Recently it has been recognized that stromal markers could be used as a clinically relevant biomarker for therapy response and prognosis. Here, we report on a serum marker for stromal activation, A ...Disintegrin and Metalloprotease 12 (ADAM12) in colorectal cancer (CRC).
Using gene expression databases we investigated ADAM12 expression in CRC and delineated the source of ADAM12 expression. The clinical value of ADAM12 was retrospectively assessed in the CAIRO2 trial in metastatic CRC with 235 patients (31% of total cohort), and an independent rectal cancer cohort (n = 20).
ADAM12 is expressed by activated CRC associated fibroblasts. In the CAIRO2 trial cohort, ADAM12 serum levels were prognostic (ADAM12 low versus ADAM12 high; median OS 25.3 vs. 17.1 months, HR 1.48 95% CI 1.11-1.96, P = 0.007). The prognostic potential was specifically high for metastatic rectal cancer (HR 1.78 95% CI 1.06-3.00, P = 0.030) and mesenchymal subtype tumors (HR 2.12 95% CI 1.25-3.60, P = 0.004). ADAM12 also showed potential for predicting recurrence in an exploratory analysis of non-metastatic rectal cancers.
Here we describe a non-invasive marker for activated stroma in CRC which associates with poor outcome, especially for primary cancers located in the rectum.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
The purpose of this study was to assess the reproducibility of the previously described T2–fluid attenuated inversion recovery (FLAIR) mismatch sign as a specific imaging marker ...in non-enhancing isocitrate dehydrogenase (IDH) mutant, 1p/19q non-codeleted lower-grade glioma (LGG), encompassing both diffuse and anaplastic astrocytoma.
Methods
MR scans (n = 154) from 3 separate databases with genotyped LGG were evaluated by 2 independent reviewers to assess (i) presence/absence of “T2-FLAIR mismatch” sign and (ii) presence/absence of homogeneous signal on T2-weighted images. Interrater agreement with Cohen’s kappa (κ) was calculated, as well as diagnostic test performance of the T2-FLAIR mismatch sign to identify IDH-mutant astrocytoma.
Results
There was substantial interrater agreement for the T2-FLAIR mismatch sign κ = 0.75 (0.64–0.87), but only fair agreement for T2 homogeneity κ = 0.38 (0.25–0.52). The T2-FLAIR mismatch sign was present in 38 cases (25%) and had a positive predictive value of 100%, negative predictive value of 68%, a sensitivity of 51%, and a specificity of 100%.
Conclusions
With a robust interrater agreement, our study confirms that among non-enhancing LGG the T2-FLAIR mismatch sign represents a highly specific imaging marker for IDH-mutant astrocytoma. This non-invasive marker may enable a more informed patient counsel and can aid in the treatment decision processes in a significant proportion of patients presenting with non-enhancing, LGG-like lesions.
The resonances of dynamically excited symmetric piezoelectric bimorphs have been determined from the equations of state. Under the effect of sinusoidal stimuli: a moment exerted at the tip M, a force ...exerted perpendicular to the plane of the bimorph also applied at the tip F, a uniformly applied pressure p, and an electrode voltage V, they respond with a sinusoidal tip rotation /spl alpha/, tip deflection /spl delta/, volume displacement /spl nu/, and electrode charge Q. All of the former are related to all of the latter through a dynamic admittance matrix B. The antiresonance frequency of the capacitance C have been found while also antiresonance in off-diagonal elements have been determined. The latter indicate that at these frequencies the bimorph does not work as an actuator or sensor in the particular domain of the off-diagonal. The mode shape at these antiresonance frequencies has been determined. The antiresonance of b/sub 14/ determines that for this frequency the tip has deflection but no rotation, while the antiresonance of b/sub 24/ indicates that the tip has rotation but no deflection. No antiresonance in the volume displacement is found, indicating that the bimorph is a pressure converter (microphone) at all frequencies. Micromachined piezoelectric heterogeneous bimorphs have been fabricated using the techniques of I.C. fabrication. Their deflections have been measured as a function of frequency and applied voltage, while these have been compared with the theoretical predictions. An anomalously large quadratic deflection has been found, superimposed on the linear piezoelectric behavior. The agreement between the linear part of the experimental deflection and the theory was quite good.
