ABSTRACT
Hematopoietic progenitor cell transplantation can contribute to revascularization of ischemic tissues. Yet, the optimal cell population to be transplanted has yet to be determined. We have ...compared the therapeutic potential of two subsets of human cord blood CD34+ progenitors, either expressing the VEGF‐A receptor 2 (KDR) or not. In serum‐free starvation culture, CD34+KDR+ cells reportedly showed greater resistance to apoptosis and ability to release VEGF‐A, as compared with CD34+KDR− cells. When injected into the hind muscles in immunodeficient SCIDbg mice subjected to unilateral ischemia, a low number (103) of CD34+KDR+ cells improved limb salvage and hemodynamic recovery better than a larger dosage (104) of CD34+KDR− cells. The neovascularization induced by KDR+ cells was significantly superior to that promoted by KDR− cells. Similarly, endothelial cell apoptosis and interstitial fibrosis were significantly attenuated by KDR+ cells, which differentiated into mature human endothelial cells and also apparently skeletal muscle cells. This study demonstrates that a low number of CD34+KDR+ cells favors reparative neovascularization and possibly myogenesis in limb ischemia, suggesting the potential use of this cell population in regenerative medicine.
Purpose
At equal TNM stage, obstructing colon cancer (OCC) is associated with worse prognosis in comparison with uncomplicated cancer. Our aim was to identify prognostic factors of overall (OS) and ...disease-free survival (DFS) in patients treated for OCC.
Methods
From 2000 to 2015, 2325 patients were treated for OCC in French surgical centers, members of the French National Surgical Association (AFC). Patients with palliative management were excluded. The main endpoints were OS and DFS. A multivariate analysis, using Cox proportional hazards regression model, was performed to determine independent prognostic factors.
Results
The cohort included 2120 patients. The median of follow-up was 13.2 months. In multivariate analysis, age > 75 years, ASA score ≥ 3, ECOG score ≥ 3, right-sided colon cancer, presence of synchronous metastases, anastomotic leakage, and absence of adjuvant chemotherapy were independent OS factors. Age > 75 years, ASA score ≥ 3, right-sided colon cancer, presence of synchronous metastases, and absence of postoperative chemotherapy were independent factors of poor OS after exclusion of patients who died postoperatively. Age ≥ 75 years, ASA score ≥ 3, ECOG score ≥ 3, right-sided colon cancer, lymph node involvement, presence of vascular, lymphatic or perineural invasion, less than 12 harvested lymph nodes, and absence of adjuvant chemotherapy were independent DFS factors.
Conclusions
Management of OCC should take into account prognostic factors related to the patient (age, comorbidities), tumor location, and tumor stage. Adjuvant chemotherapy administration plays an important role. For patients undergoing initial defunctionning stoma, neoadjuvant chemotherapy could be an option to improve prognosis.
Immunotherapeutic monoclonal antibodies (mAbs) can be defined as those that exert their functions by tampering with immune
system cell molecules, causing an enhancement of antitumor immune responses. ...Some of these antibodies are agonistic ligands
for surface receptors involved in the activation of lymphocytes and/or antigen-presenting cells, whereas others are antagonists
of mechanisms that normally limit the intensity of immune reactions. Several mAbs of this category have been described to
display in vivo antitumor activity in mouse models. Only anti-CTLA-4 (CD152) mAb has entered clinical trials, but the preclinical effects
described for anti-CD40, anti-CD137 (4-1BB), anti-CD102 (intercellular adhesion molecule-2), and regulatory T cell-depleting
mAbs should lead to their prompt clinical development. Their use in combination with immunizations against tumor antigens
has been reported to be endowed with synergistic properties. This new group of antitumor agents holds promise for at least
additive effects with conventional therapies of cancer and deserves intensive translational research.
Objective
Several questionnaires have been developed to screen for psoriatic arthritis (PsA), but head‐to‐head studies have found limitations. This study aimed to develop new questionnaires ...encompassing the most discriminative questions from existing instruments.
Methods
Data from the CONTEST study, a head‐to‐head comparison of 3 existing questionnaires, were used to identify items with a Youden index score of ≥0.1. These were combined using 4 approaches: CONTEST (simple additions of questions), CONTESTw (weighting using logistic regression), CONTESTjt (addition of a joint manikin), and CONTESTtree (additional questions identified by classification and regression tree CART analysis). These candidate questionnaires were tested in independent data sets.
