days 1-2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m 2 , days 1-3) and intravenous cyclophosphamide (250 mg/m 2 , days 1-3). Intravenous rituximab (375 mg/m 2 , day 1 of cycle 1; 500 mg/m 2 , day 1 of cycles 2-6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax-rituximab group, intravenous rituximab (375 mg/m 2 , day 1 of cycle 1; 500 mg/m 2 , day 1 of cycles 2-6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2-6: 1000 mg on day 1). In the venetoclax-obinutuzumab-ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax-rituximab and the venetoclax-obinutuzumab group and between 12 and 36 cycles in the venetoclax-obinutuzumab-ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment., Findings: Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax-rituximab group n=237; venetoclax-obinutuzumab group n=229; and venetoclax-obinutuzumab-ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6-57·9]), patients in the venetoclax-obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32-0·69], p<0·0001) and the venetoclax-rituximab group (0·57 [0·38-0·84], p=0·0011). The venetoclax-obinutuzumab-ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19-0·47]; p<0·0001) and the venetoclax-rituximab group (0·38 [0·24-0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax-obinutuzumab-ibrutinib and venetoclax-obinutuzumab groups (0·63 [0·39-1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax-rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9-91·1; 37 [16%] events) in the venetoclax-obinutuzumab-ibrutinib group, 81·8% (75·8-87·8; 55 [24%] events) in the venetoclax-obinutuzumab group, 70·1% (63·0-77·3; 84 [35%] events) in the venetoclax-rituximab group, and 62·0% (54·4-69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax-rituximab group, 127 [56%] of 228 in the venetoclax-obinutuzumab group, and 112 [48%] of 231 in the venetoclax-obinutuzumab-ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax-rituximab and venetoclax-obinutuzumab groups, and four (2%) in the venetoclax-obinutuzumab-ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy)., Interpretation: With more than 4 years of follow-up, venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax-rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination., Funding: AbbVie, Janssen, and F Hoffmann-La Roche., Competing Interests: Declaration of interests MF reports research funding from AbbVie, AstraZeneca, BeiGene, Janssen, and Roche, and honoraria from AbbVie. JvT reports honoraria from AbbVie, BeiGene, Amgen, AstraZeneca, Janssen, Lilly, and Roche; travel grants from AbbVie, AstraZeneca, BeiGene, Roche, Lilly, and Janssen; and has received consulting fees from and participated on advisory boards for AbbVe, BeiGene, Amgen, and AstraZeneca. MG has received honoraria for participation in symposia and advisory boards from AbbVie, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb (BMS)/Celgene, GSK, Novartis, Incyte, Janssen-Cilag, Jazz, Roche, Pfizer, Sanofi, and Servier; travel support from AbbVie, BeiGene, Pfizer, and Roche; all fees went to their institution. GJ has received honoraria from Astellas and AbbVie and participated on advisory boards for AbbVie and Servier. M-DL reports travel grants from AbbVie and Janssen. CdC-B reports consulting fees from Janssen, honoraria for lectures from Octapharma, support for attending meetings from AbbVie and Octapharma, and participation on advisory boards for Janssen, BeiGene, and AstraZeneca. CSchn reports speakers fees from AstraZeneca and AbbVie, travel support from AbbVie, and participation on an advisory board for Janssen. RB reports travel support from BeiGene, Janssen, and AbbVie, and honoraria for participation on an advisory board from AbbVie. TN reports honoraria for lectures or presentations and has participated at advisory boards from AbbVie, Roche, AstraZeneca, Gilead, BeiGene, and Janssen. CBP is the chairman of the Danish CLL group. HF reports research funding from Sanofi, Novartis, and Alexion and honoraria for lectures from Sanofi. NK reports research funding from AstraZeneca; honoraria from AbbVie, AstraZeneca, Kite/Gilead, BMS, and Lilly; and travel support from AbbVie, AstraZeneca, BeiGene, Lilly, and Janssen; and participation on advisory boards for AstraZeneca and Janssen. JD reports consulting fees, honoraria, and travel support from AbbVie and Janssen. SB reports honoraria from and participation on speakers bureaus for Roche, Janssen, AbbVie, AstraZeneca, and Sanofi; travel support from Janssen, BeiGene, and Roche; and research funding from Janssen and Miltenyi. FS reports speakers fees from AstraZeneca, travel support from Lilly, and research funding from AstraZeneca. A-MF reports research funding and honoraria from AstraZeneca and travel support from AbbVie. KF reports research grants from AbbVie and Roche, honoraria for advisory boards from AstraZeneca, and travel support from Roche. K-AK reports consulting fees, participation on speakers bureaus, and research funding from Roche, AbbVie, and Janssen. MR reports honoraria from Janssen, Roche, and AstraZeneca; consulting fees from Roche, Janssen, AstraZeneca, and AbbVie; research funding from AbbVie and Roche, and travel support from AstraZeneca. MBr reports research funding and consulting fees from Amgen; honoraria for speakers bureaus from Amgen, Becton Dickinson, Janssen, and Pfizer; travel support from Janssen; and participation on advisory boards for Incyte and Amgen. ET reports participation on advisory boards and honoraria from AbbVie, Janssen-Cilag, and BeiGene, AstraZeneca, and Roche; and travel support from AstraZeneca, AbbVie, BeiGene, Janssen. SS reports honoraria from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, and Sunesis; research funding from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, and Sunesis; travel support from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis; and speaker fees from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, and Sunesis. MH reports consulting fees from Roche, Gilead, Janssen, BMS, AbbVie, and AstraZeneca and honoraria from Roche, Gilead, Janssen, BMS, AbbVie, and AstraZeneca. APK reports honoraria from AbbVie, AstraZeneca, BMS, Janssen, LAVA, and Roche/Genentech; travel grants from AbbVie and Janssen; research funding from AstraZeneca, Janssen, Roche/Genentech, AbbVie, and BMS. CUN reports research funding from Octapharma and AstraZeneca; consultancy and speaker fees from AbbVie, AstraZeneca, Janssen, Genmab, BeiGene, Octapharma, CSL Behring, Takeda, Lilly, and MSD; and participation on advisory boards for AstraZeneca, MSD, Genmab, and Janssen. BE reports consulting fees fromJanssen, AbbVie, Gilead, AstraZeneca, MSD, BeiGene, and Lilly; participation on speakers bureau for Roche, AbbVie, BeiGene, AstraZeneca, and MSD; honoraria from Roche, AbbVie, AstraZeneca, BeiGene, and MSD; research funding from Janssen, Gilead, Roche, AbbVie, BeiGene, and AstraZeneca; and travel support from BeiGene. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Internet-based interventions have proven to be effective for the treatment of depression in different samples, but evidence from the Middle East and North Africa (MENA) region is scarce. The aim of this study was to investigate the acceptance and efficacy of an internet-based cognitive behavioural writing intervention for Arabic-speaking participants with depression living in the MENA region. A total of 259 participants (167 female, age in years: M = 25.58, SD = 6.39) with depressive symptoms indicative of clinical relevance were randomly allocated to a treatment group (TG; n TG  = 128) or a waitlist control group (WG; n WG  = 131). The TG received an internet-based intervention over a 6-week period. The primary outcome was depressive symptoms, and secondary outcomes were anxiety and quality of life (QoL). T-tests with change scores from pre- to post-treatment were used for data analyses. Intention-to-treat (ITT) as well as completer analyses were calculated. The ITT analysis revealed significant differences between the TG and WG in depression (T 257  = -4.89, p < 0.001, d = 0.70) and QoL (T 257  = 3.39, p < 0.001, d = 0.47). Significant differences regarding anxiety symptoms (T 257  = 3.25, p < 0.05, d = 0.53) were identified for the completer sample. The general dropout rate was 39.9%. The results indicate the feasibility and efficacy of an internet-based cognitive behavioural writing intervention in adults from Arabic-speaking countries. The development and implementation of such interventions can be used to improve access to psychological help and adequate treatment., (© 2024 The Author(s). Stress and Health published by John Wiley & Sons Ltd.)

