We have previously demonstrated a significant negative impact of intratumoral neutrophils in metastatic renal cell carcinoma. This study assessed intratumoral neutrophils in localized clear cell ...renal cell carcinoma (RCC).
The study comprised 121 consecutive patients who had a nephrectomy for localized RCC. Biomarkers (intratumoral CD8+, CD57+ immune cells, CD66b+ neutrophils, and carbonic anhydrase IX CA IX) were assessed by immunohistochemistry, and the relationship with clinical and histopathologic features and patient outcome was evaluated.
The intratumoral neutrophils ranged from zero to 289 cells/mm(2) tumor tissue. The presence of intratumoral neutrophils was statistically significantly associated with increasing tumor size, low hemoglobin, high creatinine, and CA IX < or = 85%. In multivariate analysis, the presence of intratumoral neutrophils (hazard ratio HR, 3.0; 95% CI, 1.7 to 5.4; P < .0001), pT stage T3b/T4 (HR, 2.1; 95% CI, 1.2 to 3.6; P = .007), and low hemoglobin (HR, 1.8; 95% CI, 1.0 to 3.1; P = .03) were independent prognostic factors significantly associated with short recurrence-free survival. The presence of intratumoral neutrophils was also an independent prognostic factor for cancer-specific survival (HR, 3.5; 95% CI, 1.9 to 6.4; P < .0001) and overall survival (HR, 3.1; 95% CI, 1.9 to 5.0; P < .0001). Applying the prognostic value of intratumoral neutrophils to the Leibovich low-/intermediate-risk group (n = 78) showed a 5-year recurrence-free survival of 53% (95% CI, 34.6% to 71.8%; presence of intratumoral neutrophils) versus 87% (95% CI, 77.8% to 96.8%; absence of intratumoral neutrophils). The estimated concordance index was 0.74 using the Leibovich risk score and 0.80 when intratumoral neutrophils were added.
The presence of intratumoral neutrophils is a new, strong, independent prognostic factor for short recurrence-free, cancer-specific, and overall survival in localized clear cell RCC.
IntroductionSebaceous gland carcinoma (SGC) of the eyelid is an aggressive tumour with the ability to metastasise and an increased morbidity. Controversies regarding the epidemiology of this ...malignant eyelid tumour is widespread in the scientific literature. Western reports repeatedly describes eyelid SGC as a rare occurring tumour in general, accounting for 1%–3% of all eyelid tumours, however studies from Asia have uncovered a higher frequency of eyelid SGC including 54% of all eyelid tumours in Japan, and 43%–56% in India. We wish to retrieve observational data of eyelid SGC prevalence in proportion to total eyelid tumours, from pathological studies published worldwide to resolve this controversy.Methods and analysisWe will search Ovid Medline, EMBASE, Cochrane Central Register of Controlled Trials, Scopus and Google Scholar to identify published reports on eyelid SGC prevalence proportions, aiming to clarify the incidence of the tumour. We will include observational clinicopathological studies reporting prevalence with confirmed histopathology. No limitations on publication date or language will be applied. Data from the individual studies and study quality will be extracted by two individual reviewers. Study quality will be assessed using the JBI Critical Appraisal Instrument for Studies Reporting Prevalence Data. Raw proportions will be transformed and pooled using a random effects model for meta-analysis. And subgroup analysis according to geography will be performed. If data are deemed unsuitable for a meta-analysis, a narrative synthesis will be presented. We will judge the certainty of evidence and present whether this has an overall effect on the results. The results may shed light on a long-standing academic disparity of the scientific literature.Ethics and disseminationThis systematic review does not require ethical approval. The results of this proposed review will be the subject to a publication in an international peer-reviewed journal within the ophthalmic or pathological specialty.PROSPERO registration numberCRD42023487141.
