Her-2/neu Positivity

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Analysis in Carcinoma Stomach Her-2/neu Positivity by Immuno-histochemistry

Analysis in Carcinoma Stomach Her-2/neu Positivity by Immuno-histochemistry

Various studies enumerating the prognosis of gastric cancer have been conducted across the world. In Japanese studies, conducted among 200 patients Her-2 positivity was noted in 23% by IHC. 13% positivity was noted among 166 patients in Spanish group. The median survival was poor for patients with Her-2 overexpression by IHC when compared with Her-2 negative patients in both of these studies. This shows Her-2 overexpression as an independent predictor of mortality. It is considered as the second poorest prognostic factor after lymph node status in early stage of the tumour. Her-2 staining intensity was also correlated with the metastasis to lymph node, invasion of serosa and size of tumour.
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HER 2 therapy  HER 2/neu diagnostics in breast cancer

HER 2 therapy HER 2/neu diagnostics in breast cancer

There are two FDA-approved IHC tests for determining HER-2/ neu status: Herceptest (DAKO, Carpeteria, CA, USA), which is a polyclonal antibody; and CB11 (Pathway, Ventana Medical Systems, Tucson, AZ, USA), which is a mAb. Most laboratories employing IHC generally use either Herceptest or CB11 to measure the level of p185 expression on breast cancer cells. To assess HER-2/neu status, a pathologist will determine the percentage of tumor cells that stain with a 3+ intensity. In National Comprehensive Cancer Network guidelines reported in 2006 by Carlson and coworkers [7], at least 10% of tumor cells must stain 3+ by IHC for a patient to be designated HER-2/neu positive. However, in a recent 2007 joint report from the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP), it was recommended that patients be considered HER-2/neu positive only if more than 30% of the tumor cells stain 3+ by IHC [9]. It is interesting to note, however, that HER-2/neu positivity can depend on the antibody used to assess HER-2/neu status. For instance, Fornier and coworkers [10] reported that 95% of patients evaluated using mAb CB11 were found to be 2+/3+, but in the same report they found that 84% of patients evaluated using the polyclonal Herceptest antibody were 2+/3+. Such variation in tissue results has important implications for patients with tumors that are potentially treatable with trastuzumab and chemotherapy. The FISH method directly measures the number of HER-2/ neu genes, and when there is an increase in the number of genes compared with normal it is referred to as ‘gene amplification’. FISH testing results are semiquantitative and
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HER-2/neu gene analysis on endoscopic biopsy samples and gastric resection materials in gastric carcinomas

HER-2/neu gene analysis on endoscopic biopsy samples and gastric resection materials in gastric carcinomas

Tumor heterogeneity appears to be a significant factor in evaluating HER-2/neu gene status. The frequency of heterogeneity in different studies ranged from 5% to 50% [2]. This high variability was likely due to differences in the definition of heterogeneity. The heterogeneity definitions by different authors were described as different threshold values (such as <10%, 10%-60%, 5%-50% and <66% of tumor cells) of strong HER2/neu expressions [2]. In the literature, it has been seen that there were many studies which had been performed on mucosa biopsies, whole sections (WS) and tissue microarrays (TMA) to better understand HER2/neu heterogeneity [14, 22, 33]. Different results were reported according to material analyzed in these studies. Tumor heterogeneity and sampling errors in TMA were suggested as the reason for this difference. Despite all this, Marx et al. reported that GCa were homogeneous for gene amplification in the TMA- based study [34]. In contrast, Hofmann and Lee were in an agreement on HER-2/neu heterogeneity of GCa [9, 35]. Fithy percent of the cases according to ToGA study were heterogeneous. IHC1+/2+ tumors were much more heterogeneous than IHC3+ tumors (60% vs 30) [24]. In a more comprehensive analysis of Warneke et al. [36], HER-2/neu positivity rates in WS and TMA were found as 8.1% and 6.3%, respectively. In Warneke et al’ study, the rates of FN and false positivity (FP) were 24% and 3%, respectively [36]. The concordance rate between results of WS and TMA was 81.2% [36]. Lee et al. reported a concordance rate of 74.1% between mucosa biopsy and WS [35]. Our FN rate in the mucosa biopsies was 4.65%. Warneke et al [36] suggested that their high FN ratio was due to sampling error that was caused by HER-2/neu heterogeneity. Besides avoiding unnecessary Trastuzumab treatment, loss of treatment chance due to false negativity is also a very important question. Warneke et al indicated that IHC analysis should be performed in WS obtained from resections and that it would be useful to repeat the IHC analysis in metastatic foci, if primary tumor focus was negative for HER-2/neu [36].
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Concordance of HER 2/Neu over Expression with Steroid Receptor Status in Female Breast Cancers

