Mechanisms of acquired resistance to trastuzumab‐based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post‐progression in ...patients receiving chemotherapy and trastuzumab for advanced HER2‐positive immunohistochemistry (IHC) 3+ or 2+ with in‐situ hybridization (ISH) amplification gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over‐expression were defined as post‐trastuzumab IHC score <3+ and absence of ISH amplification, and IHC “downscoring” from 2+/3+ to 0/1+, respectively. HER2 IHC was always performed, while ISH was missing in 3 post‐progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over‐expression was observed in 32 and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinicopathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80 vs. 14%; p = 0.008) and HER2 over‐expression (63 vs. 14%; p = 0.025). As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab‐based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti‐HER2 second‐line strategies in initially HER2‐positive disease.
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Patients with cancers positive for human epidermal growth factor receptor 2 (HER2) generally fail to respond to second‐line treatments, particularly when first‐line therapy included use of the HER2‐targeted agent trastuzumab. Post‐progression changes in HER2 expression, however, have not been studied extensively, and as a consequence, their therapeutic relevance is unclear. In this study, HER2 loss was associated with acquired resistance to trastuzumab in almost one‐third of patients with gastric or gastroesophageal cancers that initially were HER2‐positive. The findings suggest that after failure of trastuzumab, HER2 status should be reassessed prior to inclusion in clinical trials with targeted agents.
Immunoaffinity-mass spectrometry (IA-MS) is an emerging analytical genre with several advantages for profiling and determination of protein biomarkers. Because IA-MS combines affinity capture, ...analogous to ligand binding assays (LBAs), with mass spectrometry (MS) detection, this platform is often described using the term hybrid methods. The purpose of this report is to provide an overview of the principles of IA-MS and to demonstrate, through application, the unique power and potential of this technology. By combining target immunoaffinity enrichment with the use of stable isotope-labeled internal standards and MS detection, IA-MS achieves high sensitivity while providing unparalleled specificity for the quantification of protein biomarkers in fluids and tissues. In recent years, significant uptake of IA-MS has occurred in the pharmaceutical industry, particularly in the early stages of clinical development, enabling biomarker measurement previously considered unattainable. By comparison, IA-MS adoption by CLIA laboratories has occurred more slowly. Current barriers to IA-MS use and opportunities for expanded adoption are discussed. The path forward involves identifying applications for which IA-MS is the best option compared with LBA or MS technologies alone. IA-MS will continue to benefit from advances in reagent generation, more sensitive and higher throughput MS technologies, and continued growth in use by the broader analytical community. Collectively, the pursuit of these opportunities will secure expanded long-term use of IA-MS for clinical applications.
Background Differential diagnosis of pancreatic solid masses with EUS-guided FNA (EUS-FNA) is still challenging in about 15% of cases. Mutation of the K- ras gene is present in over 75% of pancreatic ...adenocarcinomas (PADC). Objective To assess the accuracy of K- ras gene mutation analysis for diagnosing PADC. Design We systematically searched the electronic databases for relevant studies published. Data from selected studies underwent meta-analysis by use of a bivariate model providing a pooled value for sensitivity, specificity, diagnostic odds ratio, and summary receiver operating characteristic curve. Setting Meta-analysis of 8 prospective studies. Patients Total of 931 patients undergoing EUS-FNA for diagnosis of pancreatic solid masses. Intervention K- ras mutation analysis. Main Outcome Measurements Diagnostic accuracy of K- ras mutation analysis and of combined diagnostic strategy by using EUS-FNA and K- ras mutation analysis in the diagnosis of PADC. Results The pooled sensitivity of EUS-FNA for the differential diagnosis of PADC was 80.6%, and the specificity was 97%. Estimated sensitivity and specificity were 76.8% and 93.3% for K- ras gene analysis, respectively, and 88.7% and 92% for combined EUS-FNA plus K- ras mutation analysis. Overall, K- ras mutation testing applied to cases that were inconclusive by EUS-FNA reduced the false-negative rate by 55.6%, with a false-positive rate of 10.7%. Not repeating EUS-FNA in cases in which mutation testing of the K- ras gene is inconclusive would reduce the repeat-biopsy rate from 12.5% to 6.8%. Limitations Small number of studies and between-study heterogeneity. Conclusion K- ras mutation analysis can be useful in the diagnostic work-up of pancreatic masses, in particular when tissue obtained by EUS-FNA is insufficient, and the diagnosis inconclusive.