Fusion is the final osteoclast differentiation step leading to bone resorption. In healthy trabecular bone, osteoclast fusion is restricted to bone surfaces undergoing resorption, and necessarily ...requires site-specific recruitment of mononucleated pre-osteoclasts originating from the bone marrow. However, the spatiotemporal mechanism coordinating recruitment and fusion is poorly investigated. Herein we identify a collagen/vascular network as a likely structure supporting this mechanism. We therefore used multiplex immunohistochemistry and electron microscopy on human iliac crest bone samples, in combination with functional assays performed in vitro with osteoclasts generated from healthy blood donors. First, we found that putative pre-osteoclasts are in close vicinity of a network of collagen fibers associated with vessels and bone remodeling compartment canopies. Based on 3D-reconstructions of serial sections, we propose that this network may serve as roads leading pre-osteoclasts to resorption sites, as reported for cell migration in other tissues. Importantly, almost all these bone marrow pre-osteoclasts, but only some osteoclasts, express the collagen receptor OSCAR, which is reported to induce fusion competence. Furthermore, differentiating osteoclasts cultured on collagen compared to mineral show higher fusion rates, higher expression of fusogenic cytokines, and a CD47 plasma membrane distribution pattern reported to be typical of a pre-fusion state—thus collectively supporting collagen-induced fusion competence. Finally, these in vitro assays show that collagen induces high cell mobility. The present data lead to a model where collagen fibers/vasculature support the coordination between traffic and fusion of pre-osteoclasts, by serving as a physical road and inducing fusion competence as well as cell mobility.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Study Type – Diagnostic (exploratory cohort)
Level of Evidence 2a
What's known on the subject? and What does the study add?
Staging of patients with prostate cancer is the cornerstone of treatment. ...However, after curative intended therapy a high portion of patients relapse with local and/or distant recurrence. Therefore, one may question whether surgical lymph node dissection (LND) is sufficiently reliable for staging of these patients.
Several imaging methods for primary LN staging of patients with prostate cancer have been tested. Acceptable detection rates have not been achieved by CT or MRI or for that matter with PET/CT using the most common tracer fluoromethylcholine (FCH). Other more recent metabolic tracers like acetate and choline seem to be more sensitive for assessment of LNs in both primary staging and re‐staging. However, previous studies were small. Therefore, we assessed the value of 18FFCH PET/CT for primary LN staging in a prospective study of a larger sample and with a ‘blinded’ review. After a study period of 3 years and >200 included patients, we concluded that 18FFCH PET/CT did not reach an optimal detection rate compared with LND, and, therefore, it cannot replace this procedure. However, we did detect several bone metastases with 18FFCH PET/CT that the normal bone scans had missed, and this might be worth pursuing.
OBJECTIVES
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To assess the value of 18Ffluoromethylcholine (FCH) positron emission tomography/computed tomography (PET/CT) for lymph node (LN) staging of prostate cancer.
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To evaluate if FCH PET/CT can replace LN dissection (LND) for LN staging of prostate cancer, as about one‐third of patients with prostate cancer who receive intended curative therapy will have recurrence, one reason being undetected LN involvement.
PATIENTS AND METHODS
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From January 2008 to December 2010, 210 intermediate‐ or high‐risk patients had a FCH PET/CT scan before regional LND.
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After dissection, the result of histological examination of the LNs (gold standard) was compared with the result of FCH PET/CT obtained by ‘blinded review’.
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Sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of FCH PET/CT were measured for detection of LNe metastases.
RESULTS
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Of the 210 patients, 76 (36.2%) were in the intermediate‐risk group and 134 (63.8%) were in the high‐risk group. A medium (range) of 5 (1–28) LNs were removed per patient.
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Histological examination of removed LNs showed metastases in 41 patients. Sensitivity, specificity, PPV, and NPV of FCH PET/CT for patient‐based LN staging were 73.2%, 87.6%, 58.8% and 93.1%, respectively.
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Corresponding values for LN‐based analyses were 56.2%, 94.0%, 40.2%, and 96.8%, respectively.
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The mean diameter of the true positive LN metastases was significantly larger than that of the false negative LNs (10.3 vs 4.6 mm; P < 0.001).
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In addition, FCH PET/CT detected a high focal bone uptake, consistent with bone metastases, in 18 patients, 12 of which had histologically benign LNs.
CONCLUSIONS
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Due to a relatively low sensitivity and a correspondingly rather low PPV, FCH PET/CT is not ideal for primary LN staging in patients with prostate cancer.
