Abstract
Background
The advantage of early ileocecal resection after Crohn’s disease diagnosis is a matter of debate. This study aims to assess the timing of ileocecal resection on prognosis, after ...correction for possible confounders.
Methods
Patients with Crohn's disease with primary ileocecal resection between 2000 and 2019 were included in a retrospective multicentre cohort. The primary endpoint was endoscopic recurrence (Rutgeerts score ≥i2b) within 18 months. Secondary endpoints were escalation of inflammatory bowel disease medication within 18 months and re-resection during follow-up. The association between timing of ileocecal resection and these endpoints was investigated using multivariable proportional hazard models, corrected for covariates including Montreal classification, postoperative prophylaxis, smoking, indication for surgery, medication before ileocecal resection, perianal fistulas, surgical approach, histology, length of resected segment and calendar year.
Results
In 822 patients ileocecal resection was performed after a median of 3.1 years (i.q.r. 0.7–8.0) after Crohn's disease diagnosis. The lowest incidence of endoscopic recurrence, escalation of inflammatory bowel disease medication and re-resection was observed for patients undergoing ileocecal resection shortly after diagnosis (0–1 months). After correction for covariates, patients with ileocecal resection at 0, 4 and 12 months after diagnosis had a cumulative incidence of 35 per cent, 48 per cent and 39 per cent for endoscopic recurrence, 20 per cent, 29 per cent and 28 per cent for escalation of inflammatory bowel disease medication and 20 per cent, 30 per cent and 34 per cent for re-resection, respectively. In the multivariable model ileocolonic disease (HR 1.39 (95 per cent c.i. 1.05 to 1.86)), microscopic inflammation of proximal and distal resection margins (HR 2.20 (95 per cent c.i. 1.21 to 3.87)) and postoperative prophylactic biological and immunomodulator (HR 0.16 (95 per cent c.i. 0.05 to 0.43)) were associated with endoscopic recurrence.
Conclusion
The timing of ileocecal resection was not associated with a change of disease course; in the multivariable model, the postoperative recurrence was not affected by timing of ileocecal resection.
This study aims to assess the impact of timing of ileocecal resection (ICR) on postoperative prognosis of Crohn’s disease (CD) in a multivariable model. After correction for possible confounders, patients with early and late ICR have an equally beneficial short- and long-term postoperative prognosis. Therefore, timing of ICR in CD patients is not associated with a change of disease course.
Background: Patients with relapsed and refractory multiple myeloma (RRMM) who have triple class exposure to immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs) and anti-CD38 monoclonal ...antibodies (MoABs) have a poor prognosis and high unmet medical need. Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy which may offer long-term disease control for these patients. CARTITUDE-1 is an open-label, single arm phase 1b/2 clinical trial conducted to characterize the safety and efficacy of cilta-cel in adult patients with triple-class exposed RRMM. Since CARTITUDE-1 is a single-arm study, adjusted comparisons to other currently available therapies can provide valuable information on relative efficacy and safety benefits of cilta-cel over current real-world clinical practice (RWCP). LocoMMotion is the first prospective study of RWCP efficacy and safety outcomes in triple-class exposed patients with RRMM. It was designed a priori to serve as an external control cohort for CARTITUDE-1, using aligned inclusion criteria and endpoint definitions, to enable robust, high quality indirect comparisons vs. cilta-cel.
Objective: To compare patient outcomes of cilta-cel vs. RWCP, including overall response rate (ORR), complete response or better rate (≥CR rate), progression-free survival (PFS) as assessed by a review committee and overall survival (OS) in patients with triple-class exposed RRMM.
Methods: Individual patient level data available from both CARTITUDE-1 (clinical cut-off February 2021) and LocoMMotion (clinical cut-off March 2021) were pooled to conduct the comparative analyses. Imbalances between both cohorts on key prognostic baseline characteristics, including refractory status, ISS stage, time to progression on prior line, number of prior lines, average duration of prior lines, age, creatinine clearance, ECOG PS and MM type were adjusted for using inverse probability weighting. Average treatment effect on the treated (ATT) weights derived from propensity scores estimated using multivariable logistic regression modeling were applied to the LocoMMotion patients to have the weighted RWCP cohort reflecting the CARTITUDE-1 patient population. Balance between the ATT weighted RWCP cohort versus the CARTITUDE-1 population was evaluated based on reduction of standardized mean differences and overlap of propensity score distributions. Weighted logistic and Cox proportional hazards regression were used to estimate the relative treatment effects for cilta-cel vs. RWCP on binary endpoints (Odds ratios (OR), transformed into Response-rate Ratios (RR) and time to event endpoints (Hazard ratios (HR)), respectively. The base case analyses included all enrolled (apheresed) patients from CARTITUDE-1, reflecting an intention to treat approach. Additional analyses were conducted including only patients who received cilta-cel infusion compared to an aligned population of LocoMMotion where patients that progressed or died within 52 days were excluded from the LocoMMotion cohort.