Background: Maladaptive trauma appraisal plays an important role in the development and maintenance of posttraumatic stress disorder (PTSD). While studies have demonstrated the effectiveness of exposure and cognitive treatments for PTSD symptomatology, the effect of such treatments on specific trauma appraisals is still not well understood. Objective: The study investigated the effect of an exposure and a cognitive restructuring internet-based treatment on specific trauma appraisals in Arabic-speaking participants with PTSD. Method: 334 participants received either an exposure ( n  = 167) or a cognitive restructuring ( n  = 167) internet-based treatment. PTSD symptom severity (PCL-5) and specific trauma appraisals (TAQ) were assessed at pre- and post-treatment. Changes in specific trauma appraisals within and between the two treatments were analyzed using multi-group change modelling. Associations between changes in PTSD symptom severity and changes in trauma appraisals were evaluated using Pearson product-moment correlation. For both treatments, participants with versus without reliable improvement were compared regarding changes in specific trauma appraisals using Welch tests. Analyses were performed on 100 multiple imputed datasets. Results: Both treatments yielded significant changes in shame, self-blame, fear, anger, and alienation (all p s < .001). Changes in betrayal were only significant in the cognitive restructuring treatment ( p < .001). There was no evidence of differences between treatments for any specific trauma appraisal. Changes in PTSD symptom severity were significantly associated with changes in trauma appraisals (all p s < .001). In both treatments, participants who experienced reliable improvement in PTSD symptom severity showed significantly larger pre- to post-treatment changes in specific trauma appraisals compared to those without reliable improvement. Again, differences in betrayal were only significant in the cognitive restructuring treatment. Conclusions: The findings indicate that both treatments are effective in reducing trauma appraisals in Arabic-speaking people with PTSD. Changes in trauma appraisal seem to be associated with changes in PTSD symptomatology. Trial registration: German Clinical Trials Register identifier: DRKS00010245.