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However, FCH PET/CT does convey important additional information otherwise not recognised, especially for bone metastases.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Screening for systemic amyloidosis is typically carried out with abdominal fat aspirates with varying reported sensitivities. Fat aspirates are preferred for use in primary screening instead of organ ...biopsies as they are less invasive and thereby minimize the potential risk of complications. At Odense Amyloidosis Center, we performed a prospective study on whether the combined use of fat aspirate and tru-cut skin biopsy could increase the diagnostic sensitivity. Both fat aspirates and skin biopsies were screened with Congo Red staining, and positive biopsies were subsequently subtyped using immunoelectron microscopy and mass spectrometry. Seventy-six patients were included. In total, 24 patients had systemic amyloidosis (11 AL, 12 wtATTR, 1 AA), and 6 patients had localized amyloidosis. Combined fat aspirate and skin biopsy were Congo Red-positive in 15 patients (overall sensitivity (OS) 62.5%). Fat aspirates were positive in 14 patients (OS 58.3%), and the skin biopsy was positive in 5 patients (OS 20.8%). In only one patient did the skin biopsy add extra diagnostic information. The sensitivity differed between AL and ATTR amyloidosis—81.8% and 41.7%, respectively. Using skin biopsy as the only screening method is not recommended.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Ca2+-activated K+ channels have been implicated in cancer cell growth, metastasis, and tumor angiogenesis. Here we hypothesized that high mRNA and protein expression of the intermediate-conductance ...Ca2+-activated K+ channel, KCa3.1, is a molecular marker of clear cell Renal Cell Carcinoma (ccRCC) and metastatic potential and survival.
We analyzed channel expression by qRT-PCR, immunohistochemistry, and patch-clamp in ccRCC and benign oncocytoma specimens, in primary ccRCC and oncocytoma cell lines, as well as in two ccRCC cell lines (Caki-1 and Caki-2). CcRCC specimens contained 12-fold higher mRNA levels of KCa3.1 than oncocytoma specimens. The large-conductance channel, KCa1.1, was 3-fold more highly expressed in ccRCC than in oncocytoma. KCa3.1 mRNA expression in ccRCC was 2-fold higher than in the healthy cortex of the same kidney. Disease specific survival trended towards reduction in the subgroup of high-KCa3.1-expressing tumors (p<0.08 vs. low-KCa3.1-expressing tumors). Progression-free survival (time to metastasis/recurrence) was reduced significantly in the subgroup of high-KCa3.1-expressing tumors (p<0.02, vs. low-KCa3.1-expressing tumors). Immunohistochemistry revealed high protein expression of KCa3.1 in tumor vessels of ccRCC and oncocytoma and in a subset of ccRCC cells. Oncocytoma cells were devoid of KCa3.1 protein. In a primary ccRCC cell line and Caki-1/2-ccRCC cells, we found KCa3.1-protein as well as TRAM-34-sensitive KCa3.1-currents in a subset of cells. Furthermore, Caki-1/2-ccRCC cells displayed functional Paxilline-sensitive KCa1.1 currents. Neither KCa3.1 nor KCa1.1 were found in a primary oncocytoma cell line. Yet KCa-blockers, like TRAM-34 (KCa3.1) and Paxilline (KCa1.1), had no appreciable effects on Caki-1 proliferation in-vitro.
