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Do not freeze.", "Language": "en", "Country": "XG", "Code": "Storage Conditions (Product)" }, { "Name": "Intended Use", "Value": "The CINtec® PLUS Cytology test is a qualitative immunocytochemical assay intended for the simultaneous detection of the p16INK4a and Ki-67 proteins in cervical specimens collected by a clinician using an endocervical brush/spatula or broom collection device and placed in the ThinPrep® Pap Test PreservCyt® Solution. The CINtec PLUS Cytology test includes a ready-to-use cocktail of primary antibodies which contains a mouse monoclonal antibody directed against human p16INK4a (p16) protein (clone E6H4), and a recombinant rabbit monoclonal antibody directed against human Ki-67 protein (clone 274-11AC3V1) for use on the BenchMark ULTRA instrument with 3,3ʹ-diaminobenzidine tetrahydrochloride (DAB) and Fast Red detection systems.

The CINtec PLUS Cytology test is indicated:
  • To be used in women 25 – 65 years old with 12 Other High Risk (HR) HPV positive test results using cobas® HPV for use on the cobas® 6800/8800 Systems (cobas® HPV) or the cobas® 4800 HPV Test in primary HPV screening, to determine the need for referral to colposcopy.

    To be used in women 25 – 65 years old with HPV16/18 positive test results using cobas® HPV or the cobas® 4800 HPV Test in primary HPV screening where the CINtec PLUS Cytology test results will be used in conjunction with the physician’s assessment of patient screening history, other risk factors, and professional guidelines to guide patient management.
  • To be used in women 30 – 65 years old with NILM (Negative for Intraepithelial Lesion or Malignancy) and 12 Other HR HPV positive test results using cobas® HPV or the cobas® 4800 HPV Test in adjunctive cervical cytology and HR HPV screening, to determine the need for referral to colposcopy.

    To be used in women 30 – 65 years old with NILM (Negative for Intraepithelial Lesion or Malignancy) and HPV16/18 positive test results using cobas® HPV or the cobas® 4800 HPV Test in adjunctive cervical cytology and HR HPV screening where the CINtec PLUS Cytology test results will be used in conjunction with the physician’s assessment of patient screening history, other risk factors, and professional guidelines to guide patient management.

Results from the CINtec PLUS Cytology test should be interpreted by a qualified pathologist.", "Language": "en", "Country": "XG", "Code": "Intended Use" }, { "Name": "Content", "Value": "The CINtec PLUS Cytology test contains sufficient reagent for 100 tests.
  1. One 10 mL dispenser     CINtec PLUS Cytology Primary Antibody Cocktail (p16/Ki-67)
  2. One 10 mL dispenser     CINtec PLUS Cytology Red anti-Rabbit NP Linker
  3. One 10 mL dispenser     CINtec PLUS Cytology Red AP Multimer
  4. One 10 mL dispenser     CINtec PLUS Cytology Red Naphthol Phosphate
  5. One 10 mL dispenser     CINtec PLUS Cytology Fast Red contains Fast Red
  6. One 10 mL dispenser     CINtec PLUS Cytology DAB Peroxidase Inhibitor
  7. One 10 mL dispenser     CINtec PLUS Cytology DAB anti-Mouse HQ Linker contains HQ-labeled goat anti-mouse IgG
  8. One 10 mL dispenser     CINtec PLUS Cytology DAB HRP Multimer contains a mouse monoclonal anti-HQ-labeled HRP tertiary antibody
  9. One 10 mL dispenser     CINtec PLUS Cytology DAB contains 3,3′-diaminobenzidine tetrahydrochloride
  10. One 10 mL dispenser     CINtec PLUS Cytology DAB H2O2 contains hydrogen peroxide
", "Language": "en", "Country": "XG", "Code": "Content" }, { "Name": "Background Information", "Value": "In eukaryotic cells, control of progression of the cell division cycle is regulated by a complex pattern of controlled expression and post-translational modifications of cell-cycle regulating proteins. The p16INK4a protein plays a major role in this mechanism of regulation of the eukaryotic cell cycle. It is part of the retinoblastoma protein (pRb)-mediated control of the G1/S phase transition, and it triggers cell cycle arrest in the course of cellular differentiation processes. Thus, p16INK4a provides an anti-proliferative effect during regular cell cycle progression.1 In terminally differentiated epithelial cells, p16INK4a expression is down-regulated to levels typically not detectable by immunocytochemistry (ICC).2 In cervical dysplasia, overexpression of p16 is regarded as a surrogate biomarker for transforming HPV infections, reflecting the activation of HPV E6/E7 oncoprotein-driven cell proliferation.2-5 Detection of p16 in cervical cytology preparations has been proposed as a valuable adjunctive marker to triage women with abnormal Pap cytology results as well as with positive HPV test results.3-5 However, because p16-specific staining may be observed in individual metaplastic or endocervical cells in which p16 may be expressed to exert its physiological normal, growth-suppressive cellular function, interpretation of p16 single-stained cervical cytology preparations requires identification of p16 immunoreactive cells and further classification of these cells regarding signs of morphologic abnormalities.2-4

