| 1. |
- Bjersand, Kathrine, 1972-, et al.
(författare)
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The clinical and prognostic correlation of HRNPM and SLC1A5 in pathogenesis and prognosis in epithelial ovarian cancer
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:6
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To evaluate the prognostic effect of the Heterogeneous nuclear ribonucleoprotein type M (HNRPM) and Solute carrier 1A5 (SLC1A5) in FIGO-stages I-II epithelial ovarian cancer.METHODS: A retrospective cohort study was designed to investigate the prognostic effect of HNRPM and SLC1A5, and the association with clinical-pathologic characteristics in 131 patients with FIGO-stages I-II epithelial ovarian cancer. Tissue microarrays were constructed and protein levels were assessed by immunohistochemistry (IHC).RESULTS: Positive HRNPM status was associated with positive staining for PUMA (P = 0.04), concomitant PUMA and p21 staining (P = 0.005), and VEGF-R2 (P = 0.003). Positive SLC1A5 staining was associated with positive staining of p27 (P = 0.030), PUMA (P = 0.039), concomitant PUMA and p27 staining, and VEGF-R2 (P = 0.039). In non-serous tumors (n = 72), the SLC1A5 positivity was associated with recurrent disease (P = 0.01). In a multivariable logistic regression analysis FIGO-stage (OR = 12.4), tumor grade (OR = 5.1) and SLC1A5 positivity (OR = 0.1) were independent predictive factors for recurrent disease. Disease-free survival (DFS) in women with SLC1A5-positive non-serous tumors was 92% compared with of 66% in patients with SLC1A5-negative non-serous tumors (Log-rank = 15.343; P = 0.008). In Cox analysis with DFS as endpoint, FIGO-stage (HR = 4.5) and SLC1A5 status (HR = 0.3) were prognostic factors.CONCLUSIONS: As the proteins HRNPM and SLC1A5 are associated with the cell cycle regulators p21 or p27, the apoptosis regulators PTEN and PUMA, and the VEGF-R2 it is concluded that both proteins have role in the pathogenesis of ovarian cancer. In patients with non-serous ovarian cancer SLC1A5 protects from recurrent disease, presumably by means of biological mechanisms that are unrelated to cytotoxic drug sensitivity.
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| 2. |
- Ericson Lindquist, Kajsa, et al.
(författare)
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Difficulties in diagnostics of lung tumours in biopsies : an interpathologist concordance study evaluating the international diagnostic guidelines
- 2022
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Ingår i: Journal of Clinical Pathology. - : BMJ Publishing Group Ltd. - 0021-9746 .- 1472-4146. ; 75:5, s. 302-309
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Accurate and reliable diagnosis is essential for lung cancer treatment. The study aim was to investigate interpathologist diagnostic concordance for pulmonary tumours according to WHO diagnostic criteria.METHODS: Fifty-two unselected lung and bronchial biopsies were diagnosed by a thoracic pathologist based on a broad spectrum of immunohistochemical (IHC) stainings, molecular data and clinical/radiological information. Slides stained with H&E, thyroid transcription factor-1 (TTF-1) clone SPT24 and p40 were scanned and provided digitally to 20 pathologists unaware of reference diagnoses. The pathologists independently diagnosed the cases and stated if further diagnostic markers were deemed necessary.RESULTS: In 31 (60%) of the cases, ≥80% of the pathologists agreed with each other and with the reference diagnosis. Lower agreement was seen in non-small cell neuroendocrine tumours and in squamous cell carcinoma with diffuse TTF-1 positivity. Agreement with the reference diagnosis ranged from 26 to 45 (50%-87%) for the individual pathologists. The pathologists requested additional IHC staining in 15-44 (29%-85%) of the 52 cases. In nearly half (17 of 36) of the malignant cases, one or more pathologist advocated for a different final diagnosis than the reference without need of additional IHC markers, potentially leading to different clinical treatment.CONCLUSIONS: Interpathologist diagnostic agreement is moderate for small unselected bronchial and lung biopsies based on a minimal panel of markers. Neuroendocrine morphology is sometimes missed and TTF-1 clone SPT24 should be interpreted with caution. Our results suggest an intensified education need for thoracic pathologists and a more generous use of diagnostic IHC markers.