Our study demonstrated expression of KCa3.1 in ccRCC but not in benign oncocytoma. Moreover, high KCa3.1-mRNA expression levels were indicative of low disease specific survival of ccRCC patients, short progression-free survival, and a high metastatic potential. Therefore, KCa3.1 is of prognostic value in ccRCC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Renal transplantation is the preferred treatment of end stage renal disease, but allograft survival is limited by the development of interstitial fibrosis and tubular atrophy in response to various ...stimuli. Much effort has been put into identifying new protein markers of fibrosis to support the diagnosis. In the present work, we performed an in-depth quantitative proteomics analysis of allograft biopsies from 31 prevalent renal transplant patients and correlated the quantified proteins with the volume fraction of fibrosis as determined by a morphometric method. Linear regression analysis identified four proteins that were highly associated with the degree of interstitial fibrosis, namely Coagulation Factor XIII A chain (estimate 18.7, adjusted
< 0.03), Uridine Phosphorylase 1 (estimate 19.4, adjusted
< 0.001), Actin-related protein 2/3 subunit 2 (estimate 34.2, adjusted
< 0.05) and Cytochrome C Oxidase Assembly Factor 6 homolog (estimate -44.9, adjusted
< 0.002), even after multiple testing. Proteins that were negatively associated with fibrosis (
< 0.005) were primarily related to normal metabolic processes and respiration, whereas proteins that were positively associated with fibrosis (
< 0.005) were involved in catabolic processes, cytoskeleton organization and the immune response. The identified proteins may be candidates for further validation with regards to renal fibrosis. The results support the notion that cytoskeleton organization and immune responses are prevalent processes in renal allograft fibrosis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This prospective cohort study evaluates associations between structural and ultrastructural parameters in baseline biopsies from human kidney transplants and long-term graft survival after more than ...14 years’ follow-up. Baseline kidney graft biopsies were obtained prospectively from 54 consecutive patients receiving a kidney transplant at a single institution. Quantitative measurements were performed on the baseline biopsies by computer-assisted light microscopy and electron microscopy. Stereology-based techniques estimated the fraction of interstitial tissue, the volume of glomeruli, mesangial fraction, and basement membrane thickness of glomerular capillaries. The fraction of occluded glomeruli and scores according to the Banff classification were achieved. Kidney graft survival was analyzed by Kaplan–Meier estimates and Cox regression. Association to long-term kidney function was also analyzed. The long-term surviving kidney transplants were characterized at implantation by less arteriolar hyaline thickening (
P
< 0.001) and less interstitial fibrosis (
P
= 0.001), as well as a lower fraction of occluded glomeruli (
P
= 0.004) and lower glomerular volume (
P
= 0.03). At the latest follow-up, eGFR was decreased by 12 ml/min/1.73 m
2
per unit increase in the score for arteriolar hyalinosis at implantation (
P
= 0.02), and eGFR was decreased by 19 ml/min/1.73 m
2
per 10
6
μm
3
increase in glomerular volume at baseline (
P
= 0.03). The unbiased Cavalieri estimate of glomerular volume and the ultrastructural parameters are the first to be evaluated in a cohort study with prospective follow-up for more than 14 years. The study shows that baseline biopsies from human kidney grafts contain extraordinary long-term prognostic information, and it highlights the importance of these intrinsic graft factors.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
In the last decade microRNAs (miRNAs) have been widely investigated in prostate cancer (PCa) and have shown to be promising biomarkers in diagnostic, prognostic and predictive settings. However, ...tumor heterogeneity may influence miRNA expression. The aims of this study were to assess the impact of tumor heterogeneity, as demonstrated by a panel of selected miRNAs in PCa, and to correlate miRNA expression with risk profile and patient outcome.
Prostatectomy specimens and matched, preoperative needle biopsies from a retrospective cohort of 49 patients, who underwent curatively intended surgery for localized PCa, were investigated with a panel of 6 miRNAs (miRNA-21, miRNA-34a, miRNA-125b, miRNA-126, miRNA-143, and miRNA-145) using tissue micro-array (TMA) and in situ hybridization (ISH). Inter- and intra-patient variation was assessed using intra-class correlation (ICC).
Four miRNAs (miRNA-21, miRNA-34a, miRNA-125, and miRNA-126) were significantly upregulated in PCa compared to benign prostatic hyperplasia (BPH), and except for miRNA-21 these miRNAs documented a positive correlation between the expression level in PCa cores and their matched BPH cores, (r > 0.72). The ICC varied from 0.451 to 0.764, with miRNA-34a showing an intra-tumoral heterogeneity accounting for less than 50% of the total variation. Regarding clinicopathological outcomes, only miRNA-143 showed potential as a prognostic marker with a higher expression correlating with longer relapse-free survival (p = 0.016).
The present study documents significant upregulation of the expression of miRNA-21, miRNA-34a, miRNA-125, and miRNA-126 in PCa compared to BPH and suggests a possible prognostic value associated with the expression of miRNA-143. The results, however, document intra-tumoral heterogeneity in the expression of various miRNAs calling for caution when using these tumor tissue biomarkers in prognostic and predictive settings.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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