Please cite this paper as: Albrich S, Laterza R, Skala C, Salvatore S, Koelbl H, Naumann G. Impact of mode of delivery on levator morphology: a prospective observational study with three‐dimensional ...ultrasound early in the postpartum period. BJOG 2012;119:51–61.
Objective To evaluate morphology and integrity of the levator ani muscle (LAM) with three‐dimensional ultrasound early in the postpartum period.
Design Prospective cross‐sectional observational study.
Setting University hospital in Germany.
Population Women after vaginal delivery and caesarean section with no previous vaginal delivery.
Methods Three‐dimensional perineal ultrasound was performed between 48 and 72 hours postpartum. The axial plane at the level of minimal hiatal dimension and tomographic ultrasound imaging were used to determine LAM biometry and defect.
Main outcome measures Primary outcome was to compare hiatal dimensions and levator defect following vaginal delivery or caesarean section. For secondary outcomes, we evaluated the role of caesarean section in protecting levator integrity, and the possible involvement of the first stage of labour in LAM changes.
Results In all, 157 women participated: 81 (51.6%) following vaginal delivery (70 spontaneous and 11 operative deliveries) and 76 (48.4%) following caesarean section (55 elective and 21 emergency caesarean sections). All biometric indices of the levator were higher after vaginal delivery (P < 0.001), except for LAM thickness. LAM defects were found to be significantly associated with vaginal delivery, with relative risk 7.5 (P < 0.001). Following vaginal delivery, 32 (39.5%) levator defects were found: 27 (38.5%) after spontaneous delivery and five (45.4%) after operative delivery. Four (5.2%) women had a levator defect following emergency caesarean section.
Conclusion Vaginal delivery modifies and damages the LAM: the risk of levator defect after vaginal delivery is more than seven times higher than after caesarean section. Despite this, emergency caesarean section seems to have no complete preventive effect on LAM trauma.
MicroRNAs (miRNAs) are endogenous, small noncoding RNAs. Because of their size, abundance, tissue specificity, and relative stability in plasma, miRNAs hold promise as unique accessible biomarkers to ...monitor tissue injury.
We investigated the use of liver-, muscle- and brain-specific miRNAs as circulating biomarkers of tissue injury. We used a highly sensitive quantitative PCR assay to measure specific miRNAs (miR-122, miR-133a, and miR-124) in plasma samples from rats treated with liver or muscle toxicants and from a rat surgical model of stroke.
We observed increases in plasma concentrations of miR-122, miR-133a, and miR-124 corresponding to injuries in liver, muscle, and brain, respectively. miR-122 and miR-133a illustrated specificity for liver and muscle toxicity, respectively, because they were not detectable in the plasma of animals with toxicity to the other organ. This result contrasted with the results for alanine aminotransferase (ALT) and aspartate aminotransferase, which were both increased with either organ toxicity. Furthermore, miR-122 exhibited a diagnostic sensitivity superior to that of ALT when the results were correlated to the liver histopathologic results. The miR-124 concentration increased in the plasma of rats 8 h after surgery to produce brain injury and peaked at 24 h, while the miR-122 and miR-133a concentrations remained at baseline values.
These results demonstrate that tissue-specific miRNAs may serve as diagnostically sensitive plasma biomarkers of tissue injury.
We present the development and first use of a set of movable electrostatic probes on the full-scale ITER heating neutral beam prototype negative-ion source SPIDER. The probes access the ion source ...plasma from the multi-aperture accelerator aiming at the study of the plasma formation and expansion from the RF drivers through the transverse magnetic filter. The magnetic filter separates the relatively high electron-temperature region for plasma formation and hydrogen dissociation form the negative-ion extraction region in which low electron-temperature is required to avoid negative-ion destruction, but also causes non-uniformities and drifts in the large plasma discharge which will be studied by this setup. The set of electrostatic probes encompasses eight RF-compensated Langmuir probes, one double probe, one Mach probe for the assessment of plasma drift velocities, and two gridded retarding field energy analyzers to measure the positive-ion energy distribution function. Electric aspects as well as mechanical constraints given by the large in-vacuum movable structure, and thermal requirements of these relatively heat-flux components made the design challenging. Prototyping and commissioning of the measurement system is discussed offering examples of measured characteristics with the various probes.
