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"Country": "XG", "Code": "Storage Conditions (Product)" }, { "Name": "Intended Use", "Value": "For in vitro diagnostic use.

The CINtec^® PLUS Kit is an immunocytochemistry assay for the simultaneous qualitative detection of the p16^INK4a and Ki-67 proteins in cervical cytology preparations.

It is intended to be used as an aid in the identification of women with high-grade cervical intraepithelial lesions in a screening population, and in the sub-groups of patients with a Pap cytology result of ASC-US (atypical squamous cells of undetermined significance) or LSIL (low grade squamous intraepithelial lesion), or in patients with positive high-risk HPV test results.

The kit is intended to be used in medical cytology laboratories. Interpretation of the test results may only be made by a certified professional in conjunction with the patient 's clinical history and additional diagnostic tests that have been performed.

The test is intended for manual use, or for use on Autostainer instruments.", "Language": "en", "Country": "XG", "Code": "Intended Use" }, { "Name": "Background Information", "Value": "In eukaryotic cells, control of progression of the cell division cycle is effected by a complex pattern of controlled expression and post-translational modifications (e.g., phosphorylation) of cell-cycle regulating proteins. The p16^INK4a protein plays a major role in this mechanism of regulation of the eukaryotic cell cycle. It is part of the reti-noblastoma protein (pRb)-mediated control of the G1-S-phase transition, and it triggers cell cycle arrest in the course of cellular differentiation processes. Thus, p16^INK4a provides an anti-proliferative effect when expressed during regular cell cycle progression¹. In terminally differentiated epithelial cells, p16^INK4a expression is down-regulated to levels typically not detectable by immunocytochemistry².

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 classifi-cation 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 dys-plastic cervical cells in cytology preparations without the need for morphologic in-terpretation^3,6,7. Ki-67 is a nuclear and nucleolar protein strictly associated with cell proliferation and is undetectable by standard immunostaining methods in rest-ing (G0) cells⁸. 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 suppres-sor 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 func-tional 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 intraepithe-lial 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 re-sults, 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^6,7;9-25.

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. 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.
7. 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.
8. Scholzen T,Gerdes, J. The Ki-67 protein: From the known and the unknown. J. Cell. Physiol. 2000;182:311–322.
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": "Content", "Value": "

1. Peroxidase Blocking Reagent
   11.5 mL, ready-to-use
2. Primary Antibodies Solution p16/Ki-67
   11.5 mL, ready-to-use
3. Visualization Reagent HRP
   11.5 mL, ready-to-useWarning
   H317 May cause an allergic skin reaction.
   P261 Avoid breathing dust/ fume/ gas/ mist/ vapours/ spray.
   P272 Contaminated work clothing should not be allowed out of the work-place.
   P280 Wear protective gloves.
   P333 + P313 If skin irritation or rash occurs: Get medical advice/ attention.
   P362 + P364 Take off contaminated clothing and wash it before reuse.
   P501 Dispose of contents/ container to an approved waste disposal plant.
   REF 9531 10 /215 2009-9531-001EU Rev 2.5
   Contains
   26172-54-3 2-methyl-2H-isothiazol-3-one hydrochloride
   55965-84-9 reaction mass of: 5-chloro-2-methyl-4-isothiazolin-3-one [EC no. 247-500-7] and 2-methyl-2H -isothiazol-3-one [EC no. 220-239-6] (3:1)
   Polymer reagent conjugated with horseradish peroxidase and affinity purified goat anti-Mouse Fab’ antibody fragments, supplied in stabilizing solution comprising preservatives and stabilizing protein.
    
4. ​​Visualization Reagent AP
   11.5 mL, ready-to-useWarning
   H317 May cause an allergic skin reaction.
   P261 Avoid breathing dust/ fume/ gas/ mist/ vapours/ spray.
   P272 Contaminated work clothing should not be allowed out of the work-place.
   P280 Wear protective gloves.
   P333 + P313 If skin irritation or rash occurs: Get medical advice/ attention.
   P362 + P364 Take off contaminated clothing and wash it before reuse.
   P501 Dispose of contents/ container to an approved waste disposal plant.
   Contains 26172-54-3 2-methyl-2H-isothiazol-3-one hydrochloride
   Polymer reagent conjugated with alkaline phosphatase and affinity purified goat anti-rabbit Fab’ antibody fragments, supplied in stabilizing solution com-prising preservatives and stabilizing protein.
    