Many people from the Middle East and North Africa (MENA) have experienced traumatic events due to human rights abuses, violence, and conflict in the region, with potential psychological consequences including symptoms of posttraumatic stress and comorbid mental health problems. Yet, little is known about how different posttraumatic stress symptoms unfold in Arabic-speaking people who have experienced diverse traumatic events. This study examined latent classes based on posttraumatic stress symptoms, differences across classes concerning comorbid mental health symptoms and quality of life, and several predictors, including sociodemographic characteristics, social support, and trauma-related characteristics. Participants were 5,140 traumatized Arabic-speaking individuals who had registered for an online intervention. Latent class analysis was conducted to identify distinct classes based on DSM-5 posttraumatic stress symptoms. Multinomial logistic regression was used to analyze predictors of class membership. Differences between classes in severity of posttraumatic stress, depressive, anxiety, and somatoform symptoms, as well as quality of life were examined. Five different latent classes were identified: a general high posttraumatic stress symptom class (43.8%), a high posttraumatic stress symptom-low avoidance class (12.8%), a mixed posttraumatic stress symptom class (20.9%), a high dysphoric-low reexperiencing/avoidance class (14%), and a general low posttraumatic stress symptom class (8.4%). The classes differed in severity of posttraumatic stress, depressive, anxiety and somatoform symptoms, and quality of life. Consistent significant predictors of class membership were gender, social support, cumulative trauma exposure, sexual violence and direct exposure during the most distressing trauma, as well as time since the most distressing trauma. Distinct symptom classes with quantitative and qualitative differences can emerge following exposure to trauma among help-seeking Arabic-speaking people from the MENA region, with gender, social support, and trauma-related characteristics predicting symptom presentation. The results have implications for identifying distressed people and enhancing interventions based on an individual's symptom presentation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Stein et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Cognitive behavioral interventions delivered via the internet are demonstrably efficacious treatment options for posttraumatic stress disorder (PTSD) in underserved, Arabic-speaking populations. However, the role of specific treatment components remains unclear, particularly in conflict-affected areas of the Middle East and North Africa., Objective: This study aims to evaluate 2 brief internet-based treatments in terms of efficacy, including change in PTSD symptom severity during treatment. Both treatments were developed in line with Interapy, an internet-based, therapist-assisted cognitive behavioral therapy protocol for PTSD and adapted to the specific research question. The first treatment comprised self-confrontation and social sharing (exposure treatment; 6 sessions); the second comprised cognitive restructuring and social sharing (cognitive restructuring treatment; 6 sessions). The 2 treatments were compared with each other and with a waitlist control group., Methods: In total, 365 Arabic-speaking participants from the Middle East and North Africa (mean age 25.49, SD 6.68 y) with PTSD were allocated to cognitive restructuring treatment (n=118, 32.3%), exposure treatment (n=122, 33.4%), or a waitlist control group (n=125, 34.2%) between February 2021 and December 2022. PTSD symptom severity, posttraumatic maladaptive cognitions, anxiety, depressive and somatoform symptom severity, and quality of life were assessed via self-report at baseline and after treatment or waiting time. PTSD symptom severity was also measured throughout treatment or waiting time. Treatment satisfaction was assessed after treatment completion. Treatment use and satisfaction were compared between the 2 treatment conditions using appropriate statistical tests (eg, chi-square and Welch tests). Multiple imputation was performed to address missing data and evaluate treatment-associated changes. These changes were analyzed using multigroup change modeling in the completer and intention-to-treat samples., Results: Overall, 200 (N=240, 83.3%) participants started any of the treatments, of whom 123 (61.5%) completed the treatment. Treatment condition was not significantly associated with the proportion of participants who started versus did not start treatment (P=.20) or with treatment completion versus treatment dropout (P=.71). High treatment satisfaction was reported, with no significant differences between the treatment conditions (P=.48). In both treatment conditions, PTSD, anxiety, depressive and somatoform symptom severity, and posttraumatic maladaptive cognitions decreased, and quality of life improved significantly from baseline to the posttreatment time point (P≤.001 in all cases). Compared with the baseline assessment, overall PTSD symptom severity decreased significantly after 4 sessions in both treatment conditions (P<.001). Moreover, both treatment conditions were significantly superior to the waitlist control group regarding overall PTSD symptom severity (P<.001) and most other comorbid mental health symptoms (P<.001 to P=.03). Differences between the 2 conditions in the magnitude of change for all outcome measures were nonsignificant., Conclusions: Internet-based cognitive behavioral treatments for PTSD focusing primarily on either self-confrontation or cognitive restructuring are applicable and efficacious for Arabic-speaking participants., Trial Registration: German Clinical Trials Register DRKS00010245; https://drks.de/search/de/trial/DRKS00010245., (©Jana Stein, Max Vöhringer, Birgit Wagner, Nadine Stammel, Yuriy Nesterko, Maria Böttche, Christine Knaevelsrud. Originally published in JMIR Mental Health (https://mental.jmir.org), 13.12.2023.)

