The 39 reference contexts in paper A. Mudunov, A. Ahundov, M. Bolotin, T. Braunschweig, А. Мудунов, А. Ахундов, М. Болотин, Т. Брауншвейг (2018) “Новые результаты исследования плоскоклеточного рака головы и шеи в отношении классификации и системной терапии. Расширенный обзор // An update on head and neck squamous cell carcinoma in respect to classification and systemic therapy. Extended review” / spz:neicon:ogsh:y:2018:i:1:p:48-55

  1. Start
    5497
    Prefix
    This group of carcinomas, head and neck squamous cell carcinoma (HNSCC), show a wide range of incidences among the world, being more prevalent in some parts of South America and Asia, due to consumption of alcohol, bethel quid or cigarette smoking and, rising in recent years, infection by high-risk human papilloma virus (HPV) types, mostly HPV type 16 and 18
    Exact
    [1, 2]
    Suffix
    . The way of interacting of HPV high risk types and the host genome is based on expression of viral gene products, E6 and E7, leading to an uncontrolled cell proliferation by inactivation of p53 and rb (retinoblastoma-gene product) [3].
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  2. Start
    5736
    Prefix
    The way of interacting of HPV high risk types and the host genome is based on expression of viral gene products, E6 and E7, leading to an uncontrolled cell proliferation by inactivation of p53 and rb (retinoblastoma-gene product)
    Exact
    [3]
    Suffix
    . HNSCCs are linked to high morbidity and mortality rates (up to 50 %) due to the spectrum of affected patients and high recurrence rates. While the incidence of HPV related HNSCC rise, non-HPV related HNSCC are decreasing [4, 5].
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  3. Start
    5962
    Prefix
    HNSCCs are linked to high morbidity and mortality rates (up to 50 %) due to the spectrum of affected patients and high recurrence rates. While the incidence of HPV related HNSCC rise, non-HPV related HNSCC are decreasing
    Exact
    [4, 5]
    Suffix
    . In general, the age-standardization frequency of head and neck cancer worldwide is 8.1 per 100,000. In 2008, 550,319 new head and neck cancer cases were diagnosed worldwide, while in 2012 that number grew to 599,637 with Наряду с общепринятыми схемами конкурентного химиолучевого лечения, включая таргетную терапию цетуксимабом, в последние 2 года появился совершенно новый класс препаратов – п
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  4. Start
    9391
    Prefix
    рак головы и шеи, радио- и химиотерапия, ингибирование контрольных точек, ипилимумаб, ниволумаб, пембролизумаб, атезолизумаб, дурвалумаб Для цитирования: Мудунов A., Ахундов A., Болотин M., Брауншвейг T. Новые результаты исследования плоскоклеточного рака головы и шеи в отношении классификации и системной терапии. Расширенный обзор. Опухоли головы и шеи 2018;8(1):48–55. 324,834 related deaths
    Exact
    [6]
    Suffix
    . Classical site for HPV related squamous cell carcinoma (SCC) is the oropharynx, as palatinal or lingual tonsils, but lately, the number of HPV positively tested cases of sinonasal SCC and laryngeal SCC are rising or diagnosed in a significant number as well [7, 8].
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  5. Start
    9655
    Prefix
    Classical site for HPV related squamous cell carcinoma (SCC) is the oropharynx, as palatinal or lingual tonsils, but lately, the number of HPV positively tested cases of sinonasal SCC and laryngeal SCC are rising or diagnosed in a significant number as well
    Exact
    [7, 8]
    Suffix
    . The 5-year survival rate is more favorable in HPV positive cases than in HPV negative cases, due to less recurrence rates and better response to radiochemotherapy [8, 9]. One explanation of better prognosis in HPV positive SCC is the intrinsic immune response to the tumor, reflected by infiltrating T-cells [10].
