Crohn's disease (CD) is an inflammatory bowel disease (IBD) characterized by reactivity against microbial and self antigens. Zymogen granule glycoprotein 2 (GP2) was identified as the major ...autoantigen of CD-specific pancreatic autoantibodies (PAB).
Human GP2 was expressed in the
Spodoptera frugiperda 9 (Sf9) cell line using the baculovirus system, purified by Ni-chelate chromatography, and used as antigen for anti-GP2 IgA and IgG assessment by enzyme-linked immunosorbent assays (ELISA). Antibodies to mannan of
Saccharomyces cerevisiae (ASCA), PAB, and anti-GP2 were investigated in sera of 178 CD patients, 100 ulcerative colitis (UC) patients, and 162 blood donors (BD).
Anti-GP2 IgG and IgA were found in 48/72 (66.7%) and 23/72 (31.9%) PAB positive and 5/106 (4.7%) and 1/106 (0.9%) PAB negative CD patients (p
<
0.0001), respectively. CD patients displayed significantly higher reactivity to GP2 than UC patients and BD (p
<
0.0001), respectively. Occurrence of anti-GP2 antibodies correlated with PAB reactivity (Spearmen's rho
=
0.493, p
<
0.00001). There was a significant relationship between the occurrence of ASCA IgG and anti-GP2 IgG (p
=
0.0307).
Anti-GP2 IgG and IgA constitute novel CD specific autoantibodies, the quantification of which could improve the serological diagnosis of IBD.
Background
Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of ...concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab.
Methods
We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model.
Results
A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months,
p
= 0.002) and OS (8.7 vs. 14.1 months,
p
< 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival.
Conclusions
Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.
Background
Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of ...pembrolizumab in patients recurred or progressed after platinum-based chemotherapy.
Patients and Methods
Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors.
Results
In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1–2 or 3–4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (
p
< 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (
p
< 0.001).
Conclusions
Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy.
Ring finger proteins play pivotal roles in diverse cellular processes and are implicated in contribution to cancer. Ring finger protein 34 (RNF34) has antiapoptotic and oncogenic properties. RNF34 is ...upregulated during carcinogenesis and tumor progression in the colorectal adenoma-carcinoma sequence and was already described to mediate chemoresistance. In clear cell renal cell carcinoma (ccRCC), however, the role and expression patterns of RNF34 are unknown.
First, we investigated the association of RNF34 mRNA expression with clinicopathological parameters and survival using data obtained from The Cancer Genome Atlas (TCGA) ccRCC cohort (N = 533). To assess RNA34 protein expression, we performed immunohistochemical (IHC) staining of an established ccRCC cohort (University of Bonn) in a tissue microarray (TMA) format. This validation cohort contains 109 primary ccRCC samples. IHC data were associated with clinicopathological parameters and overall survival (Kaplan-Meier analysis). Adjustment for covariables was done using the Cox regression model.
RNF34 expression is correlated with adverse clinicopathological parameters. Survival analysis revealed an association between RNF34 expression and shortened survival. Cox regression analysis confirmed RNF34 expression as an independent prognostic parameter.
Our study provides evidence for RNF34 as a prognostic biomarker in ccRCC and points toward a major role of this protein in renal cell carcinoma carcinogenesis.
There is no need to justify interest in population dynamics. But there is a pertinent need for sufficient, detailed and consistent evidence. Today, there is ample information about demographic trends ...for countries small, exceptionally large, and in-between. This was not always the case. Since the late 1940s, the United Nations Population Division endeavored to collect (often sparse) evidence for an increasingly complete picture known as World Population Prospects. Its evolution, through 26 revisions, is the topic of this article. It starts with the historical context, followed by brief discussions of the demographic components of change: fertility, mortality and (net) migration. Based on a reconstruction of past trends (or estimates), the Populations Division projects the population of today 235 countries or areas; the world’s population could reach between 9.4 to 12.7 billion people, with a median of 10.9 billion. The article closes with suggestions about further improvements.
Early pre-motor symptoms (also frequently termed “non-motor” symptoms) in Parkinson’s disease (PD), which precede the onset of motor symptoms, are being increasingly recognized by clinicians. ...Non-motor symptoms in the pre-motor phase of PD include impaired olfaction (hyposmia), sleep disturbances (i.e., radid eye movement sleep behavior disorder, daytime sleepiness), behavioral/emotional dysfunction (i.e., change of personality or change of core personal characteristics), dysautonomia (i.e., constipation, urinary dysfunction, orthostatic hypotension), depressive symptoms (i.e., fatigue, apathy, anxiety), and chronic pain (joint and muscle). The pre-motor phase of PD is based on current pathophysiological concepts that relate these symptoms to early structural changes within lower brainstem nuclei and the peripheral nervous system including the autonomic and enteric ganglia. The perspective to identify these symptoms as early as possible will enable neurologists to make a diagnosis at the pre-motor stage of PD. Thus, the development of a PD risk score will be the first means to identify individuals at risk who are most likely to develop the prototypical motor symptoms of PD later in life. More importantly, these individuals at risk will be the first to benefit from disease-modifying strategies. In this workshop report, the elements of a PD risk score are proposed, including the stepwise sequence of escalating diagnostic measures to diagnose the pre-motor stage in PD.
Background
Immuno-oncology combinations have achieved survival benefits in patients with metastatic renal cell carcinoma (mRCC).
Objective
The ARON-1 study (NCT05287464) was designed to globally ...collect real-world data on the use of immuno-combinations as first-line therapy for mRCC patients.