Results
Twelve individual questions with a Youden index score of ≥0.1 were identified, but 4 of these were excluded due to duplication and redundancy. Weighting for 2 of these questions was included in CONTESTw. Receiver operating characteristic (ROC) curve analysis showed that involvement in 6 joint areas on the manikin was predictive of PsA for inclusion in CONTESTjt. CART analysis identified a further 5 questions for inclusion in CONTESTtree. CONTESTtree was not significant on ROC curve analysis and discarded. The other 3 questionnaires were significant in all data sets, although CONTESTw was slightly inferior to the others in the validation data sets. Potential cut points for referral were also discussed.
Conclusion
Of 4 candidate questionnaires combining existing discriminatory items to identify PsA in people with psoriasis, 3 were found to be significant on ROC curve analysis. Testing in independent data sets identified 2 questionnaires (CONTEST and CONTESTjt) that should be pursued for further prospective testing.
Summary
Background
There are limited long‐term, ‘real‐world’ data on ustekinumab, or the effect of dose adjustment in suboptimal responders.
Objectives
We describe 52‐week data from TRANSIT, which ...initiated ustekinumab by licensed regimen and investigated exploratory dose adjustment.
Methods
Patients with moderate‐to‐severe psoriasis and inadequate methotrexate response received ustekinumab, with immediate or gradual methotrexate withdrawal. Outcomes were similar between treatment arms at week 12 (primary endpoint), so week 52 data were pooled. Patients weighing ≤ 100 kg or > 100 kg were administered ustekinumab 45 or 90 mg, respectively. Patients weighing ≤ 100 kg without 75% improvement in Psoriasis Area and Severity Index (PASI 75) response at weeks 28 or 40 received a dose adjustment to 90 mg. The primary analysis used observed data.
Results
Overall, 391 and 98 patients received ustekinumab 45 and 90 mg, respectively. Forty‐four patients (9%) discontinued before week 52 (0·4% due to adverse events). At week 52 (in the overall population), 369 patients (83%) achieved a PASI score ≤ 5, and 341 patients (77%) achieved PASI 75; the median PASI score decreased from 15 at baseline to 1·8. At weeks 28 and 40, 84 and 31 patients, respectively, did not achieve PASI 75 and received a dose adjustment; by week 52, 35/82 (43%) and 15/31 (48%) of these patients, respectively, achieved PASI 75 (two discontinued between weeks 28 and 40).
Conclusions
Ustekinumab showed sustained 1‐year efficacy and was well tolerated when initially administered according to label. Adjusting the ustekinumab dose to 90 mg may result in clinically meaningful improvement in response in patients weighing ≤ 100 kg with suboptimal initial response.
What's already known about this topic?
The TRANSIT trial showed that ustekinumab was effective within 12 weeks in patients with an inadequate response to methotrexate.
There was no difference in the safety profile irrespective of whether methotrexate was withdrawn abruptly or gradually.
What does this study add?
Ustekinumab showed sustained efficacy after 1 year of treatment according to European label in patients who had experienced inadequate response to methotrexate, and safety was consistent with the known profile of ustekinumab.
A Psoriasis Area and Severity Index (PASI) 75 response was achieved at week 52 in 43–48% of patients weighing ≤ 100 kg who underwent dose adjustment from 45 to 90 mg at week 28 or 40 for lack of PASI 75 response at these time points.
Summary
Background
Limited data exist on transitioning patients with psoriasis from conventional systemic agents to biologics.
Objectives
The TRANSIT study aimed to assess the efficacy and safety of ...two methotrexate‐to‐ustekinumab transition strategies.
Methods
Patients with moderate‐to‐severe psoriasis and inadequate methotrexate response were randomized 1 : 1 to receive ustekinumab with immediate (arm 1) or 4‐week gradual (arm 2) methotrexate withdrawal. Patients weighing ≤ 100 kg or > 100 kg received ustekinumab 45 mg or 90 mg, respectively. The primary endpoint was the frequency of adverse events (AEs) at week 12. Secondary endpoints included additional safety, efficacy and patient‐reported outcomes. We report the 12‐week efficacy and safety results.
