The protease uPA and its inhibitor PAI-1 play major roles in hemostasis and are also involved in cancer progression. This is mainly caused by their ability to degrade extracellular ...matrix-facilitating tumor cell migration. This study aimed to investigate the impact of uPA/PAI-1 and disseminated cytokeratin-positive cells (dCK+) on the outcome and the existence of synergistic effects.
We retrospectively analyzed a cohort of 480 breast cancer cases with known uPA/PAI-1 and dCK+ status. uPA/PAI-1 was tested on fresh tumor samples using a commercial ELISA test. Bone marrow aspirates were investigated immunocytochemically for CK18.
DCK+ cells were identified in 23% of cases. uPA positivity was significantly associated with the occurrence of dCK+ cells (P = 0.028). uPA and PAI-1 were significantly associated with outcome in the subgroup of early-stage cases without chemotherapy. DCK+ cells alone were not prognostic. However, we found synergistic effects. In the subgroup of node-negative cases with and without chemotherapy, the prognostic impact of uPA and PAI-1 was enhanced in cases with additional dCK-positivity (triple +). In cases without chemotherapy, triple-positive status was independently prognostic (HR: 9.3 CI: 1.1-75) next to T stage.
uPA and PAI-1 seem to influence the metastatic potential of dCK+ cells, which underlines its important role in tumor progression.
We retrospectively investigated concordance of EndoPredict (EPclin) with urokinase plasminogen activator and plasminogen activator inhibitor‐1 (uPA/PAI‐1) in 72 breast cancer patients and compared ...the results with grading, molecular subtype and chemotherapy recommendation. Compared to uPA/PAI‐1, EPclin proved to be more conservative concerning correlation with clinicopathological parameters and was significantly associated with the recommendation of adjuvant chemotherapy.
The prognostic significance of tumor budding in colon cancer is unequivocally documented, and the recommendations of the International Tumor Budding Consensus Conference (ITBCC) are currently the ...accepted basis for its assessment. Up to now, it is unknown whether the general use of a supporting cytokeratin immunohistochemistry can improve the interobserver variability and prognostic significance. Six investigators with different levels of experience reassessed 229 cases of colon carcinoma (pT3/4, N+/−, M0) with a supporting cytokeratin immunohistochemistry. The results were compared to previous assessments, which have been performed only on H & E. Bd3 was significantly associated with the occurrence of distant metastases according to the assessments of three out of six investigators (p < 0.05). Only one single investigator reached significant results concerning the cancer specific survival (p = 0.01). The pairwise kappa values range between a poor and moderate level of agreement (range 0.17–0.45; median 0.21). In conclusion, the results show no superiority of the use of an additional cytokeratin immunohistochemistry compared to the conventional analysis on sole H & E slides. Therefore, the general supporting use of a cytokeratin immunohistochemical staining seems to be inadvisable in colon cancer in consideration of necessary resources and costs.
Tumor budding is a mostly accepted adverse prognostic factor in colorectal carcinoma. It is on the cusp of a widespread use after agreement was reached recently on uniform assessment criteria. We ...investigated whether the interobserver variability has a direct influence on the prognostic relevance in pT3/4 colon cancer in the background of different levels of experience of the investigators. In total, six investigators with different levels of experience evaluated tumor budding on H&E slides in 244 cases with primary diagnosed (2002–2011) colon carcinoma (pT3/4, N+/−, M0). High-grade tumor budding/budding grade 3 (defined as majority assessment among the investigators) was significantly associated with an adverse outcome (overall survival
p
= 0.03, cancer-specific survival
p
= 0.08) and the occurrence of distant metastasis (
p
= 0.009). However, a detailed analysis of the rating results of the individual investigators revealed that only ratings of one investigator (advanced resident) were associated with an adverse outcome (
p
= 0.01 cancer-specific survival, overall survival
p
= 0.09, distant metastasis
p
= 0.002). The results of another investigator (consultant) were significantly associated with distant metastasis (
p
= 0.007). The kappa values among the investigators have a range between 0.077 and 0.357 (median 0.166). Total agreement of all investigators existed in 109 cases (44.7%). Our results demonstrate that the evaluation of tumor budding on H&E slides in pT3/4 colon cancer goes along with a considerable interobserver variability among investigators of different levels of experience. Furthermore, our results reveal that these findings directly influence the prognostic value.