Patients and Methods
Patients aged ≥ 18 years with a cytologically and/or histologically confirmed diagnosis of mRCC treated with first-line immuno-combination therapies were retrospectively included from 47 International Institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall clinical benefit (OCB).
Results
A total of 729 patients were included; tumor histology was clear-cell RCC in 86% of cases; 313 patients received dual immuno-oncology (IO + IO) therapy while 416 were treated with IO-tyrosine kinase inhibitor (IO + TKI) combinations. In the overall study population, the median OS and PFS were 36.5 and 15.0 months, respectively. The median OS was longer with IO+TKI compared with IO+IO therapy in the 616 patients with intermediate/poor International mRCC Database Consortium (IMDC) risk criteria (55.7 vs 29.7 months;
p
= 0.045). OCB was 84% for IO+TKI and 72% for IO + IO combination (
p
< 0.001).
Conclusions
Our study may suggest that immuno-oncology combinations are effective as first-line therapy in the mRCC real-world context, showing outcome differences between IO + IO and IO + TKI combinations in mRCC subpopulations.
Clinical Trial Registration
NCT05287464.
Obesity has been associated with improved response to immunotherapy in cancer patients. We investigated the role of body mass index (BMI) in patients from the ARON-1 study (NCT05287464) treated by ...dual immuno-oncology agents (IO+IO) or a combination of immuno-oncology drug and a tyrosine kinase inhibitors (TKI) as first-line therapy for metastatic renal cell carcinoma (mRCC).
Medical records of patients with documented mRCC treated by immuno-oncology combinations were reviewed at 47 institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (OS), and overall clinical benefit (OCB), defined as the sum of the rate of partial/complete responses and stable disease. Univariate and multivariate analyses were used to explore the association of variables of interest with survival.
A total of 675 patients were included; BMI was >25 kg/m2 in 345 patients (51%) and was associated with improved OS (55.7 vs. 28.4 months, P < .001). The OCB of patients with BMI >25 kg/m2 versus those with BMI ≤25 kg/m2 was significantly higher only in patients with nonclear cell histology (81% vs. 65%, P = .011), and patients with liver metastases (76% vs. 58%, P = .007), Neutrophil to lymphocyte ratio >4 (77% vs 62%, P = .022) or treated by nivolumab plus ipilimumab (77% vs. 64%, P = .044). In the BMI ≤25 kg/m2 subgroup, significant differences were found between patients with NLR >4 versus ≤4 (62% vs. 82%, P = .002) and patients treated by IO+IO versus IO+TKIs combinations (64% vs. 83%, P = .002).
Our study suggests that the prognostic significance and the association of BMI with treatment outcome varies across clinico-pathological mRCC subgroups.
Obesity is a well-known risk factor for the development of renal cell carcinoma (RCC), one of the most frequent malignant urogenital tumors. The development of immunotherapy (IO)-based combinations for the treatment of metastatic RCC (mRCC) has led to a marked improvement of patients’ outcomes and quality of life. The ARON-1 study (NCT05287464) was designed to globally analyze real-world treatment outcomes of mRCC patients receiving first-line immune-based combinations. In this sub-analysis, we investigated the role of body mass index (BMI) in patients treated by immuno-oncology combinations stratified by clinico-pathological features. According to our results, the prognostic significance and the association of BMI with treatment outcome may vary across clinico-pathological mRCC subgroups.
Indirect immunofluorescence (IIF) employing ethanol-fixed neutrophils (ethN) is still the method of choice for assessing antineutrophil cytoplasmic antibodies (ANCA) in ANCA-associated vasculitides ...(AAV). However, conventional fluorescence microscopy is subjective and prone to high variability. The objective of this study was to evaluate novel pattern recognition algorithms for the standardized automated interpretation of ANCA patterns.
Seventy ANCA-positive samples (20 antimyeloperoxidase ANCA, 50 antiproteinase3 ANCA) and 100 controls from healthy individuals analyzed on ethN and formalin-fixed neutrophils (formN) by IIF were used as a 'training set' for the development of pattern recognition algorithms. Sera from 342 patients ('test set') with AAV and other systemic rheumatic and infectious diseases were tested for ANCA patterns using the novel pattern recognition algorithms and conventional fluorescence microscopy.
Interpretation software employing pattern recognition algorithms was developed enabling positive/negative discrimination and classification of cytoplasmic ANCA (C-ANCA) and perinuclear ANCA (P-ANCA). Comparison of visual reading of the 'test set' samples with automated interpretation revealed Cohen's kappa (κ) values of 0.955 on ethN and 0.929 on formN for positive/negative discrimination. Analysis of the 'test set' with regard to the discrimination between C-ANCA and P-ANCA patterns showed a high agreement for ethN (κ = 0.746) and formN (κ = 0.847). There was no significant difference between visual and automated interpretation regarding positive/negative discrimination on ethN and formN, as well as ANCA pattern recognition (P > 0.05, respectively).
Pattern recognition algorithms can assist in the automated interpretation of ANCA IIF. Automated reading of ethN and formN IIF patterns demonstrated high consistency with visual ANCA assessment.
We present the experimental observation of multi-wavelength fiber Bragg gratings in As2Se3 fiber. The gratings are internally written via two-photon absorption of 1550 nm pump light and its first and ...second order Stokes waves generated by cascaded stimulated Brillouin scattering (SBS). We demonstrate a parameter regime that allows for 4 dB grating enhancement by suppression of SBS.
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