BACKGROUND AND AIMPharmacogenetic studies continue to search for pretreatment predictors of chemotherapeutic efficacy and toxicity in metastatic colorectal cancer. Both genome-wide association ...studies and candidate gene studies have yielded potential genetic markers for chemosensitivity. We conducted a clinical association study, validating the effect of specific genetic markers cited in recently published papers on the efficacy of the oral 5-fluoro-uracil prodrug capecitabine.
PATIENTS AND METHODSGermline DNA was collected for 268 metastatic colorectal cancer patients from the CAIRO trial, a multicenter phase III trial, randomizing between combined or sequential first-line treatment with capecitabine, irinotecan, and oxaliplatin. Genotyping was performed for eight single-nucleotide polymorphisms (SNPs), using high-resolution melting curves. Four SNPs are located in the MTRR gene, and another four SNPs showed significant association with 5-fluoro-uracil cytotoxicity in a recent in-vitro genome-wide association study. The primary endpoint was progression-free survival (PFS); secondary endpoints were objective response and overall survival.
RESULTSIn patients receiving capecitabine monotherapy, rs4702484, located in ADCY2 and close to MTRR, was associated with slightly reduced PFS for homozygous wild-type patients (CC 6.2 vs. CT 8.0 months; P=0.018). For the other selected genetic markers, we found no association with PFS, overall survival, or radiologic response upon treatment with capecitabine, either in the total study population or in the capecitabine monotherapy subgroup.
CONCLUSIONWith the exception of rs4702484, we found no evidence of an effect on capecitabine chemosensitivity for any of the studied SNPs. More specifically, variants in methionine synthase reductase (MTRR) are not likely associated with capecitabine efficacy.
Beta-blockade does not inhibit cold-induced thermogenesis, whereas the relation between cold-induced thermogenesis and skeletal muscle mitchondrial uncoupling disappears during beta-blockade, ...indicating a role for β3-regulation.
Context:
Recently, brown adipose tissue (BAT) gained interest as a possible target for cold-induced thermogenesis, and therefore a target for treatment of obesity in adult humans. However, mitochondrial uncoupling takes place not only in BAT but also in skeletal muscle tissue. Both tissues may be involved in cold-induced thermogenesis, which is presumably regulated by the sympathetic nervous system.
Objective:
Here we studied whether blockade of β-adrenergic receptors using propranolol diminishes cold-induced thermogenesis and mitochondrial uncoupling in skeletal muscle tissue.
Design:
Ten lean subjects participated in this study and stayed twice (control and β-blockade using propranolol) for 84 h in a respiration chamber—the first 36 h for baseline measurements, followed by 48 h of mild cold exposure (16 C). Energy expenditure was measured continuously. After 36 and 84 h, muscle biopsies were taken in which mitochondrial uncoupling was studied.
Results:
Energy expenditure increased upon mild cold exposure (+5.0 ± 1.2 W; P < 0.005), i.e. cold-induced thermogenesis. However, contrary to our hypothesis, this cold-induced thermogenesis was not diminished after β-blockade (+4.7 ± 2.1 W for blockade vs. +5.1 ± 1.4 W for control; P = 0.59 for interaction cold blockade). Skeletal muscle mitochondrial uncoupling was significantly related to cold-induced thermogenesis in the control situation (R2 = 0.650; P < 0.01). There was no such relation during β-blockade.
Conclusions:
Our results suggest that skeletal muscle mitochondrial uncoupling may be involved in cold-induced thermogenesis and that this may be regulated by β2-receptors. When the β1- and β2-receptors are blocked, a β3-regulated process like mitochondrial uncoupling in BAT might take over the role of skeletal muscle mitochondrial uncoupling.