Introduction: Prolonged grief disorder (PGD) has been included as a new diagnosis in the ICD-11 and is set to be included in the DSM-5-TR. To better identify vulnerable individuals, different factors associated with PGD have to be taken into account, but results regarding these factors remain equivocal. Moreover, few studies on PGD are available from Arabic-speaking populations and from different countries dealing with conflicts and wars. The objective was thus to examine PGD prevalence and associated characteristics in these populations., Materials and Methods: A total of N = 1,051 bereaved participants from Arabic-speaking populations completed the PG-13 as part of a screening procedure for an online mental health intervention. Multiple linear regression was conducted to examine associated factors for PGD symptom severity, and multiple logistic regression was applied to investigate associated factors for PGD according to PG-13 diagnostic criteria., Results: Of the participants, 18.8% ( n = 198) met the PGD diagnostic criteria, at an average of about 6 years post-loss. The multiple linear regression yielded eight associated factors for PGD symptom severity (age, gender, number of losses, number of traumatic event types, relationship with the deceased, age at loss, impairment during first year post-loss, perceived social support), which explained 40.2% of the variance [ F (17, N=1,033) = 40.82, p < 0.001, R 2 = 0.402]. The multiple logistic regression yielded five significant associations with PGD (gender, relationship with the deceased, number of lost persons, impairment during first year post-loss, perceived social support), which explained 33.0% (Nagelkerke R 2 ) of the variance in PGD according to PG-13 diagnostic criteria., Discussion: A substantial proportion of the participants met the PG-13 criteria for PGD, emphasizing that therapeutic services are indispensable in this population. The associated factors for PGD found in our Arab-speaking sample are largely consistent with those found in studies from other regions. The slightly differing numbers of associated factors between the linear and logistic regression underline that a continuous score reflects the continuum between normal and dysfunctional grieving, and therefore also a range of factors associated with PGD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Specht, Vöhringer, Knaevelsrud, Wagner, Stammel and Böttche.)