Results: 113 patients were enrolled in CARTITUDE-1, of which 97 were infused with cilta-cel. 246 patients were enrolled in LocoMMotion receiving RWCP in Italy (24%), Germany (15%), France (14%), UK (11%), Spain (10%), USA (9%), Belgium (5%), Poland (5%), Netherlands (4%) and Russia (3%). Therapies within the RWCP cohort were diverse and >90 unique treatment regimens were used. The most frequent regimens were Kd (13.8%), PCd (12.6%) and Pd (11.0%). The weighted LocoMMotion population was well balanced with the CARTITUDE-1 cohort. Adjusted comparisons (Table 1) showed statistically significant improvements for cilta-cel vs. RWCP for ORR (RR=4.43), ≥CR (RR=568.92), PFS (HR=0.15) and OS (HR=0.38), all comparisons with p<0.001. All additional analyses were consistent with these findings (Table 1).
Conclusions: Outcomes for patients with triple-class exposed RRMM treated with RWPC observed in LocoMMotion are poor, illustrating the high unmet medical need. Adjusted comparisons vs. CARTITUDE-1 demonstrate significantly improved ORR, ≥CR, PFS and OS for cilta-cel compared to a diverse set of RWCP. These findings highlight cilta-cel's potential as a highly effective treatment option for patients with triple-class exposed RRMM.
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Mateos: Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Weisel: GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Martin: Sanofi: Research Funding; Oncopeptides: Consultancy; Janssen: Research Funding; GlaxoSmithKline: Consultancy; Amgen: Research Funding. Berdeja: Celularity, CRISPR Therapeutics: Research Funding; Abbvie, Acetylon, Amgen: Research Funding; Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; EMD Sorono, Genentech: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding; Lilly, Novartis: Research Funding; Poseida, Sanofi, Teva: Research Funding. Jakubowiak: Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Stewart: Oncopeptides: Honoraria; Janssen: Honoraria; GSK: Honoraria; BMS: Honoraria; Amgen: Honoraria; Skyline diagnostics: Consultancy; Genomcs England: Membership on an entity's Board of Directors or advisory committees; Tempus Inc.: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; PikSci Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Sanofi Aventis: Honoraria. Jagannath: Legend Biotech: Consultancy; Bristol Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. Lin: Novartis: Consultancy; Bluebird Bio: Consultancy, Research Funding; Legend: Consultancy; Sorrento: Consultancy; Juno: Consultancy; Takeda: Research Funding; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; Vineti: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Diels: Janssen: Current Employment. Ghilotti: Janssen-Cilag SpA, Cologno Monzese, Italy: Current Employment. Perualila: Janssen: Current Employment. Cabrieto: Janssen: Current Employment. Haefliger: Janssen-Cilag AG: Ended employment in the past 24 months; Cilag GmbH International: Current Employment. Erler-Yates: Janssen: Current Employment. Hague: Janssen: Current Employment, Current equity holder in publicly-traded company. Jackson: Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Strulev: Janssen Pharmaceutica NV: Current Employment. Nesheiwat: Legend Biotech USA: Current Employment. Pacaud: Legend Biotech: Current Employment. Moreau: Janssen: Honoraria; Celgene BMS: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Oncopeptides: Honoraria. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
TRPM (transient receptor potential melastatin-like) channels are distinct from many other members of the transient receptor potential family in regard to their overall size (>1000 amino acids), the ...lack of N-terminal ankyrin-like repeats, and hydrophobicity predictions that may allow for more than six transmembrane regions. Common to each TRPM member is a prominent C-terminal coiled coil region. Here we have shown that TRPM8 channels assemble as multimers using the putative coiled coil region within the intracellular C terminus and that this assembly can be disturbed by a single point mutation within the coiled coil region. This mutant neither gives rise to functional channels nor do its subunits interact or form protein complexes that correspond to a multimer. However, they are still transported to the plasma membrane. Furthermore, wild-type currents can be suppressed by expressing the membrane-attached C-terminal region of TRPM8. To separate assembly from trafficking, we investigated the maturation of TRPM8 protein by identifying and mutating the relevant N-linked glycosylation site and showing that glycosylation is neither essential for multimerization nor for transport to the plasma membrane per se but appears to facilitate efficient multimerization and transport.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The isotopic composition of skeleton-bound organic nitrogen in shallow-water scleractinian corals (hereafter, CS-δ15N) is an emerging tool for studying the marine nitrogen cycle in the past. The ...CS-δ15N has been shown to reflect the δ15N of nitrogen (N) sources to corals, with most applications to date focusing on the anthropogenic/terrestrial N inputs to reef environments. However, many coral reefs receive their primary N sources from the open ocean, and the CS-δ15N of these corals may provide information on past changes in the open ocean regional and global N cycle. Using a recently developed persulfate/denitrifier-based method, we measured CS-δ15N in modern shallow-water scleractinian corals from 8 sites proximal to the open ocean. At sites with low open ocean surface nitrate concentrations typical of the subtropics and tropics, measured CS-δ15N variation on seasonal and annual timescales is most often less than 2‰. In contrast, a broad range in CS-δ15N (of ∼10‰) is measured across these sites, with a strong correlation between CS-δ15N and the δ15N of the deep nitrate supply to the surface waters near the reefs. While CS-δ15N can be affected by other N sources as well and can vary in response to local reef conditions as well as coral/symbiont physiological changes, this survey indicates that, when considering corals proximal to the open ocean, the δ15N of the subsurface nitrate supply to surface waters drives most of the CS-δ15N variation across the global ocean. Thus, CS-δ15N is a promising proxy for reconstructing the open ocean N cycle in the past.