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| 3. |
- Erlandsson, Ann, et al.
(författare)
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Binding of TS1, an anti-keratin 8 antibody, in small cell lung cancer after 177Lu-DOTA-Tyr3-octreotate treatment: a histological study in xenografted mice
- 2011
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Ingår i: EJNMMI Research. - 2191-219X. ; 1:1
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Background Small-cell lung carcinoma (SCLC) is an aggressive malignancy characterised by an early relapse, a tendency towards drug resistance, and a high incidence of metastasis. SCLC cells are of neuroendocrine origin and express high levels of somatostatin receptors; therefore, future treatment might involve targeting tumours with radiolabelled somatostatin analogues. This therapy induces abundant necrotic patches that contain exposed keratins; thus, keratin 8, which is one of the most abundant cytoskeletal proteins may represent an interesting secondary target for SCLC. This study aimed to investigate the effects of177Lu-DOTA-Tyr3-octerotate and the binding of the monoclonal anti-keratin 8 antibody, TS1, in vitro in treated SCLC- and midgut-xenografted mouse models. Methods NCI-H69- and GOT1-xenotransplanted mice were treated with three doses of 30 MBq177Lu-DOTA-Tyr3-octreotate administered 24 h apart. Mice xenotransplanted with NCI-H69 were sacrificed 1, 5, 12, 20 and 150 days post-injection or when the tumour had regrown to its original size. GOT1-xenotransplanted mice were sacrificed 3 days post-injection. Immunohistochemistry was performed to evaluate TS1 staining in tumours and in seven human biopsies of primary SCLC from pulmonary bronchi. Central cell density and nucleus size were determined in NCI-H69 sections. Results Twelve days after177Lu-DOTA-Tyr3-octerotate treatment, the SCLC xenograft response was extensive. Twenty days after treatment, one of three analysed tumours displayed complete remission. The other two tumours showed 1/4 the cell density of untreated controls and cell nuclei were about three times larger than those of untreated controls. At 150 days after treatment, one of four mice exhibited complete remission. Treated tumours displayed increased TS1 antibody accumulation and high TS1 binding in necrotic patches. All seven human SCLC biopsies displayed necrotic areas with TS1 staining. Conclusions Radiation treatment with three injections of 30 MBq177Lu-DOTA-Tyr3-octreotate had pronounced effects on tumour cell density and cell nuclei, which indicated mitotic catastrophe. Despite these anti-tumour effects, two of three SCLC tumours recurred. Further studies should investigate the nature of tumour cell survival and develop more effective treatments. High TS1 accumulation in tumour sections in vitro after177Lu-DOTA-Tyr3-octerotate treatment indicated that TS1 might represent a promising secondary therapeutic strategy.
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| 4. |
- Gunnarsson, Mats, et al.
(författare)
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Effects of inhalation of corticosteroids immediately after experimental chlorine gas lung injury
- 2000
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Ingår i: Journal of Trauma - Injury, Infection and Critical Care. - 1079-6061. ; 48:1, s. 101-107
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Tidskriftsartikel (refereegranskat)abstract
- Background: To assess the effects of treatment with nebulized corticosteroids immediately after chlorine gas injury. Methods: Eighteen anesthetized and mechanically ventilated pigs were exposed to chlorine gas (140 ppm for 10 minutes) and observed for 6 hours. Nine pigs were treated with nebulized beclomethasone-dipropionate 20 ╡g/kg (BDP group), and nine pigs were given no treatment (control group). Results: All animals developed severe pulmonary dysfunction. The initial decrease in PaO2 was similar in both groups, but BDP-treated animals improved whereas control animals deteriorated (p < 0.005, analysis of variance). Pulmonary vascular resistance increased in both groups but less in the BDP group (p < 0.01). Lung-thorax compliance was better preserved in the BDP group (p < 0.01), and oxygen delivery was significantly better in the BDP group (p < 0.01). One animal died in the BDP group, as did three animals in the control group. Conclusion: Immediate treatment with nebulized BDP improved pulmonary and cardiovascular function after experimental chlorine gas injury.