Metastatic colorectal cancer (mCRC) patients with liver-limited disease (LLD) have a chance of long-term survival and potential cure after hepatic metastasectomy. However, the appropriate postoperative treatment strategy is still controversial. The CELIM and FIRE-3 studies demonstrated that secondary hepatic resection significantly improved overall survival (OS). The objective of this analysis was to compare these favorable outcome data with recent results from the LICC trial investigating the antigen-specific cancer vaccine tecemotide (L-BLP25) as adjuvant therapy in mCRC patients with LLD after R0/R1 resection. Data from mCRC patients with LLD and secondary hepatic resection from each study were analyzed for efficacy outcomes based on patient characteristics, treatment and surveillance after surgery. In LICC, 40/121 (33%) patients, in CELIM 36/111 (32%) and in FIRE-3-LLD 29/133 (22%) patients were secondarily resected, respectively. Of those, 31 (77.5%) patients in LICC and all patients in CELIM were R0 resected. Median disease-free survival after resection was 8.9 months in LICC, 9.9 months in CELIM. Median OS in secondarily resected patients was 66.1 months in LICC, 53.9 months in CELIM and 56.2 months in FIRE-3-LLD. Median age was about 5 years less in LICC compared to CELIM and FIRE-3. Secondarily resected patients of LICC, CELIM and FIRE-3 showed an impressive median survival with a tendency for improved survival for patients in the LICC trial. A younger patient cohort but also more selective surgery, improved resection techniques, deep responses and a close surveillance program after surgery in the LICC trial may have had a positive impact on survival., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Internet-based cognitive-behavioural interventions seem to be effective for the treatment of posttraumatic stress disorder (PTSD) in Arabic-speaking countries in the MENA region. However, due to high prevalence rates of trauma-related mental disorders in this region, it is important to scale up existing Internet-based interventions in order to increase the number of clients., Objective: The aim of the study was to examine whether a brief Internet-based intervention with one cognitive technique (TF-short, 6 assignments) results in the same PTSD symptom change and lower dropouts compared to a longer intervention with two cognitive techniques (TF-reg, 10 assignments)., Method: A total of 224 Arab participants (67.4% female; M = 25.3 years old) with PTSD were randomly assigned to Internet-based CBT with either a TF-reg protocol ( n  = 110) or a TF-short protocol ( n  = 114). Symptoms of PTSD and secondary outcomes (anxiety, depression, somatic complaints, quality of life) were self-assessed online at baseline and post-treatment. Treatment-associated changes were estimated using multigroup latent difference score models., Results: The overall PTSD score assessed with the PDS decreased by about 15 points in both conditions. The between-group differences (TF-reg vs. TF-short) at post-assessment were non-significant, Δ = 0.29, p = .896, d = 0.02, 95% CI [-0.30, 0.34]. Like the primary outcome, all within-group changes for the secondary outcomes throughout the intervention were statistically significant and all between-group effects were non-significant. Overall, the dropout rates did not differ between the two conditions, χ2 (1/ N  = 175) = 0.83, p = .364., Conclusions: The findings suggest that the shorter condition results in the same symptom change and dropout rate as the longer condition. This highlights the potential of shorter, more scalable Internet-based interventions in socially restricted and (post-)conflict societies., Clinicaltrialsgov Id: NCT01508377., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Resection of colorectal liver metastases (CRLM) is a potential curative treatment for patients with metastatic colorectal cancer (mCRC) with liver-limited disease (LLD). Although long-term survival improved considerably within the last decades, high recurrence rates of 50-75% after resection remain a major challenge.Tecemotide (L-BLP25) is an antigen-specific cancer vaccine inducing immunity against mucin-1 (MUC1). The LICC trial aimed to improve survival in patients with mCRC after R0/R1 resection of CRLM. LICC was a binational, randomized, double-blind, placebo-controlled, multicenter phase 2 study including patients with R0/R1 resected CRLM without evidence of metastatic disease outside the liver. Co-primary endpoints were recurrence-free survival (RFS) and 3-year overall survival (OS) rate, secondary endpoints were RFS and OS in subgroups with different MUC1 expression and safety. In total, 121 patients were 2:1 randomized between Oct 2011 and Dec 2014to receive tecemotide (N=79) or placebo (N=42). Baseline characteristics were well balanced. Median RFS was 6.1 months (95% CI 4.5-8.9) and 11.4 months (95% CI 3.7-21.2) ( P = .1754), 3-year OS rate 69.1% and 79.1%, median OS 62.8 months and not reached in the tecemotide vs. placebo arm ( P = .2141), respectively. Cox regression models revealed no dependence of RFS or OS on MUC1 expression. The most common tecemotide-related grade 3/4 adverse events were diarrhea, injection site reaction, intestinal perforation, peritonitis and tinnitus (1.3% each). The LICC trial failed to meet its primary endpoints of significantly improving RFS and OS with tecemotide. However, both arms showed unexpectedly long OS. MUC1 expression was not associated with outcome.EudraCT No: 2011-000218-20Clinical Trial Information: NCT01462513Financial Support: Merck KGaA, Darmstadt, Germany., Abbreviations: AE: adverse event; CP: cyclophosphamide; CRC: colorectal cancer; CT: computed tomography; ECOG: Eastern Cooperative Oncology Group; FU: follow-up; HR: hazard ratio; IHC: immunohistochemical staining; ITT: intention-to-treat; DSMB: Data Safety Monitoring Board; LLD: liver-limited disease; mCRC: metastatic colorectal cancer; MPLA: monophosphoryl lipid; AMRI: magnetic resonance imaging; MUC1: mucin 1; NA: not applicable; NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; NS: normal saline; NSCLC: non-small-cell lung carcinoma; OS: overall surviva; lPP: per protocol; RAS: Rat sarcoma; RFS: recurrence-free survival; TEAE: treatment-emergent adverse event; UICC: Union for International Cancer Control; US: ultrasound; vs.: versus., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background : Dropout from psychotherapy has negative impacts on clients, therapists, and health-care agencies. Research has identified a variety of variables as predictors of dropout, which can be grouped in three domains: socio-demographic, psychological, and treatment-related variables. Objective : In order to further clarify the question of predictors of dropout, an exploratory research design was applied to a large sample, testing 25 different variables from the three domains as possible predictors. Method : The sample included 386 adults who started an internet-based cognitive-behavioural treatment approach for posttraumatic stress disorder (PTSD) in Arabic. As the participants had different countries of origin and of current residence, multilevel analyses were performed. For the selection of predictor variables, the Least Absolute Shrinkage and Selection Operator was used. Results : Dropout rates did not vary significantly between participants from different countries of origin or from different countries of residence. Likewise, dropout did not vary significantly between clusters of individuals with the same country of origin and the same country of residence, i.e. the same migration path. Three of the 25 variables were identified as significant predictors for dropout: marital status (divorced participants' probability to drop out was higher compared to non-divorced, i.e. single, married, or widowed, clients), treatment credibility scores (higher dropout probability of participants with lower treatment credibility), and the participants' year of registration for the treatment (earlier years of registration predicted lower dropout probability). The overall ability of the three-factor-model to discriminate between dropout and completion was poor (AUC = 0.652, with low sensitivity and acceptable specificity). Conclusions : The predictors belong to the treatment-related domain (credibility, year of registration) or are specific to the target group (marital status). However, the results show that predicting treatment dropout continues to be a very challenging endeavour and indicate that it is important to look at each intervention individually., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Contact-active antimicrobial polymer surfaces bear cationic charges and kill or deactivate bacteria by interaction with the negatively charged parts of their cell envelope (lipopolysaccharides, peptidoglycan, and membrane lipids). The exact mechanism of this interaction is still under debate. While cationic antimicrobial polymer surfaces can be very useful for short-term applications, they lose their activity once they are contaminated by a sufficiently thick layer of adhering biomolecules or bacterial cell debris. This layer shields incoming bacteria from the antimicrobially active cationic surface moieties. Besides discussing antimicrobial surfaces, this feature article focuses on recent strategies that were developed to overcome the contamination problem. This includes bifunctional materials with simultaneously presented antimicrobial and protein-repellent moieties; polymer surfaces that can be switched from an antimicrobial, cell-attractive to a cell-repellent state; polymer surfaces that can be regenerated by enzyme action; degradable antimicrobial polymers; and antimicrobial polymer surfaces with removable top layers., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The synthesis and characterization of a series of green, blue and red-fluorescent exo-oxanorbornene acid and imide monomers carrying nitrobenzofurazan, coumarin, and Rhodamin B, respectively, as fluorophores is presented. These monomers carry oxanorbornene as polymerizable unit, and were readily copolymerized with bioactive functional oxanorbornene monomers by ring-opening metathesis polymerization (ROMP), as demonstrated by gel permeation chromatography and NMR spectroscopy. Due to the ease of synthesis of these monomers, and their cost-effectiveness compared many to other fluorescent probes, they are useful for biomaterials applications.

