Jorma Isola

University of Tampere, Tampere, Western Finland, Finland

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Publications (178)891.38 Total impact

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    ABSTRACT: Mutations in BRCA1 and BRCA2 genes confer an increased lifetime risk for breast and ovarian cancer. Increased lifetime ovarian cancer risk among BRCA1/BRCA2 mutation carriers can be substantially decreased by risk-reducing salpingo-oophorectomy (RRSO), which also provides material for molecular research on early pathogenesis of serous ovarian cancer. RRSO studies have suggested fallopian tube as a primary site of serous high-grade ovarian cancer. In this study, the nuclear expression levels of γ-H2AX and p53 using immunohistochemical (IHC) study was quantitatively assessed in ovarian and fallopian tube epithelium derived from RRSOs in 29 BRCA1 and BRCA2 mutation carriers and in 1 patient with a strong family history of breast and ovarian cancer but showing an unknown BRCA status. Both p53 and γ-H2AX nuclear staining levels were significantly higher in BRCA1/2 mutation-positive fallopian tube epithelium compared with the control fallopian tube epithelium (P<0.006 and P=0.011, respectively). Nuclear expression levels of p53 and γ-H2AX were similar between the BRCA1/2 mutation-positive ovarian epithelium and controls. Both γ-H2AX and p53 showed significantly higher nuclear expression levels in BRCA1/2 mutation-positive fallopian tube epithelium compared with BRCA1/2 mutation-positive ovarian epithelium (P<0.0001 and P<0.0001, respectively). BRCA1/2 mutation-positive fallopian tube epithelium showed a positive correlation between the γ-H2AX and p53 nuclear expression levels (Pearson r=0.508, P=0.003). Our results of quantitative nuclear p53 and γ-H2AX expression levels in ovarian and fallopian tube epithelium derived from RRSO in high-risk patients support the previously suggested role of fallopian tube epithelium serving as a possible site of initial serous ovarian carcinogenesis.
    International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 03/2014; · 2.07 Impact Factor
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    ABSTRACT: Preoperative evaluation of the risk for metastases in endometrial carcinoma is challenging. The growth of new vessels, angiogenesis, is important for tumor growth and purported to be involved in the metastatic process. The aim of this study was to evaluate the significance of preoperative serum levels and immunohistochemical expression of angiogenic markers in predicting a metastasized disease. Preoperative sera from 98 consecutive women presenting with endometrial carcinoma were collected. Serum concentrations of VEGF, sFLT1, and CD105 were assessed by enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry was used to assess the expression of CD105, VEGF, FLT1, and KDR. The results were correlated to the presence of metastases, presence of deep (≥50 %) myometrial invasion, and the histological grade of the tumor. Tumors with other than endometrioid histology were excluded. Of the 80 evaluable patients, 11 had a metastasized disease. The serum concentration of VEGF was higher in the group with metastases than in the group without metastases (median [range], 743 pg/mL [546-1,183 pg/mL] vs. 383 pg/mL [31-1,524 pg/mL], p < 0.001, respectively). In the multivariable analysis, the concentration of VEGF was the sole independent, albeit weak predictive factor for the presence of metastases (odds ratio, 1.004, 95 % confidence interval, 1.002-1.007; p = 0.001). The immunohistochemical expression of the markers was not associated with any of the clinicopathological features of the tumors. The results of the present study suggest that preoperative serum VEGF concentration correlates with the presence of metastases in endometrioid endometrial carcinoma.
    Tumor Biology 01/2014; · 2.52 Impact Factor
  • Mark Barok, Heikki Joensuu, Jorma Isola
    Breast cancer research: BCR 01/2014; 16(2):R22. · 5.87 Impact Factor
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    ABSTRACT: Formalin fixation preserves tissue morphology at the expense of macromolecule integrity. Freshly frozen samples are the golden standard for DNA and RNA analyses but require laborious deep-freezing and frozen sectioning for morphological studies. Alternative tissue stabilisation methods are therefore needed. We analysed the preservation of nucleic acids, immunohistochemical staining properties and tissue morphology in paraffin-embedded clinical tissue samples fixed with Z7, RCL2, PAXgene, Allprotect and RNAlater. Formalin-fixed and deep-frozen samples were used as controls. Immunohistochemical analyses showed good preservation of antigenicity in all except Allprotect and RNAlater-fixed samples. RNA quality, based on RNA integrity number value by Bioanalyzer, was comparable with freshly frozen samples only in PAXgene-fixed samples. According to quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses, RNA from PAXgene samples yielded results similar to freshly frozen samples. No difference between fixatives was seen in DNA analyses (PCR and real-time PCR). In conclusion, PAXgene seems to be superior to other molecular fixatives and formaldehyde.