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  6. Start
    9826
    Prefix
    cell carcinoma (SCC) is the oropharynx, as palatinal or lingual tonsils, but lately, the number of HPV positively tested cases of sinonasal SCC and laryngeal SCC are rising or diagnosed in a significant number as well [7, 8]. The 5-year survival rate is more favorable in HPV positive cases than in HPV negative cases, due to less recurrence rates and better response to radiochemotherapy
    Exact
    [8, 9]
    Suffix
    . One explanation of better prognosis in HPV positive SCC is the intrinsic immune response to the tumor, reflected by infiltrating T-cells [10]. The classical surrogate marker for HPV positive cases is the immunohistochemical stain for p16 or the product of the gene CDKN2A [11].
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  7. Start
    9972
    Prefix
    The 5-year survival rate is more favorable in HPV positive cases than in HPV negative cases, due to less recurrence rates and better response to radiochemotherapy [8, 9]. One explanation of better prognosis in HPV positive SCC is the intrinsic immune response to the tumor, reflected by infiltrating T-cells
    Exact
    [10]
    Suffix
    . The classical surrogate marker for HPV positive cases is the immunohistochemical stain for p16 or the product of the gene CDKN2A [11]. In oropharyngeal squamous cell carcinoma, in some extend depending on the country or continent, p16 marks HPV high-risk positive cases up to 100 %, but down to 80 % [12, 13], due to the prevalence of infections by subtype HPV type 16.
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  8. Start
    10108
    Prefix
    One explanation of better prognosis in HPV positive SCC is the intrinsic immune response to the tumor, reflected by infiltrating T-cells [10]. The classical surrogate marker for HPV positive cases is the immunohistochemical stain for p16 or the product of the gene CDKN2A
    Exact
    [11]
    Suffix
    . In oropharyngeal squamous cell carcinoma, in some extend depending on the country or continent, p16 marks HPV high-risk positive cases up to 100 %, but down to 80 % [12, 13], due to the prevalence of infections by subtype HPV type 16.
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  9. Start
    10278
    Prefix
    The classical surrogate marker for HPV positive cases is the immunohistochemical stain for p16 or the product of the gene CDKN2A [11]. In oropharyngeal squamous cell carcinoma, in some extend depending on the country or continent, p16 marks HPV high-risk positive cases up to 100 %, but down to 80 %
    Exact
    [12, 13]
    Suffix
    , due to the prevalence of infections by subtype HPV type 16. Other types, including type 18 does not seem to be related to stable p16 expression. By publications using meta-analysis, it could be shown that p16 status is not a complete independent marker for outcome, but the combination of HPV testing by DNA extraction and PCR based detection: HPV+ / p16+ cases had the best prognosis, HPV– /
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  10. Start
    10818
    Prefix
    By publications using meta-analysis, it could be shown that p16 status is not a complete independent marker for outcome, but the combination of HPV testing by DNA extraction and PCR based detection: HPV+ / p16+ cases had the best prognosis, HPV– / p16+ intermediate and HPV+ / p16- and HPV– / p16– the worst
    Exact
    [9]
    Suffix
    . By screening HNSCC for HPV relation, p16 is the recommended marker, especially in oropharyngeal SCCs with a cut off value of 70 % stained tumor area [11]. There are no recommendations concerning the used antibody clone.
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  11. Start
    10970
    Prefix
    is not a complete independent marker for outcome, but the combination of HPV testing by DNA extraction and PCR based detection: HPV+ / p16+ cases had the best prognosis, HPV– / p16+ intermediate and HPV+ / p16- and HPV– / p16– the worst [9]. By screening HNSCC for HPV relation, p16 is the recommended marker, especially in oropharyngeal SCCs with a cut off value of 70 % stained tumor area
    Exact
    [11]
    Suffix
    . There are no recommendations concerning the used antibody clone. As it is well established as being strongly expressed in almost 100 % of SCC of the cervix uteri [14], it is up to the pathological laboratory to establish a specifically staining antibody using for example SCC of cervical SCC as a positive control.