Concordance of HER 2/Neu over Expression with Steroid Receptor Status in Female Breast Cancers

HER-2/neu over expression is associated with increased tumor aggressiveness, increased rates of recurrence, and increased mortality in node positive patients. It is amplified and/or over ex- pressed in approximately 30% of female breast cancers. This study was to detect the relation be- tween HER-2/neu over expression and steroid hormone receptor status. It was conducted at Cairo and Bani Suif university hospitals between February 2012 to February 2014. HER-2/neu over ex- pression was found to be positive in thirteen patients (41%) out of the thirty two patients in- cluded in the study, more positive (52%) HER-2/neu was found among estrogen receptor (ER) positive patients, on the other hand, only 18% positive HER-2/neu was detected among ER nega- tive patients. This difference was statistically significant (P < 0.03). The same outcome was with progesterone receptors (PR) and HER-2/neu with statistically significant difference also (P = 0.02). Conclusion: HER-2/neu over expression is strongly related to ER and PR, this was more evident in negative steroid receptors status. The failure of treatment in positive steroid receptors could be explained by HER-2/neu positivity.
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Evaluation of HER-2/neu status in Gastric Carcinoma

Evaluation of HER-2/neu status in Gastric Carcinoma

A HER-2/neu:CEP17 (centromeric probe 17) ratio of >2.2 is now used to define HER-2/neu positivity (amplification). Ratios of 1.8–2.2 to define equivocal and <1.8 are used to denote negative categories. FISH is not routinely used for testing, because it is a difficult, cumbersome and expensive technique that requires trained personnel which is not available in every pathology laboratory. Moreover, fluorescence fades upon storage for a long time thus making it difficult to preserve the slides for further reference if needed. In addition, the fluorescent probes in the kits have a limited half life. Detailed morphological features of the tumor are also usually difficult to observe due to the required protein digestion and the fluorescent mode, and heterogeneity can be missed since spots are evaluated at ×100 magnification using oil immersion. (33)
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Triple-negative (ER, PgR, HER-2/neu) breast cancer in Indian women

Triple-negative (ER, PgR, HER-2/neu) breast cancer in Indian women

Scoring for proportion staining was as follows: 0 denotes no nuclear staining, 1 denotes ,1% nuclei staining, 2 denotes 1%–10% nuclei staining, 3 denotes 11%–33% nuclei stain- ing, 4 denotes 34%–66% nuclei staining, and 5 denotes 67%–100% nuclei staining. Scoring for staining intensity was as follows: 0 denotes no staining, 1 denotes weak staining, 2 denotes moderate staining, and 3 denotes strong staining. The score for proportion staining multiplied by the score for staining intensity is equal to the score. Score 0 indicates that endocrine treatments or tamoxifen will definitely not work and such patients should receive an alternative first-line treatment. Score 2–3 indicates a 20% chance of response to endocrine treatment. Score 4–6 indicates a 50% chance of response to endocrine treatment. Score 7–8 indicates a good (75%) chance of response to endocrine treatment. 0 score is negative, which denotes no staining seen or staining seen in less than 10% of tumor cells. Score 1 + is negative, which denotes that a faint/barely perceptible membrane staining is detected in more than 10% of tumor cells but that the cells are stained in only part of the membrane. Score 2 + shows a borderline or weakly positive result, which denotes that weak to moderate complete membrane staining is seen in more than 10% of tumor cells. Score 3 + is strongly positive, which denotes that strong complete membrane staining is seen in more than 30% of tumor cells. True HER-2/neu positivity is shown by crisp brown-colored membrane staining in at least 30% of the invasive tumor. Score 3 is two steps higher than HER-2/neu expression in surrounding benign breast parenchyma.
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Frequency of Human Epidermal Growth Factor Receptor 2 (Her2/Neu) Expression in Gastric Adenocarcinoma in Rehman Medical Institute Peshawar