    Journal of clinical pathology 06/2013; · 2.43 Impact Factor
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    ABSTRACT: Gremlin 1 and noggin are inhibitors of bone morphogenetic protein (BMP) signaling. They are vital during early development but their role in adult tissues has remained largely unresolved. The BMP signaling pathway has also been implicated in tumorigenesis, however with emphasis on the role of the ligands and receptors. We performed a concurrent survey of gremlin 1 and noggin protein expression in multiple normal and cancer samples, using immunohistochemistry on tissue microarrays containing 96 samples from 34 different normal organs/tissue sites and 208 samples of 34 different tumor types. In majority of both normal and tumor samples, gremlin 1 and noggin expression was negative or weak. However, normal stomach and skin demonstrated distinct gremlin 1 and noggin expression indicating a role in adult tissues. Likewise, strong expression of both antagonists was detected in Leydig cells of testis. In the tumor panel, the expression patterns were more variable but elevated BMP antagonist expression was detected for the first time in few cases, such as glioblastoma, hepatocellular carcinoma and diffuse B-cell lymphoma for gremlin 1 and renal granular cell tumor and thyroid papillary carcinoma for noggin. Even though gremlin 1 and noggin were not widely expressed in adult tissues, in a subset of organs their expression pattern indicated a potential role in normal tissue homeostasis as well as in malignancies.
    International journal of clinical and experimental pathology 01/2013; 6(7):1400-8. · 2.24 Impact Factor
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    ABSTRACT: BACKGROUND: Disseminated tumour cells (DTCs) in the bone marrow of patients with breast cancer have been identified as an independent predictor of poor prognosis in patients with non-metastatic disease. This prospective study aimed to evaluate the presence and prognostic value of DTCs in the bone marrow of female patients with primary breast cancer. METHODS: Between 1999 and 2003, bone marrow aspirates were obtained from patients at the time of surgery for primary invasive breast cancer. DTCs in bone marrow were identified using monoclonal antibodies against cytokeratins for detection of epithelial cells. The detection of DTCs was related to clinical follow-up with distant disease-free survival (DDFS) and breast cancer-specific survival as endpoints. Bone marrow aspirates from adult healthy bone marrow donors were analysed separately. RESULTS: DTCs were analysed in 401 patients, and cytokeratin-positive cells were found in 152 of these (38%). An immunofluorescence (IF) staining procedure was used in 327 patients, and immunocytochemistry (IC) was performed in 74 patients. The IF-based method resulted in 40% DTC-positive cases, whereas 30% were positive using IC (p = 0.11). The presence of DTCs in bone marrow was not significantly related to patient or tumour characteristics. The presence of DTCs was not a prognostic factor for DDFS (IF: hazards ratio [HR], 2.2; 95% confidence interval [CI], 0.63--2.2; p = 0.60; IC: HR, 0.84; 95% CI, 0.09--8.1; p = 0.88). Significant prognostic factors were lymph node metastases, oestrogen receptor positivity, Nottingham histological grade, and tumour size using Cox univariate analysis. The analyses were positive for epithelial cells in bone marrow from adult healthy donors in 19 (25%) samples. CONCLUSIONS: The detection of DTCs in bone marrow in primary breast cancer was previously shown to be a predictor of poor prognosis. We were not able to confirm these results in a prospective cohort including unselected patients before the standard procedure was established. Future studies with a standardised patient protocol and improved technique for isolating and detecting DTCs may reveal the clinical applications of DTC detection in patients with micrometastases in the bone marrow.
