| 1. |
|
|
| 2. |
- Domanski, A M., et al.
(författare)
-
Comparison of the oestrogen and progesterone receptor status in primary breast carcinomas as evaluated by immunohistochemistry and immunocytochemistry: a consecutive series of 267 patients
- 2013
-
Ingår i: Cytopathology. - : Blackwell Publishing. - 0956-5507 .- 1365-2303. ; 24:1, s. 21-25
-
Tidskriftsartikel (refereegranskat)abstract
- A.M. Domanski, N. Monsef, H.A. Domanski, D. Grabau and M. Ferno Comparison of the oestrogen and progesterone receptor status in primary breast carcinomas as evaluated by immunohistochemistry and immunocytochemistry: a consecutive series of 267 patients Objective: The use of cytological specimens to evaluate tumour biomarkers in metastatic breast cancer lesions has attracted increased interest because of the considerable number of reports that have shown discordance between the primary tumour and metastatic lesion. Oestrogen receptor (ER) and progesterone receptor (PgR) assays are crucial for the management of patients with breast cancer, in both adjuvant and palliative settings. The aim of this study was to compare the ER and PgR immunocytochemical analysis of fine needle aspiration (FNA) samples with the immunohistochemistry (IHC) of surgical specimens and core biopsies from primary breast cancers. Methods: The FNA specimens were prepared as cell blocks (n = 25) or ThinPreps (n = 258) for the immunocytochemistry (IC) ER and PgR analyses. Sixteen patients were excluded because of lack of follow-up (n = 1), neoadjuvant therapy (n = 3) or cell counts in their fine needle aspirates that were too low (n = 12). The results of IC on 25 cell blocks and 242 ThinPreps were compared with IHC on the corresponding core needle biopsies (n = 16) or excised tumours (n = 251). The ER and PgR status was defined as negative (when less than 10% of the nuclei were stained) or positive (when equal or more than 10% of the nuclei were stained). Kappa statistics were used to evaluate the concordance. Results: The ER concordance was 98% with ThinPrep (kappa = 0.93) and 92% with cell block (kappa = 0.82). The corresponding values for PgR were 96% (kappa = 0.91) and 96% (kappa = 0.92). Conclusions: Our results confirm that, in cases in which biopsies or surgical specimens are not available, IC (with either cell block or ThinPrep techniques) is a reliable method for the determination of the ER and PgR status performed under strict conditions using primary breast carcinomas, and is therefore potentially useful in metastatic settings.
|
|
| 3. |
- Forsberg, Daniel, et al.
(författare)
-
Evaluating Cell Nuclei Segmentation for Use on Whole-Slide Images in Lung Cytology
- 2014
-
Ingår i: 2014 22nd International Conference on Pattern Recognition (ICPR). - : IEEE Computer Society. - 9781479952083 ; , s. 3380-3385
-
Konferensbidrag (refereegranskat)abstract
- This paper presents results from an evaluation of three previously presented methods for segmentation of cell nuclei in lung cytology samples scanned by whole-slide scanners. Whole-slide images from seven cases of endobronchial ultrasound-guided transbronchial needle aspiration samples were used for extracting a number of regions of interest, in which approximately 2700 cell nuclei were manually segmented to form the ground truth. The segmented cells included benign bronchial epithelium, lymphocytes, granulocytes, histiocytes and malignant epithelial cells. The best results were obtained with a method based upon adaptive thresholding and an added step of clustering for distinguishing between cytoplasm and cell nuclei. This method achieved a mean DICE-score of 0.81 and a sensitivity and specificity of 0.88 and 0.81 respectively. In addition, this method was by far the fastest method, with a mean processing time of 7.8 s per image (2048 x 2048 pixels per image). By further improvements, such as lowering the false positive rate and using parallel computing hardware, this method has the potential to form the first building block in a system for computerized screening of whole-slide images in lung cytology.
|
|
| 4. |
- Isaksson, Sofi, et al.
(författare)
-
CA 19-9 and CA 125 as potential predictors of disease recurrence in resectable lung adenocarcinoma
- 2017
-
Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 12:10
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives Among patients who underwent primary surgery for non-small cell lung cancer (NSCLC), recurrent disease is frequent and cannot be accurately predicted solely from TNM stage and histopathological features. The aim of this study was to examine the association of tumor markers in pre-operative serum with recurrent disease. Material and methods Blood samples were collected prior to lung cancer surgery from 107 patients with stage I-III lung adenocarcinoma surgically treated at Lund University hospital, Lund, Sweden, between 2005 and 2011. The serum tumor markers Carcinoembryonic antigen (CEA), Neuron-specific enolase (NSE), Cancer antigen 125 (CA 125), Human epididymis protein 4 (HE4) and Carbohydrate antigen (CA 19-9) were analyzed retrospectively and clinical follow-up data were collected from patient charts. Forty (37%) patients were diagnosed with recurrent disease. Results Sixty-eight (64%) patients had at least one elevated tumor marker prior to surgery. In analysis of disease-free survival (DFS), CA 125 and/or CA 19-9 were significantly associated with recurrent disease adjusted to stage and adjuvant treatment (hazard ratio 2.8, 95% confidence interval 1.4-5.7, p = 0.006). Conclusion High pre-operative serum CA 19-9 and/or CA 125 might indicate an increased incidence of recurrent disease in resectable lung adenocarcinomas.