Frequency of Human Epidermal Growth Factor Receptor 2 (Her2/Neu) Expression in Gastric Adenocarcinoma in Rehman Medical Institute Peshawar

16(29.1%) cases (Figures 3-4). HER2 positivity (3+) was more in females 6(42.8%) compared to males 13(31.7%). Moderately differentiated and well differentiated tumours expressed 3+ positivity in 10(47.6%) and 7(36.8%) cases respectively. Of the total 19(34.5%) cases of HER2/neu 3+positivity, 7(31.6 %) were of fundus origin. None of the 6(11%) gastrectomy specimens were HER2/neu-positive. No association was found between HER2/neu positivity and histological grade (p=0.16). Similarly, there was only a trend towards an association between HER2 positivity and site of tumour (p=0.08). HER2/neu scores of 0, 1+,2+and 3+ in different histological grades, tumour locations, age groups and gender were noted separately (Table-2).
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Update on HER 2 as a target for cancer therapy: HER2/neu peptides as tumour vaccines for T cell recognition

Update on HER 2 as a target for cancer therapy: HER2/neu peptides as tumour vaccines for T cell recognition

Few TAAs have been identified for breast cancer, and they generally correspond to differentiation antigens or over- expressed normal proteins. Potential new target antigens have recently been described for breast cancer [2], but most of them are expressed on only a small percentage of breast cancers. One of the first TAAs described for breast cancer was HER2/neu, a 185 kDa transmembrane glyco- protein and member of the epidermal growth factor recep- tor family. Amplification and/or overexpression of HER2/neu have been reported in 10–40% of primary breast cancers, and also in ovarian, renal, gastric and colorectal carcinomas. In this review, we shall focus on the identification and application of HER2/neu peptides as tumour vaccines for T cell recognition.
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Role of microvessel density, HER-2/ NEU expression and CD-34 in prognostication and grading of bladder carcinomas.

Role of microvessel density, HER-2/ NEU expression and CD-34 in prognostication and grading of bladder carcinomas.

The HER-2/neu gene was originally called ‘neu’ as it was first derived from rat neuro/glioblastoma cell lines. Coussens and coworkers named it HER2 because its primary sequence was very similar to Human Epidermal Growth Factor receptor (EGFR or ERBB or ERBB1). (86) This human proto-oncogene, also known as c-erbB2, ErbB-2 is a 185- kilodalton transmembrane receptor tyrosine kinase located at chromosome 17q. These proteins belong to subclass I of the super-family of receptor tyrosine kinases. They are expressed in many tissues of epithelial, mesenchymal, and neuronal origin and are critical for cell proliferation and tissue differentiation. The clinical significance of HER- 2/neu has already been evaluated in colorectal, breast, stomach, lung, head and neck, pancreatic, urothelial carcinoma, and gliomas and prostate cancers; patients with elevated HER-2/neu demonstrate poor survival compared with patients with lower level of HER-2/neu. (46,47,48)
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Expression of Her-2/neu in Colon Carcinoma and Its Correlation with the Histological Grades and the Lymph Nodes Status