    BMC Cancer 09/2012; 12(1):403. · 3.33 Impact Factor
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    ABSTRACT: Gastrointestinal and pancreatic neuroendocrine tumors (NETs) arise from disseminated neuroendocrine cells, expressing general and specific neuroendocrine markers. The World Health Organization 2010 classification of NETs is based on grading them according to the proliferation index (PI), which is determined by immunohistochemical staining of the nuclear antigen Ki-67. The classification introduces Ki-67 as the most important criterion for tumor grading, influencing patients' prognoses and the choice of treatment. The aim of this study was to evaluate the assessment of PI value in NETs and its influence on tumor grading. The tumor material consisted of 51 NETs from the pancreas (n=31) and ileum (n=20). The slides were stained with the Ki-67 antibody and visualized using a polymer kit. PI was assessed visually by microscope oculars and using a public domain image analysis software, ImmunoRatio. The PI was measured from the most proliferative areas of the tumor. The PI values and tumor grade by ImmunoRatio were highly reproducible as compared with conventional assessment, which suffered from variation especially if ascertained by different observers. Computer-aided assessments had almost perfect correlation (r=0.985, r=0.987, and r=0.995) (P=0.000) and reproducibility (κ=0.886, κ=0.886, and κ=1.000) (P=0.000) in PI values and tumor grades, respectively. The PI values and tumor grade between conventional and ImmunoRatio assessments by a qualified observer were in good agreement. ImmunoRatio is a qualified diagnostic aid to more objectively analyze Ki-67 PI-based tumor grade in NETs.
    The American journal of surgical pathology 09/2012; 36(9):1359-63. · 4.06 Impact Factor
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    ABSTRACT: The ATP-binding cassette (ABC) of active transporters comprises a group of proteins that which facilitate efflux of anticancer drugs from cancer cells. We focused on the gene amplification and protein expression of ABCC3 (also known as MRP3) in breast cancer cell lines and clinical tumor samples. Fluorescence and chromogenic in situ hybridization, using an ABCC3-specific probe, was used to analyze 11 breast cancer cell lines and 112 clinical tumor samples. The results of ABCC3 were correlated with the amplification status of HER2 and topoisomerase II alpha (TOP2A), which are located close to ABCC3 at 17q12-q21. Immunohistochemistry was used to assess ABCC3 protein overexpression. Of the cell lines studied 6 HER2-positive lines and 1 HER2-negative line exhibited amplification of ABCC3. In the HER-2-negative clinical tumor samples, only 4/55 (7.3%) exhibited ABCC3 amplification. In the HER2-positive tumors, ABCC3 was amplified in 16/57 tumors (28.1%, P=0.0059). TOP2A did not exhibit any consistent coamplification pattern. ABCC3 (MRP3) protein overexpression was more common in tumors with gene amplification (P=0.069). In silico analysis of 804 breast cancers with matched gene expression and copy number microarray data revealed significant differences ABCC3 across the molecular subtypes. Specifically, increased ABCC3 mRNA and gene copy numbers were most prominent in HER2 amplified and/or HER2-enriched classified tumors. Moreover, differential ABCC3 mRNA levels were found within the HER-2 amplified subset when stratified by the estrogen receptor status. We conclude that ABCC3 is frequently amplified and overexpressed in HER2-positive breast cancer, and something that warrants further studies correlating the results with therapeutic outcome.
    Genes Chromosomes and Cancer 05/2012; 51(9):832-40. · 3.55 Impact Factor
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    Gynecologic Oncology. 04/2012; 125(1):282–283.
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    ABSTRACT: Endocrine therapy by castration or anti-androgens is the gold standard treatment for advanced prostate cancer. Although it has been used for decades, the molecular consequences of androgen deprivation are incompletely known and biomarkers of its resistance are lacking. In this study, we studied the molecular mechanisms of hormonal therapy by comparing the effect of bicalutamide (anti-androgen), goserelin (GnRH agonist) and no therapy, followed by radical prostatectomy. For this purpose, 28 men were randomly assigned to treatment groups. Freshly frozen specimens were used for gene expression profiling for all known protein-coding genes. An in silico Bayesian modelling tool was used to assess cancer-specific gene expression from heterogeneous tissue specimens. The expression of 128 genes was > two-fold reduced by the treatments. Only 16% of the altered genes were common in both treatment groups. Of the 128 genes, only 24 were directly androgen-regulated genes, according to re-analysis of previous data on gene expression, androgen receptor-binding sites and histone modifications in prostate cancer cell line models. The tumours containing TMPRSS2-ERG fusion showed higher gene expression of genes related to proliferation compared to the fusion-negative tumours in untreated cases. Interestingly, endocrine therapy reduced the expression of one-half of these genes and thus diminished the differences between the fusion-positive and -negative samples. This study reports the significantly different effects of an anti-androgen and a GnRH agonist on gene expression in prostate cancer cells. TMPRSS2-ERG fusion seems to bring many proliferation-related genes under androgen regulation.