Head and neck squamous cell carcinomas (HNSCC) exhibiting resistance to the EGFR-targeting drug cetuximab poses a challenge to their effective clinical management. Here, we report a specific ...mechanism of resistance in this setting based upon the presence of a single nucleotide polymorphism encoding EGFR-K
(K-allele), which is expressed in >40% of HNSCC cases. Patients expressing the K-allele showed significantly shorter progression-free survival upon palliative treatment with cetuximab plus chemotherapy or radiation. In several EGFR-mediated cancer models, cetuximab failed to inhibit downstream signaling or to kill cells harboring a high K-allele frequency. Cetuximab affinity for EGFR-K
was reduced slightly, but ligand-mediated EGFR activation was intact. We found a lack of glycan sialyation on EGFR-K
that associated with reduced protein stability, suggesting a structural basis for reduced cetuximab efficacy. CetuGEX, an antibody with optimized Fc glycosylation targeting the same epitope as cetuximab, restored HNSCC sensitivity in a manner associated with antibody-dependent cellular cytotoxicity rather than EGFR pathway inhibition. Overall, our results highlight EGFR-K
expression as a key mechanism of cetuximab resistance to evaluate prospectively as a predictive biomarker in HNSCC patients. Further, they offer a preclinical rationale for the use of ADCC-optimized antibodies to treat tumors harboring this EGFR isoform.
.
Aims
Tumour budding is considered to be a good marker for progression and prognosis in colorectal carcinomas. A uniform classification system has been established recently. The natural element of ...uncertainty in the practice of human medicine is also exhibited in the assessment of tumour budding. We tested the hypothesis that interobserver variability can be estimated during the assessment process and investigated its potential clinical implication.
Methods and results
Six investigators with different levels of experience could perceive different levels of difficulty (LOD) and estimated different levels of interobserver variability (LOIV) (Li1, lower than average; Li2, average; Li3, higher than average) during the assessment of tumour budding in 244 cases of colon cancer (pT3/4). In total, the LOIV showed following distribution: Li1: 36.1%, Li2: 43.9% and Li3: 20.0%. The LOIV was correlated significantly with the LOD given by the investigator. In total, the agreement rates with the final consensus classification were: Li1: 93.4%, Li2: 78.5% and Li3: 58.4%. The relative risk of disagreement with the final consensus classification was more than six times higher when a case was estimated to have a high rather than a low interobserver variability.
Conclusion
Our data show that the investigator can estimate the interobserver variability during the ongoing rating process in pT3/4 colon cancer. The LOIV/LOD seems to be a valuable parameter of the assessment quality. For Li3 cases further measures seem mandatory.
The main goal of this study was to compare contrast-enhanced spectral mammography (CESM) and breast magnetic resonance imaging (MRI) with histopathological results and to compare the sensitivity, ...accuracy, and positive and negative predictive values for both imaging modalities.
After ethics approval, CESM and MRI examinations were performed in 102 patients who had suspicious lesions described in conventional mammography. All visible lesions were evaluated independently by 2 experienced radiologists using BI-RADS classifications (scale 1-5). Dimensions of lesions measured with each modality were compared to postoperative histopathology results.
There were 102 patients entered into CESM/MRI studies and 118 lesions were identified by the combination of CESM and breast MRI. Histopathology confirmed that 81 of 118 lesions were malignant and 37 were benign. Of the 81 malignant lesions, 72 were invasive cancers and 9 were in situ cancers. Sensitivity was 100% with CESM and 93% with breast MRI. Accuracy was 79% with CESM and 73% with breast MRI. ROC curve areas based on BI-RADS were 0.83 for CESM and 0.84 for breast MRI. Lesion size estimates on CESM and breast MRI were similar, both slightly larger than those from histopathology.
Our results indicate that CESM has the potential to be a valuable diagnostic method that enables accurate detection of malignant breast lesions, has high negative predictive value, and a false-positive rate similar to that of breast MRI.
The Klotho protein, encoded by the KL (Klotho) gene, exerts antiaging and antifibrotic effects. The KL-VS genotype diminishes Klotho expression and correlates with cardiovascular death, heart ...failure, and chronic kidney disease progression. The aim of this study was to analyze the contribution of donor Klotho rs9536314 and rs9527025 polymorphisms (KL-VS genotype) to renal allograft morphology and function in the early post-transplant period.
Clinical data and biopsy reports of 170 deceased donor transplantations were retrieved from standard medical files. Donor DNA was genotyped for rs9527025 and rs9536314 SNPs using custom TaqMan assays.