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| 5. |
- Hedbrant, Alexander, et al.
(författare)
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Macrophages of M1 phenotype have properties that influence lung cancer cell progression
- 2015
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Ingår i: Tumor Biology. - : Springer. - 1010-4283 .- 1423-0380. ; 36:11, s. 8715-8725
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Tidskriftsartikel (refereegranskat)abstract
- Stromal macrophages of different phenotypes can contribute to the expression of proteins that affects metastasis such as urokinase-type plasminogen activator (uPA), its receptor uPAR, and plasminogen activator inhibitor-1 (PAI-1), but knowledge of how essential their contribution is in comparison to the cancer cells in small cell lung cancer (SCLC) and lung squamous cell carcinoma (SCC) is lacking. The expression of uPA, uPAR, and PAI-1 and of the matrix metalloproteinases (MMP)-2 and MMP-9 were studied in human macrophages of M1 and M2 phenotype and compared to a lung SCC (NCI-H520) and a SCLC (NCI-H69) cell line. Effects of treatment with conditioned media (CM) from M1 and M2 macrophages on the expression of these genes in H520 and H69 cells as well as effects on the cell growth were investigated. In addition, data on the stromal macrophages immunoreactivity of uPAR, MMP-2, and MMP-9 in a few SCC and SCLC biopsies was included. uPAR, MMP-2, and MMP-9 were confirmed in stromal cells including macrophages in the SCC and SCLC biopsies. In vitro, both macrophage phenotypes expressed considerably higher mRNA levels of uPA, uPAR, PAI-1, and MMP-9 compared to the cancer cell lines, and regarding uPAR, the highest level was found in the M1 macrophage phenotype. Furthermore, M1 CM treatment not only induced an upregulation of PAI-1 in both H520 and H69 cells but also inhibited cell growth in both cell lines, giving M1 macrophages both tumor-promoting and tumor-killing potential.
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| 6. |
- Mansour, Mohammed S I, et al.
(författare)
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Comparison of immunohistochemical mesothelial biomarkers in paired biopsies and effusion cytology cell blocks from pleural mesothelioma
- 2023
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Ingår i: Cytopathology. - 1365-2303. ; 34:5, s. 456-465
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Traditionally, the diagnosis of pleural mesothelioma is based on histological material. Minimally invasive effusion cytology specimens are an alternative that, like biopsies, require ancillary analyses. Validation of immunohistochemical (IHC) analyses on cytology, including the surrogate markers for molecular alterations BAP1 and MTAP, is of interest.METHODS: IHC for eight different markers was performed on 59 paired formalin-fixed, paraffin-embedded pleural biopsies and pleural effusion cell blocks with mesothelioma. Immunoreactivity in ≥10% of tumour cells was considered positive/preserved. The concordance between histological and cytological materials was assessed.RESULTS: The overall percentage of agreement between the histological epithelioid component in 58 biopsies and paired cell blocks was 93% for calretinin, 98% for CK5, 97% for podoplanin, 90% for WT1, 86% for EMA, 100% for desmin, 91% for BAP1, and 72% for MTAP. For 11 cases with biphasic or sarcomatoid histology, the concordance between cytology and the histological sarcomatoid component was low for calretinin, CK5, and WT1 (all ≤45%). For the whole cohort, loss of both BAP1 and MTAP was seen in 40% while both markers were preserved in 11% of the biopsies for epithelioid histology. The corresponding numbers were 54% and 8%, respectively, for the paired cell blocks.CONCLUSIONS: Generally, a high concordance for IHC staining was seen between paired biopsies and pleural effusion cell blocks from mesotheliomas, but the somewhat lower agreement for WT1, EMA, and especially MTAP calls for further investigation and local quality assurance. The lower concordance for the sarcomatoid subtype for some markers may indicate biological differences.
