Induction therapy with ipilimumab and nivolumab followed by consolidative chemoradiation as organ-sparing treatment in urothelial bladder cancer:study protocol of the INDIBLADE trial

Introduction: Studies that assessed the efficacy of pre-operative immune checkpoint blockade (ICB) in locally advanced urothelial cancer of the bladder showed encouraging pathological complete response rates, suggesting that a bladder-sparing approach may be a viable option in a subset of patients. Chemoradiation is an alternative for radical cystectomy with similar oncological outcomes, but is still mainly used in selected patients with organ-confined tumors or patients ineligible to undergo radical cystectomy. We propose to sequentially administer ICB and chemoradiation to patients with (locally advanced) muscle-invasive bladder cancer. Methods: The INDIBLADE trial is an investigator-initiated, single-arm, multicenter phase 2 trial. Fifty patients with cT2-4aN0-2M0 urothelial bladder cancer will be treated with ipilimumab 3 mg/kg on day 1, ipilimumab 3 mg/kg plus nivolumab 1 mg/kg on day 22, and nivolumab 3 mg/kg on day 43 followed by chemoradiation. The primary endpoint is the bladder-intact event-free survival (BI-EFS). Events include: local or distant recurrence, salvage cystectomy, death and switch to platinum-based chemotherapy. We will also evaluate the potential of multiparametric magnetic resonance imaging of the bladder to identify non-responders, and we will assess the clearance of circulating tumor DNA as a biomarker for ICB treatment response. Discussion: This is the first trial in which the efficacy of induction combination ICB followed by chemoradiation is being evaluated to provide bladder-preservation in patients with (locally advanced) urothelial bladder cancer. Clinical Trial Registration: The INDIBLADE trial was registered on clinicaltrials.gov on January 21, 2022 (NCT05200988).</p

ACL reconstruction with hamstring tendon autograft and accelerated brace-free rehabilitation

Objective To investigate the clinical outcomes after hamstring tendon autograft ACL reconstruction (ACLR) with accelerated, brace-free rehabilitation. Design Systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Data sources Embase, MEDLINE Ovid, Web of Science, Cochrane CENTRAL and Google scholar from 1 January 1974 to 31 January 2017. Eligibility criteria for selecting studies Study designs reporting outcomes in adults after arthroscopic, primary ACLR with hamstring autograft and accelerated, brace-free rehabilitation. Results Twenty-four studies were included in the review. The clinical outcomes after hamstring tendon autograft ACLR with accelerated brace-free rehabilitation were the following: (1) early start of open kinetic exercises at 4 weeks in a limited range of motion (ROM, 90°-45°) and progressive concentric and eccentric exercises from 12 weeks did not alter outcomes, (2) gender and age did not influence clinical outcomes, (3) anatomical reconstructions showed better results than non-anatomical reconstructions, (4) there was no difference between single-bundle and double-bundle reconstructions, (5) femoral and tibial tunnel widening occurred, (6) hamstring tendons regenerated after harvest and (7) biological knowledge did not support return to sports at 4-6 months. Conclusions After hamstring tendon autograft ACLR with accelerated brace-free rehabilitation, clinical outcome is similar after single-bundle and double-bundle ACLR. Early start of open kinetic exercises at 4 weeks in a limited ROM (90°-45°) and progressive concentric and eccentric exercises from 12 weeks postsurgery do not alter clinical outcome. Further research should focus on achievement of best balance between graft loading and graft healing in the various rehabilitation phases after ACLR as well as on validated, criterion-based assessments for safe return to sports. Level of evidence Level 2b; therapeutic outcome studies

The Habitual Diet of Dutch Adult Patients with Eosinophilic Esophagitis Has Pro-Inflammatory Properties and Low Diet Quality Scores