The combined simultaneous detection of p16 and the proliferation marker Ki-67 within the same cell by ICC has been shown to be a valuable tool to identify dysplastic cervical cells in cytology preparations without the need for morphologic interpretation.3,7,8 Ki-67 is a nuclear and nucleolar protein strictly associated with cell proliferation and is undetectable by standard immunostaining methods in resting (G0) cells.6 Under normal physiologic conditions, expression of the proliferation-associated protein Ki-67 is mutually exclusive of the anti-proliferative protein p16. In contrast, cells where the retinoblastoma protein (pRB)-mediated pathway controlling the cell-cycle progression is abrogated upstream of the tumor suppressor function of p16 (such as in epithelial cells expressing the high-risk HPV E6/E7 oncoproteins) may proliferate and thus may express Ki-67 in the presence of functional p16.2-3

Therefore, the detection of individual cells in cervical cytology preparations that simultaneously co-express p16 and Ki-67 may serve as a morphology-independent indicator of cells with cell cycle dysregulation and thus may be used as an indicator of the presence of transforming HPV infections and underlying cervical intraepithelial neoplasia.2,3 In the recent past, numerous studies have been performed and published evaluating the potential value and clinical usefulness of p16/Ki-67 dual-stained cytology for the identification of women that may benefit from referral to colposcopy based on various primary cervical cancer screening results, including for the triage of women with Atypical Squamous Cells of Undetermined Significance (ASC-US) or Low grade Squamous Intraepithelial Lesion (LSIL) Pap cytology results, women who are high-risk HPV positive in primary HPV screening, or women who are Negative for Intraepithelial Lesion or Malignancy (NILM)/HPV positive in clinical settings where Pap cytology/HPV co-testing is used for primary screening.7-25

1. Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell. 2006 Oct 20;127(2):265-275.
2. Wentzensen N, von Knebel Doeberitz M. Biomarkers in cervical cancer screening. Dis Markers. 2007;23(4):315-330.
3. Cuschieri K, Wentzensen N. Human papillomavirus mRNA and p16 detection as biomarkers for the improved diagnosis of cervical neoplasia. Cancer Epidemiol Biomarkers Prev. 2008;17(10):2536-2545.
4. Roelens J, Reuschenbach M, von Knebel Doeberitz M, et al. p16INK4a immunocytochemistry versus human papillomavirus testing for triage of women with minor cytologic abnormalities: a systematic review and meta-analysis. Cancer Cytopathol. 2012;120(5):294–307.
5. Carozzi F, Grillio-Tos A, Confortini M, et al. Risk of high-grade cervical intraepithelial neoplasia during follow-up in HPV-positive women according to baseline p16-INK4A results: a prospective analysis of a nested substudy of the NTCC randomised controlled trial. Lancet Oncol. 2013;14(2):168–176.
6. Scholzen T,Gerdes, J. The Ki-67 protein: From the known and the unknown. J. Cell. Physiol. 2000;182:311–322.
7. Schmidt D, Bergeron C, Denton KJ, et al. p16/ki-67 dual-stain cytology in the triage of ASC-US and LSIL papanicolaou cytology: results from the European equivocal or mildly abnormal Papanicolaou cytology study. Cancer Cytopathol. 2011;119(3):158–166.
8. Petry KU, Schmidt D, Scherbring S, et al. Triaging Pap cytology negative, HPV positive cervical cancer screening results with p16/Ki-67 Dual-stained cytology. Gynecol Oncol. 2011;121(3):505–509.
9. Ravarino A, Nemolato S, Macciocu E, et al. CINtec PLUS immunocytochemistry as a tool for the cytologic diagnosis of glandular lesions of the cervix uteri. Am J Clin Pathol 2012;138(5):652–656.
10. Singh M, Mockler D, Akalin A, et al. Immunocytochemical colocalization of p16(INK4a) and Ki-67 predicts CIN2/3 and AIS/adenocarcinoma. Cancer Cytopathol. 2012;120(1):26–34.
11. Ikenberg H, Bergeron C, Schmidt D, et al. Screening for cervical cancer precursors with p16/Ki-67 dual-stained cytology: results of the PALMS study. J Natl Cancer Inst. 2013;105(20):1550-1557.
12. Wentzensen N, Fetterman B, Castle PE, et al. p16/Ki-67 Dual Stain Cytology for Detection of Cervical Precancer in HPV-Positive Women. J Natl Cancer Inst. 2015 Sep 15;107(12):djv257.
13. Uijterwaal MH, Polman NJ, Witte BI, et al. Triaging HPV-positive women with normal cytology by p16/Ki-67 dual-stained cytology testing: baseline and longitudinal data. Int J Cancer. 2015;136(10):2361-2368.
14. Wentzensen N, Schwartz L, Zuna RE, et al. Performance of p16/Ki-67 immunostaining to detect cervical cancer precursors in a colposcopy referral population. Clin Cancer Res. 2012;18(15):4154-4162.
15. Bergeron C, Ikenberg H, Sideri M, et al. Prospective evaluation of p16/Ki-67 dual-stained cytology for managing women with abnormal Papanicolaou cytology: PALMS study results. Cancer Cytopathol. 2015;123(6):373-381.
16. Dona MG, Vocaturo A, Giuliani M, et al. p16/Ki-67 dual staining in cervico-vaginal cytology: Correlation with histology, Human Papillomavirus detection and genotyping in women undergoing colposcopy. Gynecol Oncol. 2012;126(2):198-202.
17. Allia E, Ronco G, Coccia A, et al. Interpretation of p16(INK4a) /Ki-67 dual immunostaining for the triage of human papillomavirus-positive women by experts and nonexperts in cervical cytology. Cancer Cytopathol. 2015;123(4):212-218.
18. Gustinucci D, Giorgi Rossi P, Cesarini E, et al. Use of Cytology, E6/E7 mRNA, and p16INK4a-Ki-67 to Define the Management of Human Papillomavirus (HPV)-Positive Women in Cervical Cancer Screening. Am J Clin Pathol. 2016;145(1):35-45.
19. Rossi P, Borghi L, Ferro R, Mencarelli R. A population of 1136 HPV DNA-HR positive women: expression of p16(INK4a)/Ki67 Dual-Stain Cytology and cytological diagnosis. Histological correlations and cytological follow up. Pathologica. 2015;107(3-4):185-191.
20. Wright TC, Jr., Behrens CM, Ranger-Moore J, et al. Triaging HPV-Positive Women with p16/Ki-67 Dual-stained Cytology: Results from a Sub-study Nested into the ATHENA Trial. Gynecol Oncol. 2017;144:51-56.
21. Clarke MA, Cheung LC, Castle PE, et al. Five-Year Risk of Cervical Precancer Following p16/Ki-67 Dual-Stain Triage of HPV-Positive Women. JAMA Oncol. 2019;5(2):181-186.
22. Wentzensen N, Clarke MA, Bremer R, et al. Clinical Evaluation of Human Papillomavirus Screening With p16/Ki-67 Dual Stain Triage in a Large Organized Cervical Cancer Screening Program. JAMA Intern Med. 2019;179(7):881-888.
23. Wentzensen N, Fetterman B, Tokugawa D, et al. Interobserver reproducibility and accuracy of p16/Ki-67 dual-stain cytology in cervical cancer screening. Cancer Cytopathol. 2014;122(12):914-920.
24. Arean-Cuns C, Mercado-Gutierrez M, Paniello-Alastruey I, et al. Dual staining for p16/Ki67 is a more specific test than cytology for triage of HPV-positive women. Virchows Arch. 2018;473(5):599-606.
25. Ebisch RMF, van der Horst J, Hermsen M, et al. Evaluation of p16/Ki-67 dual-stained cytology as triage test for high-risk human papillomavirus-positive women. Mod Pathol. 2017;30(7):1021-1031.", "Language": "en", "Country": "XG", "Code": "Background Information" }, { "Name": "Principle", "Value": "The CINtec PLUS Cytology test contains a set of reagents for the simultaneous immunocytochemical detection of the p16INK4a and Ki-67 proteins in cytological specimens obtained from the uterine cervix. The proteins are detected using a ready-to-use cocktail of primary monoclonal antibodies which contains a monoclonal mouse antibody directed against human p16INK4a protein (clone E6H4) and a primary recombinant rabbit antibody directed against human Ki-67 protein (clone 274-11AC3V1). Following cell conditioning, inhibition of endogenous peroxidase activity and incubation with the primary antibody cocktail, the assay uses two ready-to-use detection systems optimized for use on cervical cytology specimens collected in PreservCyt Solution:
  • a goat anti-mouse secondary antibody covalently attached to HQ haptens (proprietary hapten) and an anti-HQ hapten, horseradish peroxidase (HRP)-conjugated tertiary antibody optimized for the detection of the monoclonal mouse antibody clone E6H4, as shown in Figure 2.
  • a goat anti-rabbit secondary antibody covalently attached to NP haptens (proprietary hapten) and an anti-NP hapten, alkaline-phosphatase (AP)-conjugated tertiary antibody optimized for the detection of the rabbit recombinant antibody clone 274-11AC3V1, as shown in Figure 3.