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  12. Start
    11138
    Prefix
    By screening HNSCC for HPV relation, p16 is the recommended marker, especially in oropharyngeal SCCs with a cut off value of 70 % stained tumor area [11]. There are no recommendations concerning the used antibody clone. As it is well established as being strongly expressed in almost 100 % of SCC of the cervix uteri
    Exact
    [14]
    Suffix
    , it is up to the pathological laboratory to establish a specifically staining antibody using for example SCC of cervical SCC as a positive control. Diagnosis Diagnostic approaches include always a biopsy taken of the tumor side by endoscopy.
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  13. Start
    11739
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    Histologically, a squamous cell carcinoma can be challenging in case of low differentiation or basaloid differentiation and depending on the surrounding inflammatory infiltration. HPV positive squamous cell carcinomas show generally a distinct pattern of basaloid cell types and no typical squamous stratification or keratinized differentiated parts
    Exact
    [15]
    Suffix
    . As shown in figure 1, a typical keratinizing squamous cell carcinoma of the tongue, p16 negative, is shown in 1A and 1B. In comparison, a basaloid squamous cell carcinoma origin in the tonsil, p16 positive, is shown in 1C and 1D.
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  14. Start
    12373
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    In unresectable cases or unresectable recurrance, systemic therapy as a combinated chemoradiotherapy, using classical chemotherapeutics, for example cisplatin and radiation or targeted therapeutics, as cetuximab and radiation
    Exact
    [16]
    Suffix
    . In non-naso-pharyngeal SCC in cases of recurrence after platinum containing therapy or progression under platinum containing therapy, a relatively new therapeutic agent, Pembrolizumab (MSD), was approved by the FDA and EMA [16].
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  15. Start
    12603
    Prefix
    In non-naso-pharyngeal SCC in cases of recurrence after platinum containing therapy or progression under platinum containing therapy, a relatively new therapeutic agent, Pembrolizumab (MSD), was approved by the FDA and EMA
    Exact
    [16]
    Suffix
    . Pembrolizumab (MSD) counts to the new group of so called checkpoint-inhibitors, representing a class of therapeutics interacting with the communication of tumor cells and cytotoxic T-cells [17]. In general, checkpoint inhibitors are blocking the ligand binding of the tumor cell on the receptor on the cytotoxic T-cell in order to activate the T-cells to attack tumor cells.
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  16. Start
    12799
    Prefix
    in cases of recurrence after platinum containing therapy or progression under platinum containing therapy, a relatively new therapeutic agent, Pembrolizumab (MSD), was approved by the FDA and EMA [16]. Pembrolizumab (MSD) counts to the new group of so called checkpoint-inhibitors, representing a class of therapeutics interacting with the communication of tumor cells and cytotoxic T-cells
    Exact
    [17]
    Suffix
    . In general, checkpoint inhibitors are blocking the ligand binding of the tumor cell on the receptor on the cytotoxic T-cell in order to activate the T-cells to attack tumor cells. In many different tumor entities, trials had been executed with different types of checkpoint inhibitors, mainly blocking interactions of PD-1 / PD-L1 and CD80 / CTLA4.
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  17. Start
    13324
    Prefix
    In many different tumor entities, trials had been executed with different types of checkpoint inhibitors, mainly blocking interactions of PD-1 / PD-L1 and CD80 / CTLA4. By several authors and speakers, checkpoint inhibitors are called “the fourth modality” next to the well established treatment options: surgery, radiation and chemotherapy
    Exact
    [18]
    Suffix
    . One of the first tumor entities in which checkpoint inhibitors were tested in trials was the malignant melanoma of the skin. Here, CTLA4 inhibitor Ipilimumab (BMS) didn’t reveal high response rates (5–15 %), but still better than prior regimes.
