Mammalian target of rapamycin (mTOR) inhibitors have been used in transplantation with the hope of minimizing calcineurin inhibitor (CNI)‐induced nephrotoxicity. However, mTOR inhibitors are also ...associated with a range of side effects, including metabolic complications. We aimed to determine the risks of metabolic complications after the conversion from CNI to mTOR inhibitor postkidney transplant. A systematic search in PubMed up to September 2013 identified nine relevant trials (a total of 2323 patients). The primary end points were the relative risks (RRs) of new‐onset diabetes after transplant (NODAT) and hypercholesterolemia. The overall RRs of NODAT and hypercholesterolemia associated with mTOR inhibitors were 1.32 (95% confidence interval CI 0.92–1.87) and 2.15 (95% CI 1.35–3.41), respectively, compared with CNI‐based regimen. Subgroup analyses revealed no differences in the incidence of NODAT or hypercholesterolemia between sirolimus‐ versus everolimus‐based regimen, or between early versus late conversion. Analyses of secondary outcomes revealed a higher risk of acute rejection, proteinuria and anemia, but no difference in the risk of opportunistic infections after mTOR inhibitor conversion. In conclusion, the conversion from CNI to mTOR inhibitor in low‐to‐moderate risk kidney transplant recipients was associated with nonsignificant trend toward increased risk of NODAT and significant increase in hypercholesterolemia, acute rejection, proteinuria and anemia.
In a systematic review and meta‐analysis of complications after conversion from calcineurin inhibitors to mTOR inhibitors in kidney transplantation, the authors demonstrate that conversion is associated with significant increase in hypercholesterolemia, hypertriglycemia, acute rejection, anemia and proteinuria, while there is a nonsignificant increase in new‐onset diabetes after transplantation.
Acral melanoma (AM) is an epidemiologically and molecularly distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma. We aimed to analyze the efficacy of ...anti-programmed cell death 1 (anti-PD-1) antibodies in advanced AM.
We retrospectively evaluated unresectable stage III or stage IV AM patients treated with an anti-PD-1 antibody in any line at 21 Japanese institutions between 2014 and 2018. The clinicobiologic characteristics, objective response rate (ORR, RECIST), survival estimated using Kaplan–Meier analysis, and toxicity (Common Terminology Criteria for Adverse Events 4.0.) were analyzed to estimate the efficacy of the anti-PD-1 antibodies.
In total, 193 patients (nail apparatus, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 patients (74.1%). Baseline lactate dehydrogenase (LDH) was within the normal concentration in 102 patients (52.8%). The ORR of all patients was 16.6% (complete response, 3.1%; partial response, 13.5%), and the median overall survival (OS) was 18.1 months. Normal LDH concentrations showed a significantly stronger association with better OS than abnormal concentrations (median OS 24.9 versus 10.7 months; P < 0.001). Although baseline characteristics were similar between the nail apparatus and the palm and sole groups, ORR was significantly lower in the nail apparatus group 6/70 patients (8.6%) versus 26/123 patients (21.1%); P = 0.026. Moreover, the median OS in this group was significantly poorer (12.8 versus 22.3 months; P = 0.03).
Anti-PD-1 antibodies have limited efficacy in AM patients. Notably, patients with nail apparatus melanoma had poorer response and survival, making nail apparatus melanoma a strong candidate for further research on the efficacy of novel combination therapies with immune checkpoint inhibitors.
•Acral melanoma is a distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma.•We retrospectively examined advanced-stage acral melanoma patients treated with an anti-PD-1 antibody.•Anti-PD-1 antibodies have limited efficacy in Japanese acral melanoma patients.•Patients with nail apparatus melanoma had poorer response and survival than patients with palm and sole melanoma.
Summary Objectives We hypothesized that high-molecular-weight (MW) cross-linked (CL) hyaluronic acid (HA) improves joint lubrication and has an enhanced chondroprotective effect. We examined the ...histopathological changes and friction coefficients in osteoarthritic knee joints after injecting high-MW CL HA. Design A bilateral anterior cruciate ligament transection (ACLT) model in 20 Japanese white rabbits was used. From week 5 after transection, low-MW HA (0.8 × 106 Da; HA80) or high-MW CL HA (6 × 106 Da; HA600) was injected weekly into 10 right knee for 3 weeks; normal saline (NS) was injected into the 10 left knee. A sham operation was undertaken to exclude spontaneous osteoarthritis (OA) in five knees. Results were evaluated with macroscopy, histopathology (Kikuchi's score), biomechanical testing, and rheological assessment of the joint fluid viscoelasticity. Statistical analysis was performed using one-way analysis of variance with a 95% confidence interval (CI) ( P < 0.05). Results The macroscopic findings showed severely damaged cartilage in 30% of the NS group and 20% of the HA80 and HA600 groups and intact cartilage in 100% of the sham group. The histological scores and friction coefficients of the HA600 group were significantly lower than those of the NS group ( P = 0.007 and P = 0.002, respectively). Viscoelasticity measurements of the joint fluid showed no significant differences between the three treatment groups. Conclusion High-MW CL HA exerts potential chondroprotective effects and produces superior friction coefficients. Our results suggest that HA600 delays the progression of OA effectively and improves joint lubrication significantly.