The chromogenic reactions are based on the HRP-mediated conversion of 3,3′-diaminobenzidine tetrahydrochloride (DAB) and the AP-mediated conversion of Fast Red with Naphthol Phosphate resulting in a brown precipitate at the p16INK4a antigen site and a red precipitate at the Ki-67 antigen site, respectively.

After automated counterstaining and bluing, a two-step mounting procedure is followed. First, the slide is mounted using an aqueous mounting medium. Subsequently, the slide is coverslipped using a permanent mounting medium. The staining results are evaluated by light microscopy.Figure 2. Detection of human p16INK4a protein.
Figure 3. Detection of human Ki-67 protein
 ", "Language": "en", "Country": "XG", "Code": "Principle" }, { "Name": "Product Purpose", "Value": "The CINtec® PLUS Cytology test is a qualitative immunocytochemical assay intended for the simultaneous detection of the p16INK4a and Ki-67 proteins in cervical specimens collected by a clinician using an endocervical brush/spatula or broom collection device and placed in the ThinPrep® Pap Test PreservCyt® Solution. The CINtec PLUS Cytology test includes a ready-to-use cocktail of primary antibodies which contains a mouse monoclonal antibody directed against human p16INK4a (p16) protein (clone E6H4), and a recombinant rabbit monoclonal antibody directed against human Ki-67 protein (clone 274-11AC3V1) for use on the BenchMark ULTRA instrument with 3,3ʹ-diaminobenzidine tetrahydrochloride (DAB) and Fast Red detection systems.

The CINtec PLUS Cytology test is indicated:
  • To be used in women 25 – 65 years old with 12 Other High Risk (HR) HPV positive test results using cobas® HPV for use on the cobas® 6800/8800 Systems (cobas® HPV) or the cobas® 4800 HPV Test in primary HPV screening, to determine the need for referral to colposcopy.