We determined the nutritional adequacy and overall quality of the diets of adult patients with eosinophilic esophagitis (EoE). Dietary intakes stratified by sex and age were compared to Dietary Reference Values (DRV). Overall diet quality was assessed by two independent Diet-Quality-Indices scores, the PANDiet and DHD-index, and compared to age- and gender-matched subjects from the general population. Lastly, food and nutrient intakes of EoE patients were compared to intakes of the general population. Saturated fat intake was significantly higher and dietary fiber intake significantly lower than the DRV in both males and females. In males, the DRV were not reached for potassium, magnesium, selenium, and vitamins A and D. In females, the DRV were not reached for iron, sodium, potassium, selenium, and vitamins A, B2, C and D. EoE patients had a significantly lower PANDiet and DHD-index compared to the general population, although the relative intake (per 1000 kcal) of vegetables/fruits/olives was significantly higher (yet still up to 65% below the recommended daily amounts) and alcohol intake was significantly lower compared to the general Dutch population. In conclusion, the composition of the habitual diet of adult EoE patients has several pro-inflammatory and thus unfavorable immunomodulatory properties, just as the general Dutch population, and EoE patients had lower overall diet quality scores than the general population. Due to the observational character of this study, further research is needed to explore whether this contributes to the development and progression of EoE

The Glasgow-Maastricht foot model, evaluation of a 26 segment kinematic model of the foot

BACKGROUND: Accurately measuring of intrinsic foot kinematics using skin mounted markers is difficult, limited in part by the physical dimensions of the foot. Existing kinematic foot models solve this problem by combining multiple bones into idealized rigid segments. This study presents a novel foot model that allows the motion of the 26 bones to be individually estimated via a combination of partial joint constraints and coupling the motion of separate joints using kinematic rhythms. METHODS: Segmented CT data from one healthy subject was used to create a template Glasgow-Maastricht foot model (GM-model). Following this, the template was scaled to produce subject-specific models for five additional healthy participants using a surface scan of the foot and ankle. Forty-three skin mounted markers, mainly positioned around the foot and ankle, were used to capture the stance phase of the right foot of the six healthy participants during walking. The GM-model was then applied to calculate the intrinsic foot kinematics. RESULTS: Distinct motion patterns where found for all joints. The variability in outcome depended on the location of the joint, with reasonable results for sagittal plane motions and poor results for transverse plane motions. CONCLUSIONS: The results of the GM-model were comparable with existing literature, including bone pin studies, with respect to the range of motion, motion pattern and timing of the motion in the studied joints. This novel model is the most complete kinematic model to date. Further evaluation of the model is warranted

Neuronal network dysfunction in a model for Kleefstra syndrome mediated by enhanced NMDAR signaling

Kleefstra syndrome (KS) is a neurodevelopmental disorder caused by mutations in the histone methyltransferase EHMT1. To study the impact of decreased EHMT1 function in human cells, we generated excitatory cortical neurons from induced pluripotent stem (iPS) cells derived from KS patients. Neuronal networks of patient-derived cells exhibit network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes are mediated by upregulation of NMDA receptor (NMDAR) subunit 1 correlating with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. In mice EHMT1 deficiency leads to similar neuronal network impairments with increased NMDAR function. Finally, we rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs. Summarized, we demonstrate a direct link between EHMT1 deficiency and NMDAR hyperfunction in human neurons, providing a potential basis for more targeted therapeutic approaches for KS

Synthetic mycobacterial diacyl trehaloses reveal differential recognition by human T cell receptors and the C-type lectin Mincle

The cell wall of Mycobacterium tuberculosis is composed of diverse glycolipids which potentially interact with the human immune system. To overcome difficulties in obtaining pure compounds from bacterial extracts, we recently synthesized three forms of mycobacterial diacyltrehalose (DAT) that differ in their fatty acid composition, DAT1, DAT2, and DAT3. To study the potential recognition of DATs by human T cells, we treated the lipid-binding antigen presenting molecule CD1b with synthetic DATs and looked for T cells that bound the complex. DAT1- and DAT2-treated CD1b tetramers were recognized by T cells, but DAT3-treated CD1b tetramers were not. A T cell line derived using CD1b-DAT2 tetramers showed that there is no cross-reactivity between DATs in an IFN-γ release assay, suggesting that the chemical structure of the fatty acid at the 3-position determines recognition by T cells. In contrast with the lack of recognition of DAT3 by human T cells, DAT3, but not DAT1 or DAT2, activates Mincle. Thus, we show that the mycobacterial lipid DAT can be both an antigen for T cells and an agonist for the innate Mincle receptor, and that small chemical differences determine recognition by different parts of the immune system