Prospective multicenter evaluation of the WHO classification and the morphometric D-score to predict endometrial hyperplasia cancer progression. In 132 endometrial hyperplasias WHO classification was ...performed by two experienced gynecologic pathologists. The D-score was assessed blindly by technicians in a routine diagnostic setting. Development of endometrial carcinoma during a 1-10-year follow-up was used as the end point. Eleven of 132 patients (8%), 10 of 61 (16%) atypical hyperplasias, and 1 of 71 (1%) nonatypical hyperplasias developed cancer. Twenty-six curettings had a D-score < or = 0 ("unfavorable" or endometrial intraepithelial neoplasia) of which 10 (38%) developed cancer. None of the 86 cases with a D-score > 1 ("favorable") and one of the 20 (5%) cases with 0 < D-score < or = 1 ("uncertain") developed cancer. Sensitivity of the D-score was 100%, specificity 82%, the positive and negative predictive values were 38% and 100%, respectively. These values are similar to those in three prior retrospective D-score studies but higher than the WHO values (which are 91%, 58%, 16%, and 99%, respectively). The D-score in endometrial hyperplasias is a more sensitive and specific marker for cancer prediction than the WHO classification, can be assessed in a routine clinical setting on standard hematoxylin and eosin sections (15-30 minutes per case), and is highly reproducible and cost-effective (U.S. $50 per case).
A task force of experts in the field of diagnostic DNA image cytometry, invited by the ESACP, and further scientists or physicians revealing experience in that diagnostic procedure (names are given ...in Addendum A), agreed upon the following 4th updated Consensus Report on Standardised Diagnostic DNA Image Cytometry during the 7th International Congress of that society in Caen, 2001. This report is based on the three preceding ones 6,14,17. It deals with the following items:- Critical review and update of the definitions given in the 1997 Consensus Update;- Review and detailed description of basic terms, principles and algorithms for diagnostic interpretation;- Recommendations concerning diagnostic or prognostic applications in specific fields of tumour pathology. This update is not aimed to substitute the 1997 consensus, but to make necessary addenda and give more detailed descriptions of those items not unequivocally to interpret by potential users of the methodology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Phosphohistone H3 assessed proliferation has strong prognostic value. Lymph vessel invasion by D2-40 is also prognostic, but D2-40+ myoepithelial expression in small ducts completely filled by ...solid-pattern ductal carcinoma in situ can mimic lymphovascular invasion. As myoepithelial cells are also p63 positive, we have investigated whether lymph vessel invasion identified by combined D2-40/p63 is stronger prognostically than by D2-40 alone, and whether it has independent prognostic value to phosphohistone H3. In 240 operable T(1-2)N(0)M(0) node negative invasive breast cancer patients <71 years, phosphohistone H3 was determined by quantitative immunohistochemistry and lymph vessel invasion by D2-40/p63 double immunostaining. Correlation analysis between the clinico-pathologic factors and lymph vessel invasion, and univariate and multivariate prognostic survival analysis were performed. With median 117 (range: 12-192) months follow-up, 36 patients (15%) developed and 28 (12%) died of distant metastases. Ten of the 61 patients (16%) with cancer cells surrounded by D2-40 were p63 positive and none of these 'false lymph vessel invasion' recurred. D2-40+/p63- lymph vessel invasion occurred in 51/239 (21%) cases and correlated with grade, mitotic activity index, phosphohistone H3, ER, cytokeratin14, and HER2. D2-40+/p63- lymph vessel invasion was strongly prognostic, but far more in women ≥55 than those <55 years (P<0.0001 and 0.04). With multivariate analysis, phosphohistone H3 proliferation was the strongest single prognosticator. Lymph vessel invasion had additional prognostic value to phosphohistone H3 only in women ≥55. This group of patients, without/with lymph vessel invasion, had 10-year survival rates of 83 and 50%, respectively (hazard ratio-lymph vessel invasion=3.0, P=0.04; hazard ratio-phosphohistone H3=6.9, P=0.002). Where age was <55 years, only phosphohistone H3 had independent prognostic value. Combinations of other features had no additional value. In conclusion, T(1-2)N(0)M(0) invasive breast cancer patients ≥55 years with phosphohistone H3≥13, D2-40+/p63- defined lymph vessel invasion identifies a subgroup with a high risk of distant metastases.