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  18. Start
    13663
    Prefix
    Here, CTLA4 inhibitor Ipilimumab (BMS) didn’t reveal high response rates (5–15 %), but still better than prior regimes. With PD-1 inhibitors like Nivolumab, up to 30–45 % stable response rates were achievable
    Exact
    [18]
    Suffix
    . For HNSCC, in case of CTLA4 several inhibitors are under investigation and mostly in combined therapies with another drug, none of the studies revealed a predicting biomarker as a immunohistochemical staining [19].
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  19. Start
    13877
    Prefix
    For HNSCC, in case of CTLA4 several inhibitors are under investigation and mostly in combined therapies with another drug, none of the studies revealed a predicting biomarker as a immunohistochemical staining
    Exact
    [19]
    Suffix
    . In case of PD-1 and PD-L1 inhibitors, many different drugs were developed (a selection is listed below) and set up in numerous trials from phase I to phase III. From beginning on, immunohistochemical expression of PD-L1 in tumor cells or so called “immune cells” in inflammatory infiltrates within the tumor (mainly histiocytic cell types) were chosen as a major depending variable in the anal
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  20. Start
    14308
    Prefix
    From beginning on, immunohistochemical expression of PD-L1 in tumor cells or so called “immune cells” in inflammatory infiltrates within the tumor (mainly histiocytic cell types) were chosen as a major depending variable in the analysis of efficacy of the drug
    Exact
    [19]
    Suffix
    . The number of PD-1 positive lymphocytes within or adjacent to the tumor was discussed in the beginning but not followed [10]. In the last years, an additional predictive biomarker for the positive response to checkpoint inhibitors revealed the tumor mutational burden, TMB.
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  21. Start
    14435
    Prefix
    From beginning on, immunohistochemical expression of PD-L1 in tumor cells or so called “immune cells” in inflammatory infiltrates within the tumor (mainly histiocytic cell types) were chosen as a major depending variable in the analysis of efficacy of the drug [19]. The number of PD-1 positive lymphocytes within or adjacent to the tumor was discussed in the beginning but not followed
    Exact
    [10]
    Suffix
    . In the last years, an additional predictive biomarker for the positive response to checkpoint inhibitors revealed the tumor mutational burden, TMB. The TMB had been tested in HNSCC and showed to be much higher in non-HPV related carcinomas [20].
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  22. Start
    14684
    Prefix
    In the last years, an additional predictive biomarker for the positive response to checkpoint inhibitors revealed the tumor mutational burden, TMB. The TMB had been tested in HNSCC and showed to be much higher in non-HPV related carcinomas
    Exact
    [20]
    Suffix
    . In theory, TMB high tumors should be related to a high internal immune response due to a higher number of neo antigens on the cell surface. Other factors are discussed to play a role as microbiome or inflammatory signatures [21].
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  23. Start
    14914
    Prefix
    In theory, TMB high tumors should be related to a high internal immune response due to a higher number of neo antigens on the cell surface. Other factors are discussed to play a role as microbiome or inflammatory signatures
    Exact
    [21]
    Suffix
    . As for Pembrolizumab (MSD), equally for Nivolumab (BMS), it inhibits the receptor on the T-cell (see figure 2). Other inhibiting drugs are blocking the ligand as there are Atezolizumab (Roche), Durvalumab (AstraZeneca) and Avelumab (Merck).
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  24. Start
    16139
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    All histological photographs at ×200, using Hamamatsu Scanner, HT2.0 (Hamamatsu, Herrsching, Germany); immunohistochemical stain by monoclonal mouse anti-p16 by Merck (Merck, Darmstadt, Germany) using DAKO/Agilent Autostainer and Flex Kit (Agilent, Waldbronn, Germany) of the receptor programmed-cell death-1 (PD-1) and programmed cell death-ligand-1 (PD-L1) is meant to be suppressed
    Exact
    [22]
    Suffix
    . As depicted in figure 2, PD-L1 is not only expressed on tumor cells, but also on antigen-presenting cells, as dendritic cells. This kind of treatment is not meant to be curative but to control the disease in order to reduce tumor burden or to receive stable disease.