5. DAB Buffered Substrate
   16.0 mL,
   Substrate buffer solution, pH 7.5, containing < 0.1% hydrogen peroxide, stabilizers and enhancers.
6. DAB Chromogen
   0.85 mL, 3,3’-diaminobenzidine chromogen solution.Danger
   H314 Causes severe skin burns and eye damage.
   H341 Suspected of causing genetic defects.
   H350 May cause cancer.
   P201 Obtain special instructions before use.
   P280 Wear protective gloves/ protective clothing/ eye protection/ face pro-tection.
   P303 + P361 + P353 IF ON SKIN (or hair): Take off immediately all contam-inated clothing. Rinse skin with water.
   P304 + P340 + P310 IF INHALED: Remove person to fresh air and keep comfortable for breathing. Immediately call a POISON CENTER/doctor.
   P305 + P351 + P338 + P310 IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Contin-ue rinsing. Immediately call a POISON CENTER/doctor.
   P308 + P313 IF exposed or concerned: Get medical advice/attention.
   Contains 868272-85-9 3,3′-Diaminobenzidine tetrahydrochloride hydrate
   NOTE: Consult Federal, State, or local regulations for disposal.
   Material Safety Data Sheet is available upon request.
7. Naphthol Phosphate Substrate
   25.0 mL,
   Substrate buffer solution, pH 9.2 containing Naphthol AS-TR Phosphate Substrate, stabilizers and enhancers.
8. Fast Red Chromogen
   1.33 mL, Fast Red chromogen solution.Danger
   H314 Causes severe skin burns and eye damage.
   P280 Wear protective gloves/ protective clothing/ eye protection/ face pro-tection.
   P301 + P330 + P331 IF SWALLOWED: Rinse mouth. Do NOT induce vom-iting.
   P303 + P361 + P353 IF ON SKIN (or hair): Take off immediately all contam-inated clothing. Rinse skin with water.
   P304 + P340 + P310 IF INHALED: Remove person to fresh air and keep comfortable for breathing. Immediately call a POISON CENTER/doctor.
   P305 + P351 + P338 + P310 IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Contin-ue rinsing. Immediately call a POISON CENTER/doctor.
   P501 Dispose of contents/ container to an approved waste disposal plant.
9. Epitope Retrieval Solution 10x
   500 mL, 100 mM Tris, 10 mM EDTA, pH 9.0, containing 15 mmol/L sodium
10. CINtec^® PLUS Mount
    18.0 mL, aqueous based permanent mounting medium for the permanent
    preservation of slide preparations stained with peroxidase and alkaline phosphatase based visualization systems. Contains 7.7 mmol/L sodium azide (NaN₃)

", "Language": "en", "Country": "XG", "Code": "Content" }, { "Name": "Principle", "Value": "The CINtec^® PLUS Kit contains a set of reagents for the immunocytochemical detection of the p16^INK4a and Ki-67 antigens. The kit is designed to perform a two-step immunocytochemical staining procedure for cytological specimens obtained from the cervix uteri. For the detection of the antigens, a primary monoclonal mouse an-tibody clone E6H4™ directed to human p16^INK4a protein and a primary monoclonal rabbit antibody clone 274-11 AC3 directed against human Ki-67 protein are used.

Ready-to-use visualization reagents comprising (i) a polymer reagent conjugated to horseradish peroxidase and goat anti-mouse Fab’ antibody fragments, and (ii) a polymer reagent conjugated to alkaline phosphatase and goat anti-rabbit Fab’ antibody fragments are used. The visualization reagents have been subjected to solid-phase absorption to eliminate cross reactivity with human immunoglobulins.

The chromogen reactions are based on horseradish peroxidase-mediated conver-sion of a DAB chromogen, and alkaline phosphatase-mediated conversion of Fast Red chromogen to visible reaction products at the respective antigen sites. After counterstaining, a two step mounting protocol must be applied: in a first step, an aqueous mounting of the specimens using an aqueous mounting medium provided with the kit must be used. Subsequently, the slides may be cover-slipped using e.g. a permanent mounting medium. The results can be evaluated by light microscopy inspection.", "Language": "en", "Country": "XG", "Code": "Principle" }, { "Name": "Product Purpose", "Value": "For in vitro diagnostic use.

The CINtec^® PLUS Kit is an immunocytochemistry assay for the simultaneous qualitative detection of the p16^INK4a and Ki-67 proteins in cervical cytology preparations.

It is intended to be used as an aid in the identification of women with high-grade cervical intraepithelial lesions in a screening population, and in the sub-groups of patients with a Pap cytology result of ASC-US (atypical squamous cells of undetermined significance) or LSIL (low grade squamous intraepithelial lesion), or in patients with positive high-risk HPV test results.

The kit is intended to be used in medical cytology laboratories. Interpretation of the test results may only be made by a certified professional in conjunction with the patient 's clinical history and additional diagnostic tests that have been performed.

The test is intended for manual use, or for use on Autostainer instruments.", "Language": "en", "Country": "XG", "Code": "Product Purpose" } ] } } ] }