Results
Overall, 244 patients in arm 1 and 245 in arm 2 were randomized and received ustekinumab. Four patients per arm discontinued the trial by week 12. At week 12 in arms 1 and 2, respectively, 61% and 65% of patients experienced an AE, 2·9% and 2·4% had a serious AE, and 1·2% and 0·4% had an AE leading to ustekinumab discontinuation. In arms 1 and 2, respectively, median Psoriasis Area and Severity Index (PASI) score decreased from 15·2 and 15·4 at baseline to 2·9 and 2·8 at week 12; 58% and 62% of patients achieved a 75% reduction from baseline in PASI score (PASI 75) at week 12; median baseline Dermatology Life Quality Index fell from 8 and 9 at baseline to 1 (both arms) at week 16.
Conclusions
Ustekinumab was well tolerated and effective in patients who had an inadequate response to methotrexate. Both transition strategies resulted in similar week 12 safety and efficacy outcomes.
What's already known about this topic?
In patients with moderate‐to‐severe psoriasis, biologics are recommended for use after conventional systemic agents have failed, or in patients for whom they are not suitable.
There are limited data on how to transition patients from conventional systemic treatment to biologics.
What does this study add?
In patients with an inadequate response to methotrexate, similar efficacy and safety/tolerability outcomes were observed at week 12 after initiating ustekinumab, irrespective of whether methotrexate was immediately or gradually withdrawn. Therefore, immediate transitioning from methotrexate to ustekinumab can be recommended and a washout period is not needed.
No adverse safety or efficacy effects were noted after overlapping ustekinumab and methotrexate treatment for up to 1 month.
Peptides released from sensory nerves during an axon reflex are thought to cause mast cell degranulation, histamine (Hi) release and Hi-induced vasodilatation leading to the flare of the triple ...response. Capsaicin stimulates peptide release from sensory neurones and causes flare in vivo but does not cause Hi release from mast cells in vitro. The effects of capsaicin on mast cell degranulation in human skin in vivo has been studied by histological examination of skin biopsies after topical capsicin (1%) treatment of stratum corneum-denuded forearm in four volunteers. The results show a significant reduction in the visible numbers of mast cells and the appearance of degranulated mast cells ghosts in the skin six hours after capsaicin application. Since capsaicin itself does not release Hi from mast cells, these data suggest that capsaicin-induced release of peptides from neurones could cause mast cell degranulation.
The immunocytochemical identification and characterization of indigenous dermal dendritic cells (dermal dendrocytes) using a rabbit polyclonal antibody to clotting enzyme factor XIII subunit A ...(FXIIIa) was carried out on normal and inflamed human cutaneous tissue. The immunophenotype of FXIIIa positive dendritic cells was analysed with a panel of 18 monoclonal antibodies using immunoperoxidase and double immunofluorescence staining techniques. The antibody against FXIIIa detected highly dendritic dermal cells located particularly in the upper reticular and papillary dermis. Double fluorescence microscopy showed that FXIIIa positive cells were bone marrow derived (HLe-I+) and co-expressed monocyte, macrophage or antigen presenting cell markers (HLA-DR+, LFA-I+, HLA-DQ+, OKM5+, Mo I+, Mono-I+, Leu M3+). No labelling was obtained with cell markers for Langerhans cells (CDI), T lymphocytes (CD2), granulocytes (LeuMI) fibroblasts (Te7), intercellular adhesion molecule-I (ICAM-I) or endothelial cells (Factor VIII related antigen). Gamma interferon induced increased expression of HLA-DR and co-expression of ICAM-I on FXIIIa+ dermal dendritic cells in normal skin in organ culture. Moreover, in benign inflammatory dermatoses such as atopic eczema and psoriasis there was an increased number of FXIIIa+, DR+, ICAM-I+ cells in the upper dermis and foci of FXIIIa+ cells in the epidermis closely associated with lymphocytes. FXIIIa positive cells in human skin represent a specific population of bone-marrow dermal dendritic cells, distinct from Langerhans cells, that share some features common to mononuclear phagocytes (monocyte/macrophages). In addition, the detection of HLA-DQ on 48% of FXIIIa+ cells and the lack of OKMI in combination with high OKM5 expression suggests an antigen-presenting cell phenotype.
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