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  25. Start
    16539
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    This kind of treatment is not meant to be curative but to control the disease in order to reduce tumor burden or to receive stable disease. Side-effects of these drugs are in general less severe, as inflammation of lungs, colon and liver, but mostly well treatable
    Exact
    [22]
    Suffix
    . So far, of the five mentioned actual drugs in use or in close future use, are primarily tested in second line and after successful first line application. Nivolumab and Pembrolizumab had been under investigation in Phase III trials in HNSCC: Nivolumab in CheckMate studies (No 141) and Pembrolizumab in Keynote studies (No 012, 048, 055).
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  26. Start
    16976
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    Nivolumab and Pembrolizumab had been under investigation in Phase III trials in HNSCC: Nivolumab in CheckMate studies (No 141) and Pembrolizumab in Keynote studies (No 012, 048, 055). Atezolizumab and Durvalumab had also been investigated on HNSCC in phase I and II studies
    Exact
    [23, 24]
    Suffix
    . In the trial of Atezolizumab, there could not be shown any connection of the response to HPV status (p16 positivity) or PD-L1 immunohistochemical expression. In Durvalumab, only tumors with a PD-L1 expression of at least 25 % of tumor cells were included.
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  27. Start
    17304
    Prefix
    In the trial of Atezolizumab, there could not be shown any connection of the response to HPV status (p16 positivity) or PD-L1 immunohistochemical expression. In Durvalumab, only tumors with a PD-L1 expression of at least 25 % of tumor cells were included. Here p16, resp. HPV positive patients showed a better outcome
    Exact
    [24]
    Suffix
    . In actual studies, the single drug as second line or first line is no longer much under investigation, but combination with other drugs / therapies or an established treatment followed by a checkpoint inhibitor (see table 2).
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  28. Start
    18447
    Prefix
    As demonstrated in figure 4 and revealed in harmonization studies of different groups, the antibody clones: 28.8, 22C3 and SP263 are staining more equally with differences in intensity. The clone SP142 stained significantly less tumor cells but highlight more immune cells
    Exact
    [25, 26]
    Suffix
    . Even if many trials resulted in an approval of one of the drugs in different entities without necessary immunohistochemical testing for PD-L1, it still remains a useful biomarker. In many entities, higher response rates or progression free survival time could be described in tumors showing high expression of PD-L1 in tumor cells.
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  29. Start
    19327
    Prefix
    situations, an immunohistological testing is useful to determine if the treatment with checkpoint inhibitors might work better: malignant melanoma and single treatment with Nivolumab due to higher side effects of Ipilimumab in combination therapy; or in patients who had to pay for the drug themselves. In general, there was no correlation mentioned concerning PD-L1 status and p16 / HPV
    Exact
    [19]
    Suffix
    . But HPV positivFig. 2. Cell interaction of checkpoint ligand/receptors: between antigenpresenting cells (APC) and T-cells via PD-1 and PD-L1 and PD-1 and PDL2 in order to inhibit cytotoxic effects on APC.