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| 7. |
- Mansour, Mohammed S I, et al.
(författare)
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Higher concordance of PD-L1 expression between biopsies and effusions in epithelioid than in nonepithelioid pleural mesothelioma
- 2021
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Ingår i: Cancer Cytopathology. - : Wiley. - 1934-6638 .- 1934-662X. ; 129:6, s. 468-478
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Malignant mesothelioma (MM) is a therapy-resistant tumor, often causing an effusion. Drugs targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway have shown promising results, but assessment of PD-L1 expression to select patients for therapy has mainly been performed on histologic tissue samples. In a previous study, we showed that MM effusions are suitable for PD-L1 assessment with results comparable to those reported in histologic studies, but no studies have compared PD-L1 expression in histologic and cytologic samples.METHODS: PD-L1 expression was determined immunohistochemically (clone 28-8) in 61 paired samples of effusions and biopsies from patients with pleural MM, obtained at the time of diagnosis. Only cases with >100 tumor cells were included. Membranous staining in tumor cells was considered positive at ≥1%, >5%, >10%, and >50% cutoff levels.RESULTS: Of 61 histologic samples, PD-L1 expression was found in 28 and 7 samples at ≥1% and >50% cutoffs, respectively; the corresponding figures for cytology were 21 and 5, respectively. The overall percentage agreement between histology and cytology was 69% and 84%, with a kappa (κ) of 0.36 and 0.08 at ≥1% and >50% cutoffs, respectively. The concordance between cytology and histology tended to be higher for epithelioid MM versus nonepithelioid MM at a ≥1% cutoff. PD-L1 positivity in biopsies, but not in effusions, correlated with the histologic subtype at a ≥1% cutoff.CONCLUSIONS: A moderate concordance of PD-L1 expression between biopsies and effusions from pleural MM, especially for the epithelioid subtype, indicates biological differences between the 2 types of specimens. Cytology and histology may be complementary.
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| 8. |
- Mansour, Mohammed S I, et al.
(författare)
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PD-L1 Testing in Cytological Non-Small Cell Lung Cancer Specimens : A Comparison with Biopsies and Review of the Literature
- 2021
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Ingår i: Acta Cytologica. - : S. Karger AG. - 0001-5547 .- 1938-2650. ; 65:6, s. 501-509
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Programmed death-ligand 1 (PD-L1) expression is used for treatment prediction in non-small cell lung cancer (NSCLC). While cytology may be the only available material in the routine clinical setting, testing in clinical trials has mainly been based on biopsies.METHODS: We included 2 retrospective cohorts of paired, concurrently sampled, cytological specimens and biopsies. Also, the literature on PD-L1 in paired cytological/histological samples was reviewed. Focus was on the cutoff levels ≥1 and ≥50% positive tumor cells.RESULTS: Using a 3-tier scale, PD-L1 was concordant in 40/47 (85%) and 66/97 (68%) of the paired NSCLC cases in the 2 cohorts, with kappa 0.77 and 0.49, respectively. In the former cohort, all discordant cases had lower score in cytology. In both cohorts, concordance was lower in samples from different sites (e.g., biopsy from primary tumor and cytology from pleural effusion). Based on 25 published studies including about 1,700 paired cytology/histology cases, the median (range) concordance was 81-85% (62-100%) at cutoff 1% for a positive PD-L1 staining and 89% (67-100%) at cutoff 50%.CONCLUSIONS: The overall concordance of PD-L1 between cytology and biopsies is rather good but with significant variation between laboratories, which calls for local quality assurance.
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| 9. |
- Mansour, Mohammed S.I., et al.