A manufacturing process for the site-selective modification of structured (bio)material surfaces with two different polymers/biomolecules is presented. In the first step, a chemical surface contrast is created (e.g., a gold-on-silicon contrast obtained by colloidal lithography), and is combined with two orthogonal surface reactions for polymer/biomolecule immobilization. To demonstrate this, an antimicrobial SMAMP polymer and a protein-repellent polyzwitterion were site-selectively surface-immobilized on the gold-silicon structures. By varying the structure spacing and the surface architecture, structure-property relationships for the interaction of these bifunctional polymer surfaces with bacteria and proteins were obtained (studied by fluorescence microscopy, atomic force microscopy, surface plasmon resonance spectroscopy, and antimicrobial assays). At 1 μm spacing, a fully antimicrobially active bifunctional material was obtained, which also near-quantitatively reduced protein adhesion. As the process is generally applicable to polymers/biomolecules with aliphatic CH-groups, it is an interesting platform technology for site-selectively functionalized bifunctional (Bio)MEMS.

Bone marrow examination plays an important role in the diagnosis of hematological and oncological diseases. Confirmation of a leukemia, clarification of cytopenias and risk stratification of a disease are possible indications for a bone marrow puncture.Here we describe, step by step, the workflow, possible pitfalls and complications of this procedere., (© Georg Thieme Verlag KG Stuttgart · New York.)

The immunoblastic variant of diffuse large B-cell lymphoma (IB-DLBCL) has recently been recognized as an aggressive lymphoma type with inferior prognosis as compared with other DLBCL variants. At the same time, the presence of MYC rearrangements in DLBCL has been shown to indicate shorter survival in R-CHOP-treated patients. In this study, we investigated the occurrence of MYC gene rearrangements in IB-DLBCL versus non-IB-DLBCL in a large series. Using fluorescence in situ hybridization with an MYC break-apart and MYC-IGH fusion probe, we found that 13/39 evaluable IB-DLBCLs (33%) harbor translocations involving MYC, in contrast with only 5/68 (7%) in the non-IB-DLBCL group (P<0.01). The immunoglobulin heavy chain gene (IGH) was the translocation partner in all rearrangements (100%) involving MYC in IB-DLBCL, which is in contrast to what has been reported for DLBCL in the literature (50% to 70%). Moreover, MYC rearrangements occurred as the sole translocation in the majority of cases (77%), whereas across all DLBCLs the majority of MYC-rearranged cases carry additional rearrangements of either BCL2 and/or BCL6 genes (between 58% and 83% of cases). Finally, MYC-rearranged IB-DLBCLs were CD10 positive in 62% (8/13), whereas this was an uncommon feature in MYC germline IB-DLBCLs (15%). In conclusion, IB-DLBCLs are genetically characterized by frequent MYC-IGH translocations that often occur without additional BCL2 and/or BCL6 translocations. The activation of MYC, therefore, may be an important pathogenetic feature in IB-DLBCL.

With older age and increasing comorbidities, conventional operative procedures for severe symptomatic aortic stenosis are associated with a high surgical risk. To date, transfemoral transcatheter aortic valve implantation (TF-TAVI) represents an accepted alternative method of intervention with a cardiovascular and all-cause mortality similar to operative replacement at early and long-term follow-up in this high risk population (Thomas et al., Circulation 124:425–433, 2011). Despite growing experience of the operators and improvement of the devices procedural and perioperative complications still occur (Panchal et al., Am J Cardiol, 2013). Aortic annulus rupture as well as the rupture of the membranous ventricular septum has been reported (Aminian et al., Catheter Cardiovasc Interv 81:E72–E75, 2013). We present the unusual case of an 80-year-old female who developed a false aneurysm following a contained aortic annulus rupture during a TF-TAVI procedure.