Orphan GPCR research Chung, S; Funakoshi, T; Civelli, O
British journal of pharmacology,
March 2008, Letnik:
153, Številka:
S1
Journal Article
Recenzirano
Odprti dostop
Orphan G protein‐coupled receptors (GPCRs) are receptors lacking endogenous ligands. Found by molecular biological analyses, they became the roots of reverse pharmacology, in which receptors are ...attempted to be matched to potential transmitters. Later, when high‐throughput screening technology was applied to reverse pharmacology, dozens of orphan GPCRs became deorphanized. Furthermore, novel neuropeptides were discovered. This review retraces the history of the orphan GPCRs and of the discoveries of their endogenous ligands, it also discusses the difficulties that the search for new ligands is presently encountering.
British Journal of Pharmacology (2008) 153, S339–S346; doi:10.1038/sj.bjp.0707606; published online 10 December 2007
Sorafenib, a multi-kinase inhibitor, has been reported to be associated with hypertension (HTN). However, the risk of severe HTN with sorafenib treatment has not been well described. We performed an ...up-to-date meta-analysis of high-grade HTN in cancer patients treated with sorafenib. Medline databases and the American Society of Clinical Oncology online database of meeting abstracts were searched up to August 2012 for relevant clinical trials. Eligible studies included phase II and III trials of sorafenib in patients with any type of cancer describing events of HTN according to the Common Terminology Criteria for Adverse Events. The summary incidence, relative risk (RR), and 95% confidence intervals (CIs) were calculated. The incidence of sorafenib-associated high-grade (grade 3-4) HTN was 6.0% (95% CI 4.7-7.3) in a total of 4722 patients from 55 trials of sorafenib as a single agent. Sorafenib-treated patients (4878 subjects from 13 randomized trials) had a significantly higher risk of high-grade HTN (RR 3.20 (95% CI 2.19-4.68)). Subgroup analysis revealed a significantly higher RR of high-grade HTN in patients receiving sorafenib as a single agent compared with patients receiving concomitant chemotherapy or immunotherapy (P=0.0076). The incidence of high-grade HTN associated with sorafenib was significantly higher in patients with renal cell carcinoma (RCC) than those with non-RCC cancer (P<0.0001) as well as patients treated with sorafenib for a longer duration than those treated for a shorter duration (P=0.003). The use of sorafenib is associated with a significantly higher risk of high-grade HTN compared with control.
Background
The detection of serum anti‐desmoglein (Dsg) IgG autoantibodies has been reported to be useful for assessment of disease activity in pemphigus. However, previous studies have reported that ...anti‐Dsg autoantibodies remain detectable in some patients without active pemphigus lesions.
Objectives
To investigate the clinical characteristics and antibody pathogenicity of pemphigus patients positive for anti‐Dsg IgG autoantibodies in remission.
Methods
We retrospectively investigated pemphigus patients with a history of clinical remission who visited the Department of Dermatology of Keio University during 2019 and 2020. The antibody pathogenicity was assessed by bead aggregation assay.
Results
When patients were recognized as having entered remission (PDAI = 0 and PSL ≦ 10 mg/day for 2 months), serum autoantibodies against Dsg were detected in 72 of 132 patients (54.5%, positive group; PG), but were not detected in 60 patients (45.5%, negative group; NG). Anti‐Dsg antibody titres in remission declined from the active phase in 33 patients in the PG for whom data were available. There were no differences in the chance of reducing PSL to 5 mg/day (P = 0.885) and rate of relapse (P = 0.279) between PG and NG, but fewer patients in PG discontinued corticosteroids (P = 0.004). The ability of patients' sera to block aggregation of Dsg/desmocollin beads was significantly reduced in remission compared to the active phase. However, our results revealed that whole sera in remission still had pathogenic activity in seven of nine patients, and the approximately equal amounts of anti‐Dsg antibodies in active phase and remission showed similar pathogenicity.
Conclusions
This study will provide guidance in cases where autoantibodies are found to be positive in pemphigus patients during remission or steroid reduction.