    The Journal of Pathology 03/2012; 227(3):336-45. · 7.59 Impact Factor
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    ABSTRACT: Assessment of the human epidermal growth factor receptor 2 (HER2) with immunohistochemistry (IHC) is routine practice in clinical pathology laboratories. Visual classification of the staining reaction (usually into 0/1+, 2+ or 3+) is subjective and prone to significant inter- and intra-observer variation. In this study, we describe ImmunoMembrane, an easy-to-use HER2 IHC analysis software, which is freely available as a web application, requiring no download or installation. ImmunoMembrane uses colour deconvolution for stain separation and a customized algorithm for cell membrane segmentation. A quantitative score (IM-score, 0-20 points) is generated according to the membrane staining intensity and completeness. Specimens are classified into 0/1+, 2+ or 3+ based on IM-score cut-offs defined using a training set. The classification and membrane segmentation are presented as a pseudo-coloured overlay image. With a validation set (144 HercepTest(®) -stained whole tissue sections), ImmunoMembrane matched well with the pathologist's visual classification (weighted kappa κ(w) =0.80), as well as fluorescence in-situ hybridization (FISH) (IHC disagreement 3.5%, n=144) and chromogenic in-situ hybridization (CISH) (IHC disagreement 2.8%, n=144). We anticipate that publicly available web applications, such as ImmunoMembrane, will accelerate the adoption of automated image analysis in clinical diagnostics of HER2 IHC. ImmunoMembrane is freely accessible at: http://jvsmicroscope.uta.fi/immunomembrane/.
    Histopathology 02/2012; 60(5):758-67. · 2.86 Impact Factor
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    ABSTRACT: Previous studies of breast cancer have shown that patients whose tumors are detected by mammography screening have a more favorable survival. Little is known, however, about the long-term prognostic impact of screen detection. The purpose of the current study was to compare breast cancer-specific long-term survival of patients whose tumors were detected in mammography screening compared with those whose tumors were detected by other methods. Breast cancer patients diagnosed within five specified geographical areas in Finland in 1991 and 1992 were identified (N = 2,936). Detailed clinical, treatment and outcome data, as well as tissue samples, were collected. Women with in situ carcinoma, distant metastases at the time of primary diagnosis and women who were not treated surgically were excluded. The main analyses were performed after excluding patients with other malignancy or contralateral breast cancer, followed by sensitivity analyses with different exclusion criteria. Median follow-up time was 15.4 years. Univariate and multivariate analyses of breast cancer-specific survival were performed. Of patients included in the main analyses (n = 1,884), 22% (n = 408) of cancers were screen-detected and 78% (n = 1,476) were detected by other methods. Breast cancer-specific 15-year survival was 86% for patients with screen-detected cancer and 66% for patients diagnosed using other methods (P < 0.0001, HR = 2.91). Similar differences in survival were observed in women at screening age (50 to 69 years), as well as in clinically important subgroups, such as patients with small tumors (≤ 1 cm in diameter) and without nodal involvement (N0). Women with breast cancer diagnosed on the basis of screening mammography had a more favorable prognosis than those diagnosed outside screening programs, following adjustments according to patient age, tumor size, axillary lymph node status, histological grade and hormone receptor status. Significant differences in the risk of having future contralateral breast cancer according to method of detection were not observed. Breast cancer detected by mammography screening is an independent prognostic factor in breast cancer and is associated with a more favorable survival rate as well as in long-term follow-up.