    To be used in women 25 – 65 years old with HPV16/18 positive test results using cobas® HPV or the cobas® 4800 HPV Test in primary HPV screening where the CINtec PLUS Cytology test results will be used in conjunction with the physician’s assessment of patient screening history, other risk factors, and professional guidelines to guide patient management.
  • To be used in women 30 – 65 years old with NILM (Negative for Intraepithelial Lesion or Malignancy) and 12 Other HR HPV positive test results using cobas® HPV or the cobas® 4800 HPV Test in adjunctive cervical cytology and HR HPV screening, to determine the need for referral to colposcopy.

    To be used in women 30 – 65 years old with NILM (Negative for Intraepithelial Lesion or Malignancy) and HPV16/18 positive test results using cobas® HPV or the cobas® 4800 HPV Test in adjunctive cervical cytology and HR HPV screening where the CINtec PLUS Cytology test results will be used in conjunction with the physician’s assessment of patient screening history, other risk factors, and professional guidelines to guide patient management.

Results from the CINtec PLUS Cytology test should be interpreted by a qualified pathologist.", "Language": "en", "Country": "XG", "Code": "Product Purpose" } ] } } ] }

CINtec® PLUS Cytology

IVD For in vitro diagnostic use.
CINtec<sup>®</sup> <i>PLUS</i> Cytology
CINtec PLUS Cytology, a biomarker-based triage test to identify transforming HPV infection

Not every HPV-positive woman will develop cervical cancer, so triage can determine who is most at risk and will benefit from more immediate follow-up, and who is at low risk and can be given more time to clear the infection on her own. CINtec PLUS is a triage cytology test that helps stratify disease risk immediately, giving clinicians confidence when selecting the appropriate management for women at every level of risk.

Detect changes at the cellular level:

The CINtec PLUS Cytology test is the only FDA approved triage test that uses dual biomarker technology to simultaneously detect p16 and Ki-67 in women with HPV-positive results.

The co-expression of these two biomarkers within the same cell is a strong indicator that an HPV infection is undergoing oncogenic transformation.

Four sets of stained slides indicating expressions of biomarkers p16 and Ki-67 versus pap cytology.
CINtec PLUS Cytology test is approved as a triage test with the cobas HPV test

CINtec PLUS Cytology test is approved as a triage test with the cobas HPV test

ages 25-65

 

 

* For HPV16/18+ use as additional information in conjunction with the physician’s assessment of patient screening history, other risk factors, and professional guidelines to guide patient management.

Source: Adapted from CINtec PLUS Cytology package insert; Refer to the CINtec PLUS Cytology package insert for the FDA approved intended use.

ages 30-65

 

 

* For HPV16/18+ use as additional information in conjunction with the physician’s assessment of patient screening history, other risk factors, and professional guidelines to guide patient management.

Source: Adapted from CINtec PLUS Cytology package insert; Refer to the CINtec PLUS Cytology package insert for the FDA approved intended use.

CINtec PLUS Cytology is approved for use on cobas® 4800/6800/8800 instruments.

woman who participated in the landmark registational cervical cancer portfolio IMPACT trial.

The IMPACT Trial: 
The landmark registational cervical cancer portfolio trial

  • Included cobas® HPV test, CINtec PLUS Cytology test, and CINtec® Histology
  • Multicenter, prospective trial enrolling ~35,000 women at 32 collection sites across the US
  • Representative of routine cervical cancer screening population in the US:
    • Ages 25-65
    • Non-vaccinated and vaccinated
    • Diverse races and ethnicities
  • More than 5,000 HPV-positive subjects 
  • More than 530 ≥CIN2 disease cases

Risk of disease in Pap normal/HPV+ women (≥CIN2, age 30-65)

A bar chart comparing risk reduction  for CIN2 or greater cervical cancer using CINtec plus with non 16-18 HPV

 

 

 

 

CINtec PLUS Cytology provides further risk stratification in 12 other HPV+ women

The addition of the CINtec PLUS Cytology test can provide a more accurate quantification of a woman's risk for high grade disease.