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Results: Her-2/neu was positive in 65% of the cases. It was seen in 68.75% cases of well differentiated, 53.84% cases of moderately differentiated and 100% cases of poorly differentiated conventional adenocarcinomas. Mucinous carcinomas showed more positivity (71.4%)for Her-2/neu as compared to conventional adenocarcin- omas (64.5%). The positivity was more in the grade III tumours as compared to that in the other grades. All the colorectal carcinoma cases with metastatic nodes were positive for Her-2/neu staining. Conclusion: Thus, it was concluded that colorectal carcinomas, especially those with lymph node metastasis, should be subjected to Her-2/neu expression studies, as the tumours which expressed Her-2/neu could carry a poor prognosis and therefore would require a different therapeutic approach, as these cases could respond to Trastuzumab (Herceptin) therapy.
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C myc, not HER 2/neu, can predict recurrence and mortality of patients with node negative breast cancer

C myc, not HER 2/neu, can predict recurrence and mortality of patients with node negative breast cancer

Results were evaluated using the SPSS system (SPSS GmbH Software, Munich, Germany). The monoparametric survival curves were determined using the Kaplan–Meier method in order to estimate the impacts of intratumoural c-myc and HER-2/neu oncogene amplification on DFS and OS. Statistical deviations were defined using the log- rank test. Recurrence of disease was found at the follow- ing locations: local (n = 2), contralateral (n = 1), axilla (n = 2), lung (n = 1), brain (n = 1), liver (n = 1) and skin (n = 1). During the period of observation, 14 patients died. In order to derive relevant information regarding the effects of oncogene amplification on the course of breast cancer disease, the accumulated values were determined after postoperative periods of 36 and 95 months. We applied the multivariate Cox model to enable us to identify independently predictive parameters [42]. Parameters considered included the oncogenes c-myc and HER- 2/neu, tumour size, histopathological grading, oestrogen receptor status and age (< 40 or ≥ 40 years). P < 0.05 was considered statistically significant.
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Cytoplasmic p21WAF1/CIP1 expression is correlated with HER 2/ neu in breast cancer and is an independent predictor of prognosis

Cytoplasmic p21WAF1/CIP1 expression is correlated with HER 2/ neu in breast cancer and is an independent predictor of prognosis

HER-2 immunostaining was performed using the mouse monoclonal anti-HER-2 antibody (RTU-CB11) (NovaCastra/ Vector, Newcastle upon Tyne, UK), and the DAKO Envi- sion Plus HRP system (K4006; DAKO, Ely, Cam- bridgeshire, UK). Formalin-fixed paraffin sections of breast cancer tissue were baked, dewaxed and rehydrated prior to a peroxidase block (0.1%, v/v hydrogen peroxide) and an incubation in 10% v/v normal goat serum. The primary antibody and horseradish peroxide-labelled polymer were used as per the DAKO Envision kit, followed by 3,3-diaminobenzidine and counterstaining with haema- toxylin before mounting.
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HER-2/neu Marker Examination using Immunohistochemical Method in Patients Suffering from Gastric Adenocarcinoma

HER-2/neu Marker Examination using Immunohistochemical Method in Patients Suffering from Gastric Adenocarcinoma

The expression of HER-2/neu marker was examined by immunohistochemical staining by Envision method using Hercep Test Kit (Dako, Denmark) according to manufacture's instructions. Briefly, first, 3-4 microns sections of paraffin blocks were prepared and placed on sinalized slides. Then deparaffinisation and rehydration were performed and antigenic recovery was performed in a microwave oven in the presence of citrate buffer. After antigen retrieval, peroxidase was blocked to avoid endogenous peroxidase activity. Then staining with DAB chromogen followed by counterstaining with hematoxylin were performed (15). Also, a sample of breast carcinoma with over- expression of HER-2/neu was used (positive control) during coloration. Then, the slides were scored based on HercepTest Scoring in Dako instruction for gastric biopsies. Zero score was for the cases where the tumor cells or membrane were not stained. +1 score was for weak and diffuse membrane staining of tumor cell clusters (at least 5 cells). +2 score was for weak to moderate, lateral or basolateral complete membrane staining of tumor cell clusters; and+3 score was for strong, lateral or basolateral complete membrane staining of tumor cell clusters (Figures 1-4).
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A study on role of HER 2/NEU over expression in gastric carcinoma in south Indian population