Antioxidants for male subfertility Ligny, Wiep; Ligny, Wiep; Smits, Roos M ...
Cochrane database of systematic reviews,
05/2022, Letnik:
2022, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Background
The inability to have children affects 10% to 15% of couples worldwide. A male factor is estimated to account for up to half of the infertility cases with between 25% to 87% of male ...subfertility considered to be due to the effect of oxidative stress. Oral supplementation with antioxidants is thought to improve sperm quality by reducing oxidative damage. Antioxidants are widely available and inexpensive when compared to other fertility treatments, however most antioxidants are uncontrolled by regulation and the evidence for their effectiveness is uncertain. We compared the benefits and risks of different antioxidants used for male subfertility.
Objectives
To evaluate the effectiveness and safety of supplementary oral antioxidants in subfertile men.
Search methods
The Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, AMED, and two trial registers were searched on 15 February 2021, together with reference checking and contact with experts in the field to identify additional trials.
Selection criteria
We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment, or treatment with another antioxidant, among subfertile men of a couple attending a reproductive clinic. We excluded studies comparing antioxidants with fertility drugs alone and studies that included men with idiopathic infertility and normal semen parameters or fertile men attending a fertility clinic because of female partner infertility.
Data collection and analysis
We used standard methodological procedures recommended by Cochrane. The primary review outcome was live birth. Clinical pregnancy, adverse events and sperm parameters were secondary outcomes.
Main results
We included 90 studies with a total population of 10,303 subfertile men, aged between 18 and 65 years, part of a couple who had been referred to a fertility clinic and some of whom were undergoing medically assisted reproduction (MAR). Investigators compared and combined 20 different oral antioxidants. The evidence was of 'low' to 'very low' certainty: the main limitation was that out of the 67 included studies in the meta‐analysis only 20 studies reported clinical pregnancy, and of those 12 reported on live birth. The evidence is current up to February 2021.
Live birth: antioxidants may lead to increased live birth rates (odds ratio (OR) 1.43, 95% confidence interval (CI) 1.07 to 1.91, P = 0.02, 12 RCTs, 1283 men, I2 = 44%, very low‐certainty evidence). Results in the studies contributing to the analysis of live birth rate suggest that if the baseline chance of live birth following placebo or no treatment is assumed to be 16%, the chance following the use of antioxidants is estimated to be between 17% and 27%. However, this result was based on only 246 live births from 1283 couples in 12 small or medium‐sized studies. When studies at high risk of bias were removed from the analysis, there was no evidence of increased live birth (Peto OR 1.22, 95% CI 0.85 to 1.75, 827 men, 8 RCTs, P = 0.27, I2 = 32%).
Clinical pregnancy rate: antioxidants may lead to increased clinical pregnancy rates (OR 1.89, 95% CI 1.45 to 2.47, P < 0.00001, 20 RCTs, 1706 men, I2 = 3%, low‐certainty evidence) compared with placebo or no treatment. This suggests that, in the studies contributing to the analysis of clinical pregnancy, if the baseline chance of clinical pregnancy following placebo or no treatment is assumed to be 15%, the chance following the use of antioxidants is estimated to be between 20% and 30%. This result was based on 327 clinical pregnancies from 1706 couples in 20 small studies.
Adverse events Miscarriage: only six studies reported on this outcome and the event rate was very low. No evidence of a difference in miscarriage rate was found between the antioxidant and placebo or no treatment group (OR 1.46, 95% CI 0.75 to 2.83, P = 0.27, 6 RCTs, 664 men, I2 = 35%, very low‐certainty evidence). The findings suggest that in a population of subfertile couples, with male factor infertility, with an expected miscarriage rate of 5%, the risk of miscarriage following the use of an antioxidant would be between 4% and 13%.
Gastrointestinal: antioxidants may lead to an increase in mild gastrointestinal discomfort when compared with placebo or no treatment (OR 2.70, 95% CI 1.46 to 4.99, P = 0.002, 16 RCTs, 1355 men, I2 = 40%, low‐certainty evidence). This suggests that if the chance of gastrointestinal discomfort following placebo or no treatment is assumed to be 2%, the chance following the use of antioxidants is estimated to be between 2% and 7%. However, this result was based on a low event rate of 46 out of 1355 men in 16 small or medium‐sized studies, and the certainty of the evidence was rated low and heterogeneity was high.