As rs9527025 remained in full linkage with rs9536314, we report results for the latter. The analyses were performed for G dominant model (GG+GT vs TT). We found an association between reported SNP alleles, morphologic changes in the peritransplant biopsy, and kidney function 3 months after engraftment. A chronic glomerulopathy score of >0 was found in 12.2% of GG+GT cases and in 3.2% of TT cases (P = .023). For G allele carriers, the third month’s median estimated glomerular filtration rate value was 35.0 (range, 20.4-76.6 mL/min), while for TT haplotype, the value was 46.3 (range, 15.5-96.8 mL/min), P = .001. At the third post-transplant month, proteinuria incidence was higher for organs with G allele than with TT haplotype (24.4% vs 9.5%; P = .030; odds ratio 3.09; 95% confidence interval 1.22-7.69).
Deceased donor KL-VS polymorphism, altering protein dimerization and coreceptor function, predicts early renal transplant glomerular lesions and function. Further analyses for mentioned effect durability are necessary.
This study complies with the Helsinki Congress and the Istanbul Declaration regarding donor source. Donors were not prisoners, and were not paid or coerced.
•The study provides evidence of predictive value of donor Klotho genotyping in renal transplantation.•KL-VS genotype is associated with allograft morphology.•In the early post-transplant period transplanted kidney function correlates with KL-VS genotype.
BACKGROUND Contrast enhanced spectral mammography (CESM) is a new method of breast cancer diagnosis in which an iodinated contrast agent is injected and dual-energy mammography is obtained in ...multiple views of the breasts. The aim of this study was to compare the degree of enhancement on CESM with lesion characteristics on mammography (MG) and lesion histology in women with suspicious breast lesions. MATERIAL AND METHODS The degree of enhancement on CESM (absent, weak, medium, or strong) was compared to lesion characteristics on MG (mass, mass with microcalcifications, or microcalcifications alone) and histology (infiltrating carcinoma, intraductal carcinoma, or benign) to compare sensitivity of the two modalities and to establish correlations that might improve diagnostic accuracy. RESULTS Among 225 lesions identified with CESM and MG, histological evaluation revealed 143 carcinomas (127 infiltrating, 16 intraductal) and 82 benign lesions. This is the largest cohort investigated with CESM to date. The sensitivity of CESM was higher than that of MG (100% and 90%, respectively, p=0.010). Medium or strong enhancement on CESM and the presence of a mass on MG was the most likely indictor of malignancy (55.1% p=0.002). Among benign lesions, 60% presented as enhancement on CESM (were false-positive), and most frequently as medium or weak enhancement, together with a mass on MG (53%, p=0.047). Unfortunately, the study did not find combinations of MG findings and CESM enhancement patterns that would be helpful in defining false-positive lesions. We observed systematic overestimation of maximum lesion diameter on CESM compared to histology (mean difference: 2.29 mm). CONCLUSIONS Strong or medium enhancement on CESM and mass or mass with microcalcifications on MG were strong indicators of malignant transformation. However, we found no combination of MG and CESM characteristics helpful in defining false-positive lesions.
BACKGROUND Radiotherapy is explicitly indicated as one of the excluding factors in diagnosing overactive bladder syndrome (OAB). Nevertheless, symptoms of OAB such as urgent episodes, incontinence, ...pollakiuria, and nocturia, which are consequences of irradiation, led us to test the effectiveness of VESIcare®/Solifenacin in patients demonstrating these symptoms after radiation therapy of small pelvis organs due to malignant neoplasm. MATERIAL AND METHODS We conducted an observatory clinical study including 300 consecutive patients with symptoms of post-irradiation bladder; 271 of those patients completed the study. The observation time was 6 months and consisted of 3 consecutive visits taking place at 12-week intervals. We used VESIcare® at a dose of 5 mg a day. Every sixth patient was examined urodynamically at the beginning and at the end of the observation period, with an inflow speed of 50 ml/s. RESULTS We noticed improvement and decline in the average number of episodes a day in the following parameters: number of micturitions a day (-36%, P<0.01), nocturia (-50%, P<0.01), urgent episodes (-41%, P<0.03), and episodes of incontinence (-43%, P<0.01). The patients' quality of life improved. The average maximal cystometric volume increased by 34 ml (21%, p<0.01), average bladder volume of "first desire" increased by 42 ml (49%, P<0.01), and average detrusor muscle pressure at maximal cystometric volume diminished by 9 cmH2O (-36%, P<0.03). CONCLUSIONS The substance is well-tolerated. Solifenacin administered long-term to patients with symptoms of OAB after radiotherapy of a malignant neoplasm of the small pelvis organs has a daily impact in decreasing number of urgent episodes, incontinence, pollakiuria, and nocturia.
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