A study on role of HER 2/NEU over expression in gastric carcinoma in south Indian population

Sex difference with male preponderance is correlating with others studies owing to risk factors such as smoking and drinkind are common among males. Gastric adeno carcinoma even thogh it is a disease of the 6 th and seventh decade , occurred at even young age of 20 years. A.Ieni and his colleagues studied the incidence of her2/neu in gastric carcinoma patients. The mean age in their study 68.3 years and the youngest incidence was 41 years{A.IENI, 2013 #2}. But our study reveals the mean age to be a decade less than Sicilian study. Antral carcinomas are common which could be explained by association with H.pylori infection.
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Antiangiogenesis immunotherapy induces epitope spreading to Her-2/neu resulting in breast tumor immunoediting

Antiangiogenesis immunotherapy induces epitope spreading to Her-2/neu resulting in breast tumor immunoediting

Tumors were excised fresh and placed into RNAlater solution (Ambion, Austin, TX), stored at 4 ° C for less than two weeks. We extracted mRNA from stored tumors using a Qiagen RNeasy kit (Qiagen, Valencia, CA). We then generated cDNA via PCR using an Applied Biosystems high capacity cDNA reverse transcription kit (Applied Biosystems, Foster City, CA). PCR reactions were performed using PureTaq RTG PCR Beads (GE Healthcare, Piscataway, NJ). Individual PCR samples were further divided to allow sequencing of each individual fragment of Her-2/neu in stretches of 500–800 bp each (EC1 [AA 20–326], EC2 [AA 303–501], EC3 [AA 479–655], IC1 [AA 690–1081], IC2 [AA 1020– 1260]) as was described elsewhere. 11 Primers for these reactions
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Expression and prognostic significance of E Cadherin, EGFR,    p53 and HER-2/NEU in Gastric Carcinoma.

Expression and prognostic significance of E Cadherin, EGFR, p53 and HER-2/NEU in Gastric Carcinoma.

Immunohistochemical analysis was done in paraffin embedded tissue samples using supersensitive polymer HRP system based on non- biotin polymeric technology. 4 micron thick sections from formalin fixed paraffin embedded tissue samples were transferred onto gelatin coated slides. Heat induced antigen retrieval was done. The antigen was bound with mouse monoclonal antibody (Biogenex) against E Cadherin, EGFR, p53 and HER-2/Neu proteins and then detected by the addition of secondary antibody conjugated with horse radish peroxidase polymer and diaminobenzidine substrate. Step by step procedure of Immunohistochemistry is given in Annexure IV.
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Original Article Evaluation of p16 and HER-2/neu expression in Adenocarcinoma of uterine cervix- A study from tertiary health care center

Original Article Evaluation of p16 and HER-2/neu expression in Adenocarcinoma of uterine cervix- A study from tertiary health care center

Detection of HPV in adenocarcinoma poses a technical troubleshoots due to low viral load in these lesions as glandular cells do not support productive HPV infection. Highly sensitive polymerase chain reaction technique proved HPV involvement in the pathogenesis of three most common histologic subtypes of adenocarcinoma, viz, endocervical, endometrioid, and intestinal variants. 3-5 Diffuse positivity with p16 in the cervix can be regarded as a surrogate marker for high-risk human papillomavirus (HPV) infection. In glandular lesions, p16 is useful, as part of a panel, in the distinction between adenocarcinoma in situ (diffusely positive) and benign mimics, including tubo- endometrial metaplasia and endometriosis, which are usually p16-negative or focally positive. In the past, p16 has been used in combination with other immunomarkers to distinguish between cervical adenocarcinoma (diffuse positivity) and an endometrioid-type of endometrial adenocarcinoma (negative or focally positive). 6
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The impact of nottinghem prognostic index (NPI) on the occurrence of relapses in her 2 / NEU positive breast cancer