    Breast cancer research: BCR 12/2011; 13(6):R134. · 5.87 Impact Factor
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    ABSTRACT: Some molecular subtypes of breast cancer have preferential sites of distant relapse. The protein expression pattern of the primary tumor may influence the first distant metastasis site. We identified from the files of the Finnish Cancer Registry patients diagnosed with breast cancer in five geographical regions Finland in 1991-1992, reviewed the hospital case records, and collected primary tumor tissue. Out of the 2,032 cases identified, 234 developed distant metastases after a median follow-up time of 2.7 years and had the first metastatic site documented (a total of 321 sites). Primary tumor microarray (TMA) cores were analyzed for 17 proteins using immunohistochemistry and for erbB2 using chromogenic in situ hybridization, and their associations with the first metastasis site were examined. The cancers were classified into luminal A, luminal B, HER2+ enriched, basal-like or non-expressor subtypes. A total of 3,886 TMA cores were analyzed. Luminal A cancers had a propensity to give rise first to bone metastases, HER2-enriched cancers to liver and lung metastases, and basal type cancers to liver and brain metastases. Primary tumors that gave first rise to bone metastases expressed frequently estrogen receptor (ER) and SNAI1 (SNAIL) and rarely COX2 and HER2, tumors with first metastases in the liver expressed infrequently SNAI1, those with lung metastases expressed frequently the epidermal growth factor receptor (EGFR), cytokeratin-5 (CK5) and HER2, and infrequently progesterone receptor (PgR), tumors with early skin metastases expressed infrequently E-cadherin, and breast tumors with first metastases in the brain expressed nestin, prominin-1 and CK5 and infrequently ER and PgR. Breast tumor biological subtypes have a tendency to give rise to first distant metastases at certain body sites. Several primary tumor proteins were associated with homing of breast cancer cells.
    Breast cancer research: BCR 09/2011; 13(5):R87. · 5.87 Impact Factor
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    ABSTRACT: Prediction of response to anthracycline-based therapy for breast cancer is challenging. We aimed to assess the value of HER2 and TOP2A as predictive markers of response to anthracycline-based adjuvant therapy in patients with early breast cancer. We did a meta-analysis of individual patient data from five randomised adjuvant trials that compared anthracycline-based regimens with cyclophosphamide, methotrexate, and fluorouracil (CMF) regimens. We assessed the status of HER2 and TOP2A genes with fluorescent in-situ hybridisation. Tumour samples were submitted to an external laboratory for validation. We calculated hazard ratios (HR) to compare event-free survival (EFS) and overall survival in patients receiving anthracycline-based treatment with those receiving CMF in two HER2 cohorts (HER2 amplified and non-amplified tumours) and in three TOP2A cohorts (normal, amplified, and deleted tumours). We analysed data for 3452 patients for HER2 and 3102 patients for TOP2A. For EFS, HRs were 0·89 (95% CI 0·79-1·01) for HER2 non-amplified patients and 0·71 (0·58-0·86) for HER2-amplified patients (p(interaction)=0·0485); for overall survival, HRs were 0·91 (95% CI 0·79-1·05) for HER2 non-amplified patients and 0·73 (0·59-0·89) for HER2-amplified patients (p(interaction)=0·0718). In analysis of TOP2A status, HRs for EFS were 0·88 (0·78-1·00) for normal, 0·63 (0·46-0·87) for deleted, and 0·62 (0·43-0·90) for amplified (p(interaction)=0·0513); HRs for overall survival were 0·89 (0·78-1·03) for normal, 0·68 (0·49-0·95) for deleted, and 0·67 (0·46-0·98) for amplified (p(interaction)=0·1608). When patients with TOP2A-deleted and TOP2A-amplified tumours were grouped together (altered cohort) and compared with data from patients with normal TOP2A tumours, HRs for EFS were 0·64 (0·50-0·81) for altered and 0·88 (0·78-1·00) for normal (p(interaction)=0·0183); HRs for overall survival were 0·67 (0·52-0·86) for altered and 0·89 (0·78-1·03) for normal (p(interaction)=0·0455). Although HER2 amplification and combined TOP2A amplification and deletion may have some value in the prediction of responsiveness to anthracycline-based chemotherapy, our findings do not support the use of anthracyclines only in patients with HER2-amplified or TOP2A-aberrated tumours. Associazione Italiana Ricerca Cancro, Academy of Finland, Belgian Federation Against Cancer, Cancer Research UK, Les Amis de l'Institut Bordet, Scottish Breast Cancer Trials Group, NCIC Clinical Trials Group, Canadian Cancer Society Research Institute, Danish Council for Strategic Research, Pharmacia-Upjohn (now Pfizer), and Abbott Laboratories.