|
|
| 5. |
- Karlsson, Anna, et al.
(författare)
-
A combined gene expression tool for parallel histological prediction and gene fusion detection in non-small cell lung cancer
- 2019
-
Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- Accurate histological classification and identification of fusion genes represent two cornerstones of clinical diagnostics in non-small cell lung cancer (NSCLC). Here, we present a NanoString gene expression platform and a novel platform-independent, single sample predictor (SSP) of NSCLC histology for combined, simultaneous, histological classification and fusion gene detection in minimal formalin fixed paraffin embedded (FFPE) tissue. The SSP was developed in 68 NSCLC tumors of adenocarcinoma (AC), squamous cell carcinoma (SqCC) and large-cell neuroendocrine carcinoma (LCNEC) histology, based on NanoString expression of 11 (CHGA, SYP, CD56, SFTPG, NAPSA, TTF-1, TP73L, KRT6A, KRT5, KRT40, KRT16) relevant genes for IHC-based NSCLC histology classification. The SSP was combined with a gene fusion detection module (analyzing ALK, RET, ROS1, MET, NRG1, and NTRK1) into a multicomponent NanoString assay. The histological SSP was validated in six cohorts varying in size (n = 11-199), tissue origin (early or advanced disease), histological composition (including undifferentiated cancer), and gene expression platform. Fusion gene detection revealed five EML4-ALK fusions, four KIF5B-RET fusions, two CD74-NRG1 fusion and three MET exon 14 skipping events among 131 tested cases. The histological SSP was successfully trained and tested in the development cohort (mean AUC = 0.96 in iterated test sets). The SSP proved successful in predicting histology of NSCLC tumors of well-defined subgroups and difficult undifferentiated morphology irrespective of gene expression data platform. Discrepancies between gene expression prediction and histologic diagnosis included cases with mixed histologies, true large cell carcinomas, or poorly differentiated adenocarcinomas with mucin expression. In summary, we present a proof-of-concept multicomponent assay for parallel histological classification and multiplexed fusion gene detection in archival tissue, including a novel platform-independent histological SSP classifier. The assay and SSP could serve as a promising complement in the routine evaluation of diagnostic lung cancer biopsies.
|
|
| 6. |
- Liljedahl, Helena, et al.
(författare)
-
A gene expression-based single sample predictor of lung adenocarcinoma molecular subtype and prognosis
- 2021
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 148:1, s. 238-251
-
Tidskriftsartikel (refereegranskat)abstract
- Disease recurrence in surgically treated lung adenocarcinoma (AC) remains high. New approaches for risk stratification beyond tumor stage are needed. Gene expression-based AC subtypes such as the Cancer Genome Atlas Network (TCGA) terminal-respiratory unit (TRU), proximal-inflammatory (PI) and proximal-proliferative (PP) subtypes have been associated with prognosis, but show methodological limitations for robust clinical use. We aimed to derive a platform independent single sample predictor (SSP) for molecular subtype assignment and risk stratification that could function in a clinical setting. Two-class (TRU/nonTRU=SSP2) and three-class (TRU/PP/PI=SSP3) SSPs using the AIMS algorithm were trained in 1655 ACs (n = 9659 genes) from public repositories vs TCGA centroid subtypes. Validation and survival analysis were performed in 977 patients using overall survival (OS) and distant metastasis-free survival (DMFS) as endpoints. In the validation cohort, SSP2 and SSP3 showed accuracies of 0.85 and 0.81, respectively. SSPs captured relevant biology previously associated with the TCGA subtypes and were associated with prognosis. In survival analysis, OS and DMFS for cases discordantly classified between TCGA and SSP2 favored the SSP2 classification. In resected Stage I patients, SSP2 identified TRU-cases with better OS (hazard ratio [HR] = 0.30; 95% confidence interval [CI] = 0.18-0.49) and DMFS (TRU HR = 0.52; 95% CI = 0.33-0.83) independent of age, Stage IA/IB and gender. SSP2 was transformed into a NanoString nCounter assay and tested in 44 Stage I patients using RNA from formalin-fixed tissue, providing prognostic stratification (relapse-free interval, HR = 3.2; 95% CI = 1.2-8.8). In conclusion, gene expression-based SSPs can provide molecular subtype and independent prognostic information in early-stage lung ACs. SSPs may overcome critical limitations in the applicability of gene signatures in lung cancer.
|
|
| 7. |
- Monsef, Nastaran, et al.