Abstract
Objectives
The objective of this study was to compare DMARD-free remission rates (DFRs) and sustained DFRs (SDFRs), defined as, respectively, DFR for ≥6 months and ≥1 year, after 2 and 5 ...years, between three clinical arthritis phenotypes: undifferentiated arthritis (UA), autoantibody-negative (RA−) and autoantibody-positive RA (RA+).
Methods
All UA (n = 130), RA− (n = 176) and RA+ (n = 331) patients from the tREACH trial, a stratified single-blinded trial with a treat-to-target approach, were included in the study. (S)DFR comparisons between phenotypes after 2 and 5 years were performed with logistic regression. Medication use and early and late flares (DAS ≥ 2.4), defined as at <12 months and >12 months after reaching DMARD-free remission (DFR), respectively, were also compared. Cox proportional hazard models were used to evaluate potential predictors for (S)DFR.
Results
Over the study periods of 2 and 5 years, less DFR was seen in RA+ (17.2–25.7%), followed by RA− (28.4–42.1%) and UA patients (43.1–58.5%). This also applied for SDFR over the 2- and 5-year periods in these three clinical arthritis phenotypes (respectively, 7.6% and 21.4%; 20.5% and 38.1%; and 35.4% and 55.4%). A flare during tapering was seen in 22.7% of patients. Of the patients in DFR, 7.5% had an early flare and 3.4% a late flare. Also, more treatment intensifications occurred in RA+ compared with RA− and UA. We found that higher baseline DAS, ACPA positivity, higher BMI and smoking were negatively associated with (S)DFR, while clinical phenotype (reference RA+), short symptom duration (<6 months) and remission within 6 months were positively associated with (S)DFR.
Conclusion
Long-term clinical outcomes differ between UA, RA– and RA+. These data reconfirm that RA can be subdivided into the aforementioned clinical phenotypes and that treatment might be best stratified upon these phenotypes, although validation is needed.
Trial registration
ISRCTN, https://www.isrctn.com/, ISRCTN26791028.
The severity of COVID-19 after SARS-CoV-2 infection is unpredictable. Angiotensin-converting enzyme-2 (ACE2) is the receptor responsible for coronavirus binding, while subsequent cell entry relies on ...priming by the serine protease TMPRSS2 (transmembrane protease, serine 2). Although renin-angiotensin-aldosterone-system (RAAS) blockers have been suggested to upregulate ACE2, their use in COVID-19 patients is now considered well tolerated. The aim of our study was to investigate parameters that determine COVID-19 severity, focusing on RAAS-components and variation in the genes encoding for ACE2 and TMPRSS2.
Adult patients hospitalized due to SARS-CoV-2 infection between May 2020 and October 2020 in the Haga Teaching Hospital were included, and soluble ACE2 (sACE2), renin, aldosterone (in heparin plasma) and polymorphisms in the ACE2 and TMPRSS2 genes (in DNA obtained from EDTA blood) were determined.
Out of the 188 patients who were included, 60 were defined as severe COVID-19 (ICU and/or death). These patients more often used antidiabetic drugs, were older, had higher renin and sACE2 levels, lower aldosterone levels and a lower aldosterone/renin ratio. In addition, they displayed the TMPRSS2-rs2070788 AA genotype less frequently. No ACE2 polymorphism-related differences were observed. Multivariate regression analysis revealed independent significance for age, sACE2, the aldosterone/renin ratio, and the TMPRSS2 rs2070788 non-AA genotype as predictors of COVID-19 severity, together yielding a C-index of 0.79. Findings were independent of the use of RAAS blockers.
High sACE2, a low aldosterone/renin ratio and having the TMPRSS2 rs2070788 non-AA genotype are novel independent determinants that may help to predict COVID-19 disease severity.
retrospectively registered.
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