    The Lancet Oncology 09/2011; 12(12):1134-42. · 25.12 Impact Factor
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    ABSTRACT: S100P is a member of the S100 family of calcium-binding proteins involved in calcium sensing and signal transduction. Its abnormal expression and biological activities are linked to tumor phenotype, namely to increased survival, proliferation, invasion and metastatic propensity of tumor cells. Association of S100P with outcome of tumor treatment and preliminary data from S100P promoter analysis prompted us to study regulation of S100P expression by glucocorticoids, which are implicated in tumor response to chemotherapy. We showed that dexamethasone (DX), a representative glucocorticoid, was capable to induce activity of S100P promoter by means of increased expression, nuclear translocation, and transactivation properties of the glucocorticoid receptor (GR). Moreover, DX treatment led to decreased phosphorylation of ERK1/2, reduced transcriptional activity of AP1, and modulated activity of some additional transcription factors. We identified a promoter region responsible for DX-mediated transactivation and proved GR binding to S100P promoter. We found that the effect of DX was enhanced by partial but not complete inhibition of the MAPK/ERK pathway, supporting an active crosstalk between GR and MAPK/ERK signal transduction in control of S100P expression. On the other hand, suppression of GR mRNA level by transient siRNA expression resulted in reduced S100P transcription. The role of GR activation in S100P regulation was supported by co-expression of GR with S100P in cells treated with DX. These data suggest that S100P is a direct transcriptional target of glucocorticoid-mediated signaling in tumor cells that is activated through the interplay of GR and MAPK pathways.
    Journal of Cellular Biochemistry 07/2011; 112(11):3373-84. · 3.06 Impact Factor
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    ABSTRACT: • To evaluate the prognostic value of histopathological variables and immunostainings of biomarkers enhancer of zeste homologue 2 (EZH2), Ki-67 and minichromosome maintenance protein 7 (MCM7) from core biopsies of hormonally treated patients with prostate cancer. • Biopsies of 247 primarily endocrine-treated patients were analysed for histopathological characteristics and Gleason scores (GS) according to the revised guidelines of International Society of Urologic Pathology (ISUP) consensus conference 2005. • Immunohistochemical stainings were analysed with the aid of digital image analysis. • The prognostic value of the histopathological variables and the biomarkers was analysed with univariate and multivariate Cox regression analysis, with biochemical recurrence as an endpoint. • Biomarkers EZH2 (relative risk [RR] 2.0, 95% confidence interval 1.2-3.3), Ki-67 (3.4, 2.1-5.5) and MCM7 (2.4, 1.5-3.9) were significantly associated with progression-free survival in a univariate analysis. • Ki-67 immunostaining index detected high-risk patients with GS of 7 (9.1, 8.0-10.3). • In a multivariate analysis with non-conventional GS groups 5-7 (3 + 4), 7(4 + 3)-8, and 9-10, the independent prognostic markers were pretreatment GS (2.2, 1.5-3.2), prostate-specific antigen (PSA) level (2.1, 1.1-4.2), perineural invasion (PNI) (1.6, 1.2-2.2), and clinical T-stage (cT) (1.9, 1.0-3.7). • Combination of the independent markers (PSA level > 20 ng/mL or GS >3 + 4 or PNI >3 or cT >2) yielded best risk stratification (RR 11.6, 10.4-12.7). • GS remains one of the most important prognostic factors in prostate cancer. However, the refined guidelines by ISUP 2005 might have shifted the threshold between low-grade and high-grade cancers from GS 6 vs 7 to GS 3 + 4 vs 4 + 3. • PNI is an independent prognostic marker superior to cT. • Ki-67 is the most useful biomarker in detecting patients with GS = 7 at high risk for progression.