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  30. Start
    21913
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    Actual studies on combination of checkpoint inhibitors and other treatments GroupDrugShort descriptionNameRef anti-CTLA4 Ipilimumab (BMS) Combination of Cetuximab, Radiation and Ipilimumab in first line PULA HNSCC–
    Exact
    [27]
    Suffix
    Ipilimumab plus NivolumabCheckMate651&714[28, 29] Tremelimumab (AstraZeneca)Tremelimumab plus DurvalumabKestrel[30] anti-PD-1 PembrolizumabCombination with Chemo and Radiation and Pembrolizumab–[31] Nivolumab Ipilimumab plus NivolumabCheckMate651&714[28, 29] Nivolumab plus ChemotherapyCheckmate 227[32] Induction of Chemo plus Nivolumab followed by surgery (similar to neoadjuvant)Optima2[33] anti
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  31. Start
    21958
    Prefix
    Actual studies on combination of checkpoint inhibitors and other treatments GroupDrugShort descriptionNameRef anti-CTLA4 Ipilimumab (BMS) Combination of Cetuximab, Radiation and Ipilimumab in first line PULA HNSCC–[27] Ipilimumab plus NivolumabCheckMate651&714
    Exact
    [28, 29]
    Suffix
    Tremelimumab (AstraZeneca)Tremelimumab plus DurvalumabKestrel[30] anti-PD-1 PembrolizumabCombination with Chemo and Radiation and Pembrolizumab–[31] Nivolumab Ipilimumab plus NivolumabCheckMate651&714[28, 29] Nivolumab plus ChemotherapyCheckmate 227[32] Induction of Chemo plus Nivolumab followed by surgery (similar to neoadjuvant)Optima2[33] anti-PD-L1DurvalumabDurvalumab plus TremelimumabKestre
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  32. Start
    22026
    Prefix
    Actual studies on combination of checkpoint inhibitors and other treatments GroupDrugShort descriptionNameRef anti-CTLA4 Ipilimumab (BMS) Combination of Cetuximab, Radiation and Ipilimumab in first line PULA HNSCC–[27] Ipilimumab plus NivolumabCheckMate651&714[28, 29] Tremelimumab (AstraZeneca)Tremelimumab plus DurvalumabKestrel
    Exact
    [30]
    Suffix
    anti-PD-1 PembrolizumabCombination with Chemo and Radiation and Pembrolizumab–[31] Nivolumab Ipilimumab plus NivolumabCheckMate651&714[28, 29] Nivolumab plus ChemotherapyCheckmate 227[32] Induction of Chemo plus Nivolumab followed by surgery (similar to neoadjuvant)Optima2[33] anti-PD-L1DurvalumabDurvalumab plus TremelimumabKestrel[30] Fig. 4.
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  33. Start
    22107
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    on combination of checkpoint inhibitors and other treatments GroupDrugShort descriptionNameRef anti-CTLA4 Ipilimumab (BMS) Combination of Cetuximab, Radiation and Ipilimumab in first line PULA HNSCC–[27] Ipilimumab plus NivolumabCheckMate651&714[28, 29] Tremelimumab (AstraZeneca)Tremelimumab plus DurvalumabKestrel[30] anti-PD-1 PembrolizumabCombination with Chemo and Radiation and Pembrolizumab–
    Exact
    [31]
    Suffix
    Nivolumab Ipilimumab plus NivolumabCheckMate651&714[28, 29] Nivolumab plus ChemotherapyCheckmate 227[32] Induction of Chemo plus Nivolumab followed by surgery (similar to neoadjuvant)Optima2[33] anti-PD-L1DurvalumabDurvalumab plus TremelimumabKestrel[30] Fig. 4.
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  34. Start
    22161
    Prefix
    GroupDrugShort descriptionNameRef anti-CTLA4 Ipilimumab (BMS) Combination of Cetuximab, Radiation and Ipilimumab in first line PULA HNSCC–[27] Ipilimumab plus NivolumabCheckMate651&714[28, 29] Tremelimumab (AstraZeneca)Tremelimumab plus DurvalumabKestrel[30] anti-PD-1 PembrolizumabCombination with Chemo and Radiation and Pembrolizumab–[31] Nivolumab Ipilimumab plus NivolumabCheckMate651&714
    Exact
    [28, 29]
    Suffix
    Nivolumab plus ChemotherapyCheckmate 227[32] Induction of Chemo plus Nivolumab followed by surgery (similar to neoadjuvant)Optima2[33] anti-PD-L1DurvalumabDurvalumab plus TremelimumabKestrel[30] Fig. 4