Objectives: To determine predictors of permanent pacemaker (PPM) implantation up to 30 days after transcatheter aortic valve implantation (TAVI) in a prospective multicenter registry., Background: Conduction disorders requiring PPM implantation are one of the most common complications seen after TAVI. Knowledge about possible predictors may help to decrease the rate of PPM implantations., Methods: In total, 1347 consecutive patients who underwent TAVI in 22 centers were prospectively enrolled in the German transcatheter aortic valve interventions registry. Both Medtronic CoreValve™ and Edwards Sapien™ valves were implanted. Patients with preprocedurally implanted PPM or implantable cardioverter defibrillator were excluded from the analysis (n = 199). Regression analysis of baseline and procedure characteristics of the remaining 1,147 patients was performed., Results: Procedural success was achieved in 97.4% of the cases. The rate for PPM after TAVI was 33.7%. The absence of prior valve surgery, the use of Medtronic CoreValve™ prosthesis and the presence of a porcelain aorta were identified as independent predictors for PPM after TAVI. Mortality at 30 days did not differ between patients with or without PPM necessity (6.0% vs. 8.1%, respectively; HR 0.72; CI (0.45-1.16); P = 0.17)., Conclusions: PPM is a common postprocedure requirement after TAVI. The absence of prior valve surgery, the implantation of Medtronic CoreValve™ prosthesis, and the presence of a porcelain aorta were independently associated with PPM after TAVI., (Copyright © 2013 Wiley Periodicals, Inc.)

In humans, cerebrovascular responses to alterations in arterial Pco(2) and Po(2) are well documented. However, few studies have investigated human coronary vascular responses to alterations in blood gases. This study investigated the extent to which the cerebral and coronary vasculatures differ in their responses to euoxic hypercapnia and isocapnic hypoxia in healthy volunteers. Participants (n = 15) were tested at rest on two occasions. On the first visit, middle cerebral artery blood velocity (V(P)) was assessed using transcranial Doppler ultrasound. On the second visit, coronary sinus blood flow (CSBF) was measured using cardiac MRI. For comparison with V(P), CSBF was normalized to the rate pressure product [an index of myocardial oxygen consumption; normalized (n)CSBF]. Both testing sessions began with 5 min of euoxic [end-tidal Po(2) (Pet(O(2))) = 88 Torr] isocapnia [end-tidal Pco(2) (Pet(CO(2))) = +1 Torr above resting values]. Pet(O(2)) was next held at 88 Torr, and Pet(CO(2)) was increased to 40 and 45 Torr in 5-min increments. Participants were then returned to euoxic isocapnia for 5 min, after which Pet(O(2)) was decreased from 88 to 60, 52 and 45 Torr in 5-min decrements. Changes in V(P) and nCSBF were normalized to isocapnic euoxic conditions and indexed against Pet(CO(2)) and arterial oxyhemoglobin saturation. The V(P) gain for euoxic hypercapnia (%/Torr) was significantly higher than nCSBF (P = 0.030). Conversely, the V(P) gain for isocapnic hypoxia (%/%desaturation) was not different from nCSBF (P = 0.518). These findings demonstrate, compared with coronary circulation, that the cerebral circulation is more sensitive to hypercapnia but similarly sensitive to hypoxia.

Background: As myocardial oxygenation may serve as a marker for ischemia and microvascular dysfunction, it could be clinically useful to have a non-invasive measure of changes in myocardial oxygenation. However, the impact of induced blood flow changes on oxygenation is not well understood. We used oxygenation-sensitive CMR to assess the relations between myocardial oxygenation and coronary sinus blood oxygen saturation (SvO2) and coronary blood flow in a dog model in which hyperemia was induced by intracoronary administration of vasodilators., Results: During administration of acetylcholine and adenosine, CMR signal intensity correlated linearly with simultaneously measured SvO2 (r2 = 0.74, P < 0.001). Both SvO2 and CMR signal intensity were exponentially related to coronary blood flow, with SvO2 approaching 87%., Conclusions: Myocardial oxygenation as assessed with oxygenation-sensitive CMR imaging is linearly related to SvO2 and is exponentially related to vasodilator-induced increases of blood flow. Oxygenation-sensitive CMR may be useful to assess ischemia and microvascular function in patients. Its clinical utility should be evaluated.