    BJU International 05/2011; 108(9):1430-8. · 3.05 Impact Factor
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    ABSTRACT: Trastuzumab is widely used for the treatment of HER2-positive breast cancer. Despite encouraging clinical results, a significant fraction of patients are, or become, refractory to the drug. To overcome this, trastuzumab-DM1 (T-DM1), a newer, more potent drug has been introduced. We tested the efficacy and mechanisms of action of T-DM1 in nine HER2-positive breast cancer cell lines in vitro and in vivo. The nine cell lines studied included UACC-893, MDA-453 and JIMT-1, which are resistant to both trastuzumab and lapatinib. AlamarBlue cell-proliferation assay was used to determine the growth response of breast cancer cell lines to trastuzumab and T-DM1 in vitro. Trastuzumab- and T-DM1-mediated antibody-dependent cellular cytotoxicity (ADCC) was analysed by measuring the lactate dehydrogenase released from the cancer cells as a result of ADCC activity of peripheral blood mononuclear cells. Severe Combined Immunodeficient (SCID) mice were inoculated with trastuzumab-resistant JIMT-1 cells to investigate the tumour inhibitory effect of T-DM1 in vivo. The xenograft samples were investigated using histology and immunohistochemistry. T-DM1 was strongly growth inhibitory on all investigated HER2-positive breast cancer cell lines in vitro. T-DM1 also evoked antibody-dependent cellular cytotoxicity (ADCC) similar to that of trastuzumab. Outgrowth of JIMT-1 xenograft tumours in SCID mice was significantly inhibited by T-DM1. Histologically, the cellular response to T-DM1 consisted of apoptosis and mitotic catastrophe, the latter evidenced by an increased number of cells with aberrant mitotic figures and giant multinucleated cells. Our results suggest mitotic catastrophe as a previously undescribed mechanism of action of T-DM1. T-DM1 was found effective even on breast cancer cell lines with moderate HER2 expression levels and cross-resistance to trastuzumab and lapatinib (MDA-453 and JIMT-1).
    Breast cancer research: BCR 04/2011; 13(2):R46. · 5.87 Impact Factor
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    ABSTRACT: We performed dual-color immunostaining with a 3-antibody cocktail (α-methylacyl coenzyme-A racemase, CK34betaE12, and p63) on prostate biopsies from 200 patients. Current practice (hematoxylin and eosin staining followed by dual-color immunostaining on selected cases) was compared with a protocol in which routine dual-color immunostaining was provided in all cases. In the original pathology reports, adenocarcinoma was diagnosed in 87/200 (43%) patients. Small foci interpreted as putative cancers were detected with dual-color immunostaining in 14/113 patients who were originally diagnosed with a nonmalignant lesion. All of the suggested cancerous foci were independently reevaluated by 5 pathologists. A diagnosis of adenocarcinoma was assessed by consensus in 8 cases, and atypical small acinar proliferation was diagnosed in 1 case. Consensus was not reached in 5 cases. Six of the foci reclassified as cancer were of Gleason score 3 + 3 = 6, while 2 were graded as Gleason score 4 + 4 = 8. The feasibility of routine dual-color immunostaining was also tested by analyzing the time spent on microscopic assessment. Because small, atypical lesions expressing α-methylacyl coenzyme-A racemase (blue chromogen) were easy to detect using dual-color immunostaining, the microscopic analysis of dual-color immunostaining and hematoxylin-eosin staining was faster than that of hematoxylin-eosin staining alone that was later followed by dual-color immunostaining in selected cases (median 251 seconds versus 299 seconds, P < .0001). We concluded that routine dual-color immunostaining of all prostate biopsies would produce better diagnostic sensitivity with a smaller microscopy workload for the pathologist. However, minute foci interpreted as cancer with dual-color immunostaining need to be confirmed with hematoxylin-eosin staining, and minimal criteria for a definitive diagnosis of cancer are still lacking.
    Human pathology 04/2011; 42(11):1635-42. · 3.03 Impact Factor
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    ABSTRACT: A novel antibody-drug conjugate (trastuzumab-DM1, T-DM1) is currently in clinical trials for patients with trastuzumab resistant HER2-positive breast cancer. Since no clinical data is available from gastric cancer, we studied T-DM1 on HER2-positive human gastric cancer cells and xenograft tumors. Effects of T-DM1 were studied in four HER2-positive gastric cancer cell lines (N-87, OE-19, SNU-216 and MKN-7) in vitro. Xenograft tumors from N-87 and OE-19 were studied to determine the effect of T-DM1 in vivo. T-DM1 was found more effective than trastuzumab in N-87 and OE-19, and moderately effective in MKN-7 cells. On SNU-216 cells both trastuzumab and T-DM1 showed limited efficacy. In xenograft tumor experiments, complete pathological response was observed in all OE-19 xenografted mice and in half of the N-87 xenografted mice. The results were equally good irrespective of the tumor burden at therapy initiation, or preceding trastuzumab treatment. T-DM1 treatment showed direct effects (apoptotic cell death and aberrant mitosis) as well as it mediated antibody-dependent cellular cytotoxicity (ADCC). T-DM1 showed a promising anti-tumor effect in HER2-positive gastric cancer cell lines in vitro and in vivo, even in tumors which had developed resistance to trastuzumab. T-DM1 therapy may warrant clinical trials for HER2-positive gastric cancer patients.