(författare)
-
HIF1 alpha isoforms in benign and malignant prostate tissue and their correlation to neuroendocrine differentiation
- 2010
-
Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Neuroendocrine (NE) differentiation in prostate cancer has been correlated with a poor prognosis and hormone refractory disease. In a previous report, we demonstrated the presence of immunoreactive cytoplasmic hypoxia inducible factor 1 alpha (HIF1 alpha), in both benign and malignant NE prostate cells. HIF1 alpha and HIF1 beta are two subunits of HIF1, a transcription factor important for angiogenesis. The aim of this study was to elucidate whether the cytoplasmic stabilization of HIF1 alpha in androgen independent NE differentiated prostate cancer is due to the presence of certain HIF1 alpha isoforms. Methods: We studied the HIF1 alpha isoforms present in 8 cases of benign prostate hyperplasia (BPH) and 43 cases of prostate cancer with and without NE differentiation using RT-PCR, sequencing analysis, immunohistochemistry and in situ hybridization. Results: We identified multiple isoforms in both benign and malignant prostate tissues. One of these isoforms, HIF1 alpha 1.2, which was previously reported to be testis specific, was found in 86% of NE-differentiated prostate tumors, 92% of HIF1 alpha immunoreactive prostate tumors and 100% of cases of benign prostate hyperplasia. Immunohistochemistry and in situ hybridization results showed that this isoform corresponds to the cytoplasmic HIF1 alpha present in androgen-independent NE cells of benign and malignant prostate tissue and co-localizes with immunoreactive cytoplasmic HIF1 beta. Conclusion: Our results indicate that the cytoplasmic stabilization of HIF1 alpha in NE-differentiated cells in benign and malignant prostate tissue is due to presence of an HIF1 alpha isoform, HIF1 alpha 1.2. Co-localization of this isoform with HIF1 beta indicates that the HIF1 alpha 1.2 isoform might sequester HIF1 beta in the cytoplasm.
|
|
| 8. |
- Monsef, Nastaran, et al.
(författare)
-
Localization of immunoreactive HIF-1alpha and HIF-2alpha in neuroendocrine cells of both benign and malignant prostate glands.
- 2007
-
Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 67:11, s. 1219-1229
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Hypoxia induces increased tumor growth by promoting angiogenic and glycolytic pathways. Tumors expressing hypoxia-inducible factor-la (HIF-1 alpha), an important transcriptional activator of oxygen-regulated genes, are resistant to chemotherapy and radiotherapy. The major challenge in prostate cancer therapy today is to gain a better understanding of the development of hormone-refractory tumors, which is often characterized by neuroendocrine differentiation. Here we studied the expression of HIF-1 alpha and HIF-2 alpha in neuroendocrine cells of the benign prostate and in prostate cancer. METHODS. Tissue sections from 30 patients who underwent radical prostatectomy and from 21 patients operated by transurethral resection of the prostate were selected for immunohistochemical analysis for expression of HIF-l a, HIF-2a, androgen receptor (AR), neuroendocrine markers (chromogranin A, synaptophysin), and two gene products downstream of HIF-1a: VEGF and GAPDH. RESULTS. Immunoreactive HIF-1 alpha was detected in a subpopulation of AR-negative neuroendocrine cells in benign and malignant prostate tissue. Analysis of serial sections showed that the levels of expression of GAPDH and VEGF proteins are increased in AR-negative malignant neuroendocrine cells expressing HIF-1 alpha. in situ-hybridization indicated that HIF-1 alpha mRNA levels are not higher in neuroendocrine prostate cancer cells relative to corresponding non-neuroendocrine tumor cells. We also demonstrated induced stabilization of nuclear HIF-1 alpha in LNCaP cells by hypoxia and long-term stimulation with interleukin-6. Focal HIF-2 expression was detected in benign neuroendocrine-like cells and in malignant prostatic cells. CONCLUSIONS. The expression of HIF-1 alpha and HIF-2a in prostate cancer has been confirmed, but we also identified immunoreactive HIF-1 alpha and downstream gene products in benign and malignant prostate neuroendocrine cells. Prostate 67:1219-1229, 2007, (c) 2007 Wiley-Liss, Inc.