Summary
Background
Extramammary Paget disease (EMPD) is a rare intraepithelial adenocarcinoma affecting the genitals and axillary regions. As metastasis of these tumours is itself rare, solid disease ...management strategies have not been established. Serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragment 21‐1 (CYFRA 21‐1) levels have been identified as candidate biomarkers for tumour progression in EMPD.
Objectives
To determine the accuracy of and the correlation between these markers in patients with EMPD.
Methods
Serum CEA and CYFRA 21‐1 levels were examined in 30 patients with EMPD treated at Keio University Hospital, and compared against clinical information. Both assays were performed at the time of diagnosis, during the postoperative observation period, and following systemic treatment in those with confirmed metastasis. Serum levels were then correlated with tumour progression status and treatment responses.
Results
Normal levels for both assays were observed in all 11 patients with primary localized disease (100%). In patients with metastatic disease the CEA positivity rate was 79% (15 of 19 patients), with a rate of 63% (12 of 19 patients) for CYFRA 21‐1. Changes in CEA and CYFRA 21‐1 levels were statistically independent; however, using a combined view, elevated levels of either marker improved the positivity rate to 95% (18 of 19 patients). Use of both markers also correlated well with treatment responses.
Conclusions
The combination of CEA and CYFRA 21‐1 is useful for predicting metastasis and treatment response in patients with EMPD, especially in those who only have elevation of a single marker.
What's already known about this topic?
Serum levels of carcinoembryonic antigen (CEA) and cytokine 19 fragment 21‐1 (CYFRA 21‐1) have been shown to be elevated in patients with extramammary Paget disease (EMPD).
Elevation of serum CEA levels is associated with tumour progression of EMPD.
A single small study reported that serum CYFRA 21‐1 levels are elevated in patients with EMPD with lymph node metastasis.
What does this study add?
Serum CEA and CYFRA 21‐1 were present in 79% and 63% of 19 cases of metastatic EMPD, respectively.
Elevations of CEA and CYFRA 21‐1 were statistically independent.
CEA and CYFRA 21‐1 combination assays were positive in 95% of cases of metastatic EMPD.
What is the translational message?
Combination assays with CEA and CYFRA 21‐1 are useful for monitoring treatment response in patients with metastatic EMPD, particularly in those with elevation of either marker.
Linked Comment: Ellis. Br J Dermatol 2019; 181:439–440.
Plain language summary available online
Summary
Background
A subset of patients with bullous pemphigoid (BP) show deposition of IgE in the basement membrane zone (BMZ), yet the relationship between BMZ IgE and the clinical presentation of ...BP remains unclear.
Objectives
To investigate the relationship between IgE deposition, IgE levels in serum, and disease severity in patients with BP.
Methods
We investigated IgE autoantibodies in 53 patients with BP by direct immunofluorescence (DIF), indirect immunofluorescence and enzyme‐linked immunosorbent assay.
Results
Of 53 patients with BP, 23 (43%) had IgE deposition, 10 (19%) of whom were IgE+ and 13 (25%) IgE± according to DIF analyses. Erosion/blister (E/B) Bullous Pemphigoid Disease Area Index (BPDAI) scores were significantly higher in IgE+ patients than in IgE− patients (n = 15), while no significant differences were found for urticaria/erythema BPDAI scores. IgE+ and IgE± patients took longer to reduce their E/B BPDAI score by 75% after systemic corticosteroid treatment. BP180‐IgE levels were significantly higher among IgE+ patients than IgE± or IgE− patients (n = 10). Total IgE levels in the serum and blood eosinophil counts did not differ between IgE+, IgE± and IgE− patients. A significant correlation was detected between BP180‐IgG and BP180‐IgE, but not between BPDAI scores and any of BP180‐IgG, BP180‐IgE or blood eosinophil count.
Conclusions
IgE deposition in the BMZ is associated with higher E/B BPDAI scores and longer treatment periods. We conclude that IgE binding in the BMZ may contribute to BP pathogenesis by promoting blister formation.
What's already known about this topic?
BP180‐IgE autoantibodies have an important role in the pathogenesis of bullous pemphigoid (BP).
A subset of patients with BP display deposition of IgE within the basement membrane zone (BMZ) of skin tissue.
What does this study add?
Patients with in vivo IgE deposition in the BMZ displayed higher erosion/blister Bullous Pemphigoid Disease Area Index (BPDAI) scores, while urticaria/erythema BPDAI scores were not significantly different.
Patients with in vivo IgE deposition in the BMZ took longer to reduce their erosion/blister BPDAI score by 75% after systemic corticosteroid treatment.
BP180‐specific IgE levels in serum were higher among patients with linear IgE deposition in the BMZ than in those with granular or no IgE deposition.
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