    Cancer letters 03/2011; 306(2):171-9. · 4.86 Impact Factor
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    ABSTRACT: The aim of the study was to develop a virtual microscopy enabled method for assessment of Ki-67 expression and to study the prognostic value of the automated analysis in a comprehensive series of patients with breast cancer. Using a previously reported virtual microscopy platform and an open source image processing tool, ImageJ, a method for assessment of immunohistochemically (IHC) stained area and intensity was created. A tissue microarray (TMA) series of breast cancer specimens from 1931 patients was immunostained for Ki-67, digitized with a whole slide scanner and uploaded to an image web server. The extent of Ki-67 staining in the tumour specimens was assessed both visually and with the image analysis algorithm. The prognostic value of the computer vision assessment of Ki-67 was evaluated by comparison of distant disease-free survival in patients with low, moderate or high expression of the protein. 1648 evaluable image files from 1334 patients were analysed in less than two hours. Visual and automated Ki-67 extent of staining assessments showed a percentage agreement of 87% and weighted kappa value of 0.57. The hazard ratio for distant recurrence for patients with a computer determined moderate Ki-67 extent of staining was 1.77 (95% CI 1.31-2.37) and for high extent 2.34 (95% CI 1.76-3.10), compared to patients with a low extent. In multivariate survival analyses, automated assessment of Ki-67 extent of staining was retained as a significant prognostic factor. Running high-throughput automated IHC algorithms on a virtual microscopy platform is feasible. Comparison of visual and automated assessments of Ki-67 expression shows moderate agreement. In multivariate survival analysis, the automated assessment of Ki-67 extent of staining is a significant and independent predictor of outcome in breast cancer.
    BMC Clinical Pathology 01/2011; 11:3.

Publication Stats

8k Citations
891.38 Total Impact Points

Institutions

  • 1988–2013
    • University of Tampere
      • • Institute of Biomedical Technology
      • • Institute of Medical Technology
      • • Laboratory of Cancer Genetics
      • • Department of Clinical Chemistry
      • • Department of Biomedical Sciences
      Tampere, Western Finland, Finland
  • 2011
    • Vaasa Central Hospital
      Vaasa, Province of Western Finland, Finland
  • 2003–2011
    • University of Helsinki
      • • Institute for Molecular Medicine Finland (FIMM)
      • • Molecular/Cancer Biology Laboratory
      • • Department of Oncology
      Helsinki, Province of Southern Finland, Finland
    • Institut Jules Bordet
      Bruxelles, Brussels Capital Region, Belgium
  • 1993–2010
    • Tampere University Hospital (TAUH)
      Tammerfors, Province of Western Finland, Finland
  • 2008
    • Columbia University
      • Institute of Cancer Genetics
      New York City, NY, United States
    • Karolinska Institutet
      • Institutionen för mikrobiologi, tumör- och cellbiologi
      Solna, Stockholm, Sweden
  • 2002–2008
    • Helsinki University Central Hospital
      • Department of Oncology
      Helsinki, Southern Finland Province, Finland
    • Helsingborgs Lasarett
      Hälsingborg, Skåne, Sweden
  • 2007
    • The Ohio State University
      • Department of Molecular Virology, Immunology and Medical Genetics
      Columbus, OH, United States
  • 2005–2007
    • Seinäjoki Central Hospital
      Seinäjoki, Province of Western Finland, Finland
  • 1999–2007
    • Lund University
      • Department of Oncology
      Lund, Skane, Sweden
  • 2006
    • Turku University Hospital
      Turku, Province of Western Finland, Finland
  • 2003–2006
    • University of Turku
      • • MediCity Research Laboratory
      • • Turku Graduate School of Biomedical Sciences
      Turku, Province of Western Finland, Finland
  • 1995
    • University of California, San Francisco
      • Department of Laboratory Medicine
      San Francisco, CA, United States