We were unable to draw conclusions from the antioxidant versus antioxidant comparison as insufficient studies compared the same interventions.
Authors' conclusions
In this review, there is very low‐certainty evidence from 12 small or medium‐sized randomised controlled trials suggesting that antioxidant supplementation in subfertile males may improve live birth rates for couples attending fertility clinics. Low‐certainty evidence suggests that clinical pregnancy rates may increase. There is no evidence of increased risk of miscarriage, however antioxidants may give more mild gastrointestinal discomfort, based on very low‐certainty evidence. Subfertile couples should be advised that overall, the current evidence is inconclusive based on serious risk of bias due to poor reporting of methods of randomisation, failure to report on the clinical outcomes live birth rate and clinical pregnancy, often unclear or even high attrition, and also imprecision due to often low event rates and small overall sample sizes. Further large well‐designed randomised placebo‐controlled trials studying infertile men and reporting on pregnancy and live births are still required to clarify the exact role of antioxidants.
•We present a unique method of correlating in vivo imaging to immunohistochemistry.•3D heatmaps of biomarker presence are created from whole-mount tumor resections.•By registering the 3D heatmaps to ...imaging, we can spatially compare them.•The method provides insight into how well imaging portrays the tumor microenvironment.
In this study, we present a method that enables voxel-by-voxel comparison of in vivo imaging to immunohistochemistry (IHC) biomarkers. As a proof of concept, we investigated the spatial correlation between dynamic contrast enhanced (DCE-)CT parameters and IHC biomarkers Ki-67 (proliferation), HIF-1α (hypoxia), and CD45 (immune cells). 54 whole-mount tumor slices of 15 laryngeal and hypopharyngeal carcinomas were immunohistochemically stained and digitized. Heatmaps of biomarker positivity were created and registered to DCE-CT parameter maps. The adiabatic approximation to the tissue homogeneity model was used to fit the following DCE parameters: Ktrans (transfer constant), Ve (extravascular and extracellular space), and Vi (intravascular space). Both IHC and DCE maps were downsampled to 4 × 4 × 3 mm3 voxels. The mean values per tumor were used to calculate the between-subject correlations between parameters. For the within-subject (spatial) correlation, values of all voxels within a tumor were compared using the repeated measures correlation (rrm). No between-subject correlations were found between IHC biomarkers and DCE parameters, whereas we found multiple significant within-subject correlations: Ve and Ki-67 (rrm = -0.17, P < .001), Ve and HIF-1α (rrm = -0.12, P < .001), Ktrans and CD45 (rrm = 0.13, P < .001), Vi and CD45 (rrm = 0.16, P < .001), and Vi and Ki-67 (rrm = 0.08, P = .003). The strongest correlation was found between IHC biomarkers Ki-67 and HIF-1α (rrm = 0.35, P < .001). This study shows the technical feasibility of determining the 3 dimensional spatial correlation between histopathological biomarker heatmaps and in vivo imaging. It also shows that between-subject correlations do not reflect within-subject correlations of parameters.
When a T cell and an antigen-presenting cell form an immunological synapse, rapid dynein-driven translocation of the centrosome toward the contact site leads to reorganization of microtubules and ...associated organelles. Currently, little is known about how the regulation of microtubule dynamics contributes to this process. Here, we show that the knockout of KIF21B, a kinesin-4 linked to autoimmune disorders, causes microtubule overgrowth and perturbs centrosome translocation. KIF21B restricts microtubule length by inducing microtubule pausing typically followed by catastrophe. Catastrophe induction with vinblastine prevented microtubule overgrowth and was sufficient to rescue centrosome polarization in KIF21B-knockout cells. Biophysical simulations showed that a relatively small number of KIF21B molecules can restrict mirotubule length and promote an imbalance of dynein-mediated pulling forces that allows the centrosome to translocate past the nucleus. We conclude that proper control of microtubule length is important for allowing rapid remodeling of the cytoskeleton and efficient T cell polarization.
Hepatic Arteriography and C-Arm CT-Guided Ablation of liver tumors (HepACAGA) is a novel technique, combining hepatic-arterial contrast injection with C-arm CT-guided navigation. This study compared ...the outcomes of the HepACAGA technique with patients treated with conventional ultrasound (US) and/or CT-guided ablation.