•A survey study of skeletal δ15N in modern shallow-water scleractinian corals•Coral skeletal δ15N is mainly controlled by the δ15N of oceanic N supply at the study sites•Fossil corals are promising archives of the marine N cycle in the past
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract only Introduction: Injury to the corticospinal tract (CST) has been shown to have a major effect on upper extremity motor recovery after stroke. This study aimed to examine how well CST ...injury, measured from neuroimaging acquired during the acute stroke workup, predicts upper extremity motor recovery. Methods: Patients (N = 48) with upper extremity weakness after ischemic stroke were assessed using the upper extremity Fugl-Meyer (FM) during the acute stroke hospitalization and again at 3-month follow-up. CST injury was quantified and compared, using four different methods, from images obtained as part of the stroke standard-of-care workup. Logistic and linear regression were performed using CST injury to predict delta FM. Injury to primary motor and premotor cortices were included as potential modifiers of the effect of CST injury on recovery. Results: 48 patients were enrolled 4.2 ± 2.7 days post-stroke and completed this study. CST injury distinguished patients who reached their recovery potential (as predicted from initial impairment) from those who did not, with AUC values ranging from 0.75 to 0.8. In addition, CST injury explained ~20% of the variance in the magnitude of upper extremity recovery, even after controlling for the severity of initial impairment. Results were consistent when comparing four different methods of measuring CST injury. Extent of injury to primary motor and premotor cortices did not significantly influence the predictive value that CST injury had for recovery. Conclusions: Structural injury to the CST, as estimated from standard-of-care imaging available during the acute stroke hospitalization, is a robust way to distinguish patients who achieve their predicted recovery potential and explains a significant amount of the variance in post-stroke upper extremity motor recovery.
Abstract
Background
The modified Rutgeerts’ score (mRS) is widely used for the assessment of endoscopic postoperative recurrence (ePOR) in Crohn’s disease (CD) after ileocolic resection to guide ...therapeutic decisions. To improve the validity and prognostic value of this endoscopic assessment, two new scores have been proposed. This study assessed the interobserver agreement of the current (mRS) and new endoscopic scores for ePOR in CD.
Methods
Sixteen academic and non-academic IBD specialists assessed endoscopic videos (n=71) of postoperative CD patients (n=66) retrieved from nine Dutch centers. Each video was assessed for the degree of inflammation by four gastroenterologists using the mRS, REMIND score (separate score of anastomosis and neoterminal ileum) and anatomic score (separate score of lesions at the anastomotic line, ileal body, ileal inlet, neoterminal ileum, colonic and/or ileal blind loop). Interobserver agreement was assessed using Fleiss’ weighted kappa.
Results
Fleiss’ weighted kappa for the mRS was 0.67 (95% confidence interval CI 0.59–0.74). The weighted kappa for the REMIND score was 0.73 (95% CI 0.65–0.80) for lesions in the neoterminal ileum and 0.46 (95% CI 0.35–0.58) for anastomotic lesions. In the anatomic score, the weighted kappa for lesions in the ileal body, ileal inlet, neoterminal ileum, colonic and ileal blind loop was 0.61 (95% CI 0.49–0.73), 0.63 (95% CI 0.54–0.72), 0.61 (95% CI 0.49–0.74), 0.83 (95% CI 0.62–1.00) and 0.68 (95% CI 0.46–0.89), and 0.44 (95% CI 0.32–0.55) for lesions at the anastomotic line.
Conclusion
The interobserver agreement of the mRS is substantial. Similarly, the interobserver agreement is substantial for lesions in the neoterminal ileum according to both the REMIND and anatomic score, whereas only moderate for anastomotic lesions. Since therapeutic decisions in clinical practice are based on these assessments and these scores are used as outcome measure in clinical studies, further improvement of agreement is essential.
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