|
|
| 9. |
- Monsef, Nastaran
(författare)
-
Prostate cancer and neuroendocrine differentiation. Molecular aspects in prostate cancer development
- 2010
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hormone refractory prostate cancer occurs when androgen-deprivation therapy (ADT) fails to stop the growth of prostate cancer for any longer. Recent studies point towards a role for neuroendocrine (NE) differentiation in the development of hormone refractory disease. It has been hypothesized that NE-differentiated malignant tumor cells survive during ADT and promote development of androgen-independent disease through autocrine and paracrine signaling pathways. In vitro studies have shown that androgen depletion, stimulation with growth factors such as IL-6 and cAMP inducing agents cause NE-differentiation in prostate cancer cell lines. In this thesis, we have analyzed the tumorogenic characteristics of NE tumor cells with regard to expression of key transcription factors, stem cell markers and clinical prognostic markers. Hypoxia has been shown to induce increased tumor growth by promoting angiogenic and glycolytic pathways. Tumors overexpressing hypoxia inducible factors (HIF1a and HIF2a), important transcriptional activators of oxygen-regulated genes, are resistant to chemo- and radiotherapy. We found overexpression and cytoplasmic stabilization of HIF1a and HIF2a in androgen receptor negative NE cells in benign and malignant prostate tissue. Furthermore, we showed that stabilization of HIF1a in NE cells in prostate cancer is due to the presence of a HIF1a isoform, HIF1a1.2. This isoform is co-localized with ARNT, a subunit important for the function of HIF1 transcription factor. This finding indicates that the HIF1a1.2 isoform might sequester ARNT in the cytoplasm. We also studied presence of stem cell marker Oct 3/4 in prostate cancer and benign prostate hyperplasia. Transcription of type 1 of Oct 3/4 as well as protein expression with nuclear localization of Oct 3/4 were not detected in any of prostate tumors or benign prostate hyperplasia but we found only the cytoplasmic isoform 2 of Oct3/4 in prostate tumors with NE-differentiation and also in benign prostate hyperplasia. We studied NE-differentiation in hormone-naive high-grade prostate adenocarcinoma with four immunohistochemial NE markers, Chromogranin A (CgA), synaptophysin, serotonin and neuron-specific enolase (NSE). We showed that synaptophysin immunoreactivity detects the highest number of NE-differentiated tumors. In addition, NE-differentiation measured with synaptophysin, serotonin and NSE immunoreactivity, was correlated to Gleason grade 4 rather than Gleason grade 5 cancer. Univariate statistical analysis revealed that the immunoexpression of CgA, serotonin and NSE is correlated to longer patient survival time. In conclusion, NE-differentiation in hormone-naive high-grade prostate adenocarcinoma, measured with three of four NE markers, is correlated to Gleason grade 4 cancer, a better prognosis and longer patient survival time.
|
|
| 10. |
- Monsef, Nastaran, et al.
(författare)
-
The expression of pluripotency marker Oct 3/4 in prostate cancer and benign prostate hyperplasia.
- 2009
-
Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 69, s. 909-916
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Oct 3/4 (Octamer 3/4), a member of POU family has been considered as an important stem cell marker and essential transcription factor during human embryogenesis. In recent years, there have also been reports on presence of Oct 3/4 in differentiated benign and malignant human cells. The objective of this study was to investigate the transcription and the protein expression of Oct 3/4 isoforms in prostate cancer and benign prostate tissue. METHODS: Thirty sex adenocarcinomas and eight cases of benign prostate hyperplasia were studied. The transcription of Oct 3/4 was analyzed using RT-PCR approach associated with restriction digestion analysis. Oct 3/4 protein expression was studied by immunohistochemistry on paraffin sections using two different antibodies. RESULTS: We identified only the transcript 2 of Oct 3/4 in prostate tumors and benign prostate hyperplasia. Immunohistochemistry verified these results, demonstrating only cytoplasmic localization of Oct 3/4. Transcription of type 1 of Oct 3/4 as well as protein expression with nuclear localization of Oct 3/4 isoform 1 were not detected. Oct 3/4 immunopositive tumors were also displayed neuroendocrine differentiation and showed androgen receptor immunopositivity. The stem cell markers CD44 and CD117 were not detected in Oct 3/4 immunopositive cells. CONCLUSION: Our results indicate that only the cytoplasmic isoform 2 of Oct 3/4 is present in prostate cancer and benign prostate hyperplasia. The malignant and benign prostate cells, which are immunopositive for variant 2 of Oct 3/4, lack other stem cell markers supporting previously published data that variant 2 of Oct 3/4 is not a pluripotency marker. Prostate (c) 2009 Wiley-Liss, Inc.
|
|