In this retrospective cohort study, all consecutive patients with hepatocellular carcinoma (HCC) or colorectal liver metastases (CRLM) treated with conventional US-/CT-guided ablation between 1 January 2015, and 31 December 2020, and patients treated with HepACAGA between 1 January 2021, and 31 October 2023, were included. The primary outcome was local tumor recurrence-free survival (LTRFS). Secondary outcomes included the local tumor recurrence (LTR) rate and complication rate.
68 patients (120 tumors) were included in the HepACAGA cohort and 53 patients (78 tumors) were included in the conventional cohort. In both cohorts, HCC was the predominant tumor type (63% and 73%, respectively). In the HepACAGA cohort, all patients received microwave ablation. Radiofrequency ablation was the main ablation technique in the conventional group (78%). LTRFS was significantly longer for patients treated with the HepACAGA technique (
= 0.015). Both LTR and the complication rate were significantly lower in the HepACAGA cohort compared to the conventional cohort (LTR 5% vs. 26%, respectively;
< 0.001) (complication rate 4% vs. 15%, respectively;
= 0.041).
In this study, the HepACAGA technique was safer and more effective than conventional ablation for HCC and CRLM, resulting in lower rates of local tumor recurrence, longer local tumor recurrence-free survival and fewer procedure-related complications.
•GTV delineations based on anatomical MRI overestimated the tumor volume by 95%•Geometrically accurate DW-MRI increases tumor delineation accuracy.•DW-MRI reduces the CTV volumes, while maintaining ...high tumor coverage.
This study aims to determine the added value of a geometrically accurate diffusion-weighted (DW-) MRI sequence on the accuracy of gross tumor volume (GTV) delineations, using pathological tumor delineations as a ground truth.
Sixteen patients with laryngeal or hypopharyngeal carcinoma were included. After total laryngectomy, the specimen was cut into slices. Photographs of these slices were stacked to create a 3D digital specimen reconstruction, which was registered to the in vivo imaging. The pathological tumor (tumorHE) was delineated on the specimen reconstruction.
Six observers delineated all tumors twice: once with only anatomical MR imaging, and once (a few weeks later) when DW sequences were also provided. The majority voting delineation of session one (GTVMRI) and session two (GTVDW-MRI), as well as the clinical target volumes (CTVs), were compared to the tumorHE.
The mean tumorHE volume was 11.1 cm3, compared to a mean GTVMRI volume of 18.5 cm3 and a mean GTVDW-MRI volume of 15.7 cm3. The median sensitivity (tumor coverage) was comparable between sessions: 0.93 (range: 0.61–0.99) for the GTVMRI and 0.91 (range: 0.53–1.00) for the GTVDW-MRI.
The CTV volume also decreased when DWI was available, with a mean CTVMR of 47.1 cm3 and a mean CTVDW-MRI of 41.4 cm3. Complete tumor coverage was achieved in 15 and 14 tumors, respectively.
GTV delineations based on anatomical MR imaging tend to overestimate the tumor volume. The availability of the geometrically accurate DW sequence reduces the GTV overestimation and thereby CTV volumes, while maintaining acceptable tumor coverage.
Oncological applications of Raman spectroscopy have been contemplated, pursued, and developed at academic level for at least 25 years. Published studies aim to detect pre-malignant lesions, detect ...cancer in less invasive stages, reduce the number of unnecessary biopsies and guide surgery towards the complete removal of the tumour with adequate tumour resection margins. This review summarizes actual clinical needs in oncology that can be addressed by spontaneous Raman spectroscopy and it provides an overview over the results that have been published between 2007 and 2017. An analysis is made of the current status of translation of these results into clinical practice. Despite many promising results, most of the applications addressed in scientific studies are still far from clinical adoption and commercialization. The main hurdles are identified, which need to be overcome to ensure that in the near future we will see the first Raman spectroscopy-based solutions being used in routine oncologic diagnostic and surgical procedures.
This review summarizes actual clinical needs in oncology that can be addressed by Raman spectroscopy, provides results published in the last 10 years and analyses the current status of translation of these results into clinical practice.
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