This review addresses some myths about coronary vasospasm as the cause of angina pectoris. Coronary artery vasospasm is a common phenomenon, which is clinically encountered by busy cardiologists almost on a daily basis. It is the cause of resting angina in many patients without significant coronary artery disease, but also in patients with atherosclerotic coronary artery disease but no subtotal lesion. Although coronary artery vasospasm can be suspected clinically, proof cannot usually be obtained by non-invasive means but is easily available during cardiac catheterization. Patients with vasospastic angina are repeatedly exposed to this invasive procedure as most cardiologists suspect a coronary lesion requiring intervention as the cause of the patient's resting angina. Adding an intracoronary acetylcholine test to the catheterization procedure may establish the correct diagnosis and enable treatment with calcium antagonists and nitrates. Epicardial vasospasm may be observed during the test in patients with and without angiographically visible lesions in the coronary arteries. Almost 50% of all pathological tests, however, do not show epicardial vasospasm but reproduction of symptoms and electrocardiogram signs of ischemia indicating spasm of the microvessels.

The introduction deals with two main issues: First, it focuses on the question why a history of scientific concepts should not be limited to the analysis of scientific texts alone. Secondly, it shows how the history of the reflex concept gains from looking at various fields such as art, literature and brain research. The crucial role the reflex played in 19th and 20th century and the different meanings it adopted allowed us to conclude with Bruno Latour that the distinction between art and science is in itself historical. Thus, the distinction proves to be of little use for the historiography of complex concepts such as the reflex which rarely appear to be purely scientific.

In 1907 the taxidermist Aleksandr Feodorovich Kohts founded a so-called "Museum Darwinianum" in Moscow. This museum first of all hosted a growing collection of stuffed, modelled, and visualized species and secondly--from 1913 on--a laboratory for the exploration of the evolution of species ruled by Koht's wife and psychologist Nadeshda Nikolaevna Ladygina-Kohts. While he was mainly dealing with dead animals and models, his wife was comparing the behaviour of a young chimpanzee to the behaviour of her little son. Ladygina-Koht's study was unique at the time and therefore acknowledged by colleagues worldwide. That she was using photomontages for her comparisons and how this has influenced her research has not yet been considered in historical accounts. The article will examine this medial practice in order to understand how these seemingly opposing approaches could have both been dedicated to Darwin's evolutionary theory.

Cardiovascular magnetic resonance imaging (CMR) permits optimal differentiation between normal and diseased myocardium with the use of gadoliniumbased contrast agents and special magnetic resonance pulse sequences. Imaging is performed 10-20 min after contrast agent application to produce so-called late gadolinium enhancement (LGE) images which depict diseased myocardium with excellent reproducibility. Areas showing LGE correspond to zones of myocyte necrosis or myocardial fibrosis as shown by comparison with histopathology. Typical patterns of hyperenhancement exist in ischemic heart disease but also in dilated cardiomyopathy, hypertrophic cardiomyopathy and other inflammatory or infiltrative myocardial disease and are described in this article. LGE-CMR is helpful to distinguish advanced ischemic heart disease from nonischemic dilated cardiomyopathy. In ischemic heart disease LGE can also predict the functional recovery after revascularization procedures by directly showing the remaining viable myocardium. LGE may also become useful to predict malignant arrhythmias in patients with ischemic heart disease or nonischemic cardiomyopathy. This may lead in future to an increased role of LGE-CMR as a prognostic tool.

Objective: To describe a single-center experience of using retrospectively gated multislice computed tomographic (MSCT) coronary angiography for imaging congenital coronary anomalies., Patients and Methods: We retrospectively reviewed the clinical information and imaging studies for 9 patients diagnosed as having congenital coronary anomalies on invasive, selective coronary angiography between February 2001 and October 2003 at the Mayo Clinic in Jacksonville, Fla. Two experienced observers classified by consensus the origin and proximal course of the abnormal coronary arteries as seen on MSCT., Results: In 1 patient, MSCT showed a normal but extremely anterior origin of the right coronary artery from the right aortic sinus of Valsalva. In the other 8 patients, the origin and course of 4 anomalous right coronary arteries, 2 anomalous left circumflex coronary arteries, and 2 single coronary arteries were recognized easily on MSCT., Conclusion: Similar to electron beam computed tomography and magnetic resonance imaging, widely available MSCT can characterize the proximal course of congenitally abnormal coronary arteries and thus aid in clinical decision making for patients with such anomalies.

Prior studies have noted a pain relieving effect of baroreceptor stimulation and of higher tonic blood pressure in animals and humans. The present study used a new technique for the controlled, noninvasive stimulation of human carotid baroreceptors (PRES). PRES baroreceptor manipulation was delivered to both normotensive subjects (n = 11) and medication-free labile hypertensive subjects (n = 10) during both thermal and mechanical pain. Consistent with prior research, hypertensives had a higher threshold for thermal pain than did normotensives. PRES baroreceptor manipulation had no significant effect on thermal pain threshold for either group. For the mechanical pain model, the opposite results were obtained; group pain thresholds did not differ, but there was a significant PRES baroreceptor stimulation effect of increasing pain threshold for both groups. Results are discussed in terms of specific features of the stimuli, dampening of pain in hypertensives, and adaptation to pain.