(författare)
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PD‐L1 Expression in Non‐Small Cell Lung Cancer Specimens : Association with Clinicopathological Factors and Molecular Alterations
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:9
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Tidskriftsartikel (refereegranskat)abstract
- Immune checkpoint inhibitors (ICI) targeting programmed cell death‐1 or its ligand (PD‐ L1) have improved outcomes in non‐small cell lung cancer (NSCLC). High tumor PD‐L1 expression, detected by immunohistochemistry (IHC) typically on formalin‐fixed paraffin‐embedded (FFPE) histological specimens, is linked to better response. Following our previous investigation on PD‐L1 in cytological samples, the aim of this study was to further explore the potential impacts of various clinicopathological and molecular factors on PD‐L1 expression. Two retrospective NSCLC cohorts of 1131 and 651 specimens, respectively, were investigated for PD‐L1 expression (<1%/1– 49%/≥50%), sample type, sample site, histological type, and oncogenic driver status. In both cohorts, PD‐L1 was positive (≥1%) in 55% of the cases. Adenocarcinomas exhibited lower PD‐L1 expression than squamous cell carcinomas (p < 0.0001), while there was no difference between sample types, tumor locations, or between the two cohorts in multivariate analysis (all p ≥ 0.28). Mutational status correlated significantly with PD‐L1 expression (p < 0.0001), with the highest expression for KRASmutated cases, the lowest for EGFR‐mutated, and the KRAS/EGFR wild‐type cases in between. There was no difference in PD‐L1 levels between different prevalent KRAS mutations (all p ≥ 0.44), while mucinous KRAS‐mutated adenocarcinomas exhibited much lower PD‐L1 expression than non‐mucinous (p < 0.0001). Our data indicate that cytological and histological specimens are comparable for PD‐L1 evaluation. Given the impact of KRAS mutations and the mucinous growth pattern on PD‐L1 expression, these factors should be further investigated in studies on ICI response.
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| 10. |
- Mansour, Mohammed S. I., et al.
(författare)
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The impact of different fixatives on immunostaining of lung adenocarcinomas in pleural effusion cell blocks
- 2024
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Ingår i: CANCER CYTOPATHOLOGY. - 1934-662X .- 1934-6638.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cell blocks (CBs) are widely used for biomarker analyses such as immunostaining. Although immunohistochemistry on formalin-fixed paraffin-embedded tissues is standardized, there are multiple preparation methods and fixatives for cytology. Our objective was to investigate the effect of different common fixatives on the immunoreactivity of pleural effusion CBs with metastatic lung adenocarcinomas. Methods: This prospective study included 24 malignant pleural effusions from different patients with lung adenocarcinoma. From each case, four identical CBs were fixed in 10% neutral buffered formalin, PreservCyt, CytoLyt, and CytoRich Red (only 17 of the cases), respectively. Samples containing <100 malignant cells were excluded. All CBs were stained with thyroid transcription factor 1 (TTF-1; clones 8G7G3/1 and SPT24), napsin A, claudin 4, CEA, CK7, and epithelial cell adhesion molecule (EpCAM; clones BS14, Ber-Ep4, and MOC-31). The fraction and intensity of stained cells were evaluated. Results: Of the investigated markers, a significant difference in staining proportion was seen for TTF-1 clone 8G7G3/1 and EpCAM clone MOC-31, especially with cases being negative in CytoLyt (33.3% and 83.3% positive, respectively) and PreservCyt (62.5% and 83.3%) whereas being positive in CytoRich Red (76.5% and 94.1%) and formalin (both 95.8%). A significantly weaker intensity of staining was seen for all alcohol-based fixatives compared to formalin for TTF-1 clone 8G7G3/1, napsin A, and EpCAM clone MOC-31, whereas EpCAM clone Ber-Ep4 was significantly weaker only in PreservCyt compared with formalin. Conclusions: Immunocytochemical expression and concordance with formalin-fixed CBs differ depending on the used fixative as well as the antibody and clone, warranting investigation of the reliability of each biomarker for non-formalin-fixed cytology.
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