 

Increased testing sensitivity

When added as a triage to discrepant co-testing results, CINtec PLUS Cytology identified 7 our of 10 women as having cells undergoing oncogenic transformation allowing identification of disease earlier in their screening process.

Percentage of disease detected with CINtec PLUS in Pap normal/HPV+ women (≥CIN2, age 30-65)

A bar chart comparing the percentage of disease detected with CINtec PLUS cytology in Pap normal/HPV+ women.

 

 

 

CINtec PLUS Cytology offers greater sensitivity compared to Pap cytology

CINtec PLUS Cytology improves disease detection independent of genotype, patient age, or vaccination status.

Percentage of disease detected with CINtec PLUS (≥CIN2, age 25-65)

A bar chart comparing the percentage of disease detected with CINtec PLUS cytology versus pap cytology
Integrates with automated testing procedures to improve efficiency

CINtec PLUS Cytology is performed from the same ThinPrep sample as HPV and Pap tests, and run on the BenchMark ULTRA. The BenchMark ULTRA system is a fully automated immunohistochemistry and in situ hybridization slide staining system, offering multiple features designed to provide diagnostic confidence to histopathology laboratories worldwide. With 30 independent slide drawers, the system gives histotechnologists continuous random access and supports single-piece workflow, which numerous studies have shown improves laboratory operational efficiency.

VENTANA BenchMark ULTRA performs the CINtec plus cytology test using dual biomarkers.
Key resources to learn more

The following publications provide further evidence of the clinical utility of p16/Ki-67 dual staining in cervical cancer screening:

  1. CINtec PLUS Cytology package insert.
  2. T.C. Wright Jr. et al., Triaging HPV-Positive Women with p16/Ki-67 Dual-stained Cytology: Results from a Sub-study Nested into the ATHENA Trial. Gynecologic Oncology 144 (2017) 51–56.Gynecol Oncol. 2017 Jan;144(1):51-56. doi: 10.1016/j.ygyno.2016.10.031.
  3. Wentzensen N., et al., Performance of p16/Ki-67 Immunostaining to Detect Cervical Cancer Precursors in a Colposcopy Referral Population. Clin Cancer Res. 2012 Aug 1;18(15):4154-62. doi: 10.1158/1078-0432.CCR-12-0270. Epub 2012 Jun 6.

Considering implementing CINtec PLUS Cytology in your lab?

Roche experts will be with you every step of the way

Complete this form if you would like more information about implementing CINtec PLUS Cytology in your lab

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Here is a checklist of what you need to implement CINtec PLUS Cytology in your lab:

☐ VENTANA BenchMark ULTRA instrument with required software

☐ Required bulks and ancillaries

  BenchMark ULTRA
  Ordering code     Material description  
  5424534001     ULTRA LCS  
  5353955001     Reaction Buffer Concentrate (10X)  
  5424569001     ULTRA CCI  
  5266726001     Hematoxylin  
  5266769001     Bluing reagent  

 

☐ Additional supplies

  Supplies required but not provided
  Part of Catalogue #     Vendor     Material description  
  70126-002     Hologic     ThinPrep® Arcless Microscope Slides or ThinPrep® Microscope Slides for Special Processing—75 slides/box 
  1001350487     Sigma     CC Mount aqueous mounting media  

 

☐ 25-30 residual HSIL or known positive ThinPrep® sample vials and/or SurePath™ cell pellet tubes

☐ Schedule lab implementation & training with a Roche expert

CINtec PLUS

Lab Implementation & Training sessions are offered to all customers to ensure a smooth, successful implementation of CINtec PLUS Cytology into the laboratory. Sessions can last approximately 2-5 days depending on the size of the lab and number of staff requiring training. 

Training includes:

  • Slide preparation & staining with laboratory staff 
  • Interpretation training sessions, including interactive glass slide review, with Cytotechnologists and Pathologists
  • Interpretation proficiency testing
Reagent catalog

IHC and ISH reagents and ancillaries

To view associated reagents, ancillaries and bulks, please visit the Roche Tissue Diagnostics reagent catalog. 

Reagent catalog

Overview

Detailed Specifications

Ordering Information

Compatible Instruments

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    Technical Documents

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