Background. High neutrophil to lymphocyte ratio (NLR) has shown to be a predictor of poor outcomes in various malignancies, including pancreatic cancer. Methods. We assessed 70 consecutive pts with ...histologically confirmed mPC who received chemotherapy with nab-paclitaxel/gemcitabine at two different European oncologic centers between January 2012 and November 2015. Variables assessed for prognostic correlations included age ≥ 66, sex, Karnofsky PS score, primary tumor site, baseline CA19.9 level ≥ 59xULN, 12-week decrease of the CA19.9 level ≥ 50% from baseline, basal bilirubin level, baseline NLR, biliary stent implantation, and liver metastasis. Survival analyses were generated according to the Kaplan-Meier method. Univariate and multivariate analyses were performed by a Cox proportional hazard model. Results. According to NLR values, the patients were divided into two groups: high and low. Low group patients showed a better median PFS (7 months versus 5 months) and median OS (13 months versus 7 months) in respect to high group patients. At multivariate analysis, Karnofsky PS < 80% (HR = 0.4; CI 0.2–1.2), liver metastases (HR = 0.4; CI 0.18–0.82), and NLR ≥ 5 (HR = 2.7; 95% CI 1.4–5.2) were predictors of poorer OS. Based on the presence of one or more independent prognostic factors, three risk categories were identified: good-risk, intermediate-risk and poor-risk. The median OS was 22, 10, and 7 months, respectively. Conclusions. Baseline NLR is an independent predictor of survival of patients with mPC receiving palliative chemotherapy and could be useful to develop a simple clinical score to identify a subgroup of patients with a low chance to benefit from chemotherapy.
Previous study showed that muscle sympathetic nerve activity (MSNA) was augmented in anabolic steroids users (AASU). In the present study, we tested the hypothesis that the heart rate (HR) responses ...after maximal exercise testing would be reduced in AASU. 10 male AASU and 10 AAS nonusers (AASNU) were studied. Cardiopulmonary exercise was performed to assess the functional capacity and heart rate recovery. MSNA was recorded directly from the peroneal nerve by microneurography technique. Peak oxygen consumption (VO₂) was lower in AASU compared to AASNU (43.66±2.24 vs. 52.70±1.68 ml/kg/min, P=0.005). HR recovery (HRR) at first and second minute was lower in AASU than AASNU (21±2 vs. 27±2 bpm, P=0.02 and 37±4 vs. 45±2 bpm, P=0.05, respectively). MSNA was higher in AASU than AASNU (29±3 vs. 20±1 bursts/min, P=0.01). Further analysis showed a correlation between HRR and MSNA (r=- 0.64, P=0.02), HRR at first minute and peak VO₂ (r=0.70, P=0.01) and HRR at second minute and peak VO₂ (r=0.62, P=0.02). The exacerbated sympathetic outflow associated with a lower parasympathetic activation after maximal exercise, which impairs heart rate recovery, strengthens the idea of autonomic imbalance in AASU.
Glomerular filtration rate (GFR) is routinely assessed by measuring the concentrations of endogenous serum markers such as blood urea nitrogen and serum creatinine (SCr). Although widely used, these ...endogenous markers are not ideal and do not perform optimally in certain clinical settings. The purpose of this review is to critically review the potential utility of cystatin C (CysC), especially in patient populations in which CysC may have an advantage over routinely used endogenous markers of GFR.
In a narrative approach, we extensively review publications, primarily from the last 5 years, that address the development of methods to measure CysC, reference intervals, and the diagnostic accuracy of CysC to assess GFR. Between June 2000 and September 2001 Medline was searched using "cystatin c" as a textword, and articles that examined >75 individuals (except for renal transplant studies) and/or used accepted "gold standards" for assessing GFR were selected for inclusion. A total of 17 studies are reviewed that provide reference interval data for several populations. A total of 24 studies make conclusions about the utility of CysC vs SCr and/or creatinine clearance, with 20 providing data on the sensitivity and specificity of CysC for detecting impaired GFR. These publications are organized into subgroups that deal with specific patient populations or clinical situations.
This review focuses on two areas: (a) the evolution of immunoassays used to determine the concentration of CysC in serum, their analytic sensitivity, and reference intervals; and (b) the diagnostic performance of CysC against other renal markers in the general population and in specific subpopulations of patients.
Studies of reference intervals for CysC overwhelmingly demonstrated that CysC values in blood are independent of age and sex. Of the 24 studies that examined clinical utility, 15 concluded that CysC is superior to SCr, whereas 9 concluded that CysC is equivalent but provides no advantage. Summary ROC plot analysis of 20 studies that provide sensitivity and specificity data strongly suggests that CysC will be superior to SCr for detecting impaired GFR. Taken together, it is clear that CysC performs at least as well as SCr in the population at large and that it is likely to be superior to SCr in specific patient populations.
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