The impact of nottinghem prognostic index (NPI) on the occurrence of relapses in her 2 / NEU positive breast cancer

Lymph-vascular invasion is a phenomenon which is more prevalent in certain molecular subtypes of breast cancers and is associated with lymph-node status (Pinder et al., 1993; Simpson and Page, 1994) and the expression of HER-2 / neu, as it is published in some studies (Kim et al., 2006; Millar et al., 2009) and as shown results in our series. Immunohistochemical parameters reported in our series showed a positive correlation with the expression of HER-2 / neu. According to the results, as it was expected, the high mitotic index reflects the strong expression of proliferative index determined by monoclonal antibody Ki67 in this particular group of patients, especially that in most studies this parameter is treated as an independent prognostic factor regardless of the type of breast cancer (Bhargava et al., 2009; Reed et al., 2000; Millar et al., 2009). Expression of the protein
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Unraveling the role of preexisting immunity in prostate cancer patients vaccinated with a HER-2/neu hybrid peptide

Unraveling the role of preexisting immunity in prostate cancer patients vaccinated with a HER-2/neu hybrid peptide

preexisting) and during vaccinations, T cell responses (measured as % of dextramer-specific CD8 + T cells) against other HER-2/neu epitopes or against epitopes from other tumor antigens, representing intramolecular and intermolecular spreading, respectively. Because epi- tope spreading reflects an endogenous immunologic response closely related to the broader spectrum of tumor-specific preexisting immunity, we also analyzed our vaccinated patients for preexisting immunity to the vaccine by AE36-specific IFNγ-based ELISPOT assay and by LR1. We also planned to evaluate whether preexisting immunity to AE36 in combination with epitope spreading was predictive of treatment benefit. With respect to the latter, we analyzed frequencies of CD8 + T cells recognizing CTL specific epitopes restricted by HLA-A2 or HLA-A24, which are the most commonly expressed alleles among our study patients. It has to be mentioned that statistical significance could not be reached in many instances mostly due to the very limited patient numbers compared in each subgroup. However consistent trends can be inter- preted as proof-of-principle data and require further con- sideration. Our data demonstrated that patients with high preexisting immunity to AE36, irrespectively of HLA-A2 or A24 expression, showed statistically significant longer PFS, than patients with low AE36 preexisting immunity, in accordance with our previous observation of improved OS in these patients with high baseline IFN-γ response to the peptide AE36 [10]. Similar results were also obtained in a phase II clinical trial of breast cancer patients vacci- nated with AE37 in the adjuvant setting [48]. To our knowledge, this is the first observation which renders pre- existing immunity to a long peptide vaccine as a predictive biomarker, for the selection of patients most likely to benefit clinically from vaccination.
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Exposure to depleted uranium does not alter the co expression of HER 2/neu and p53 in breast cancer patients

Exposure to depleted uranium does not alter the co expression of HER 2/neu and p53 in breast cancer patients

In conclusion, the positive expression of these biomar- kers is associated with biologically aggressive tumors and poor prognostic profile. Although the samples were taken from an area where the exposure to depleted ura- nium is a risk, the incidence of co-expression of both p53 and HER-2/neu markers does not differ from simi- lar cancer samples in areas that have not been exposed to depleted uranium, though, the greater immunoex- pression of Her-2/neu in breast cancer in this popula- tion with risk for DU exposure, compared with findings on other populations not at risk, requires further inves- tigation as it may reflect the possible role of DU in the induction or acceleration of network signaling between different Her-2 receptors. New lines of treatment which includes genetic modulation of the signaling pathway of both genes should be considered in patients’ medical follow up. Unfortunately for DU, knowledge of the exposure time, dose absorbed, route, length of exposure and its health consequences on the Iraqi population is still lacking. This is chiefly due to restricted access of scientists required to conduct such study and should form the basis for future investigations.
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