Concomitant CIS on TURBT does not impact oncological outcomes in patients treated with neoadjuvant or induction chemotherapy followed by radical cystectomy

© Springer-Verlag GmbH Germany, part of Springer Nature 2018Background: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer improves all-cause and cancer specific survival. We aimed to evaluate whether the detection of carcinoma in situ (CIS) at the time of initial transurethral resection of bladder tumor (TURBT) has an oncological impact on the response to NAC prior to radical cystectomy. Patients and methods: Patients were identified retrospectively from 19 centers who received at least three cycles of NAC or induction chemotherapy for cT2-T4aN0-3M0 urothelial carcinoma of the bladder followed by radical cystectomy between 2000 and 2013. The primary and secondary outcomes were pathological response and overall survival, respectively. Multivariable analysis was performed to determine the independent predictive value of CIS on these outcomes. Results: Of 1213 patients included in the analysis, 21.8% had concomitant CIS. Baseline clinical and pathologic characteristics of the ‘CIS’ versus ‘no-CIS’ groups were similar. The pathological response did not differ between the two arms when response was defined as pT0N0 (17.9% with CIS vs 21.9% without CIS; p = 0.16) which may indicate that patients with CIS may be less sensitive to NAC or ≤ pT1N0 (42.8% with CIS vs 37.8% without CIS; p = 0.15). On Cox regression model for overall survival for the cN0 cohort, the presence of CIS was not associated with survival (HR 0.86 (95% CI 0.63–1.18; p = 0.35). The presence of LVI (HR 1.41, 95% CI 1.01–1.96; p = 0.04), hydronephrosis (HR 1.63, 95% CI 1.23–2.16; p = 0.001) and use of chemotherapy other than ddMVAC (HR 0.57, 95% CI 0.34–0.94; p = 0.03) were associated with shorter overall survival. For the whole cohort, the presence of CIS was also not associated with survival (HR 1.05 (95% CI 0.82–1.35; p = 0.70). Conclusion: In this multicenter, real-world cohort, CIS status at TURBT did not affect pathologic response to neoadjuvant or induction chemotherapy. This study is limited by its retrospective nature as well as variability in chemotherapy regimens and surveillance regimens.Peer reviewedFinal Accepted Versio

Mechanistic target of rapamycin (MTOR) protein expression in the tumor and its microenvironment correlates with more aggressive pathology at cystectomy

Background: The mechanistic target of rapamycin (mTOR) has been implicated in driving tumor biology in multiple malignancies, including urothelial carcinoma (UC). We investigate how mTOR and phosphorylated mTOR (pmTOR) protein expression correlate with chemoresponsiveness in the tumor and its microenvironment at final pathologic staging after neoadjuvant chemotherapy (NAC). Methods: A single-institution retrospective analysis was performed on 62 patients with cT2–4Nany UC undergoing NAC followed by radical cystectomy. Diagnostic (transurethral resection specimens, TURBT) and postchemotherapy radical cystectomy specimens were evaluated for mTOR and pmTOR protein expression using immunohistochemistry of the tumor, peritumoral stroma, and normal surrounding stroma. Protein expression levels were compared between clinical and pathologic stage. Whole transcriptome analysis was performed to evaluate mRNA expression relative to mTOR pathway activation. Results: Baseline levels of mTOR and pmTOR within TURBT specimens were not associated with clinical stage and response to chemotherapy overall. Nonresponders with advanced pathologic stage at cystectomy (ypT2–4/ypTanyN+) had significantly elevated mTOR tumor staining (P = 0.006) and a sustained mTOR and pmTOR staining in the peritumoral and surrounding normal stroma (NS). Several genes relevant to mTOR activity were found to be up-regulated in the tumors of nonresponders. Remarkably, complete responders at cystectomy (ypT0) had significant decreases in both mTOR and pmTOR protein expression in the peritumoral and normal stroma (P = 0.01–0.03). Conclusions: Our results suggest that mTOR pathway activity is increased in tumor and sustained in its microenvironment in patients with adverse pathologic findings at cystectomy. These findings suggest the relevance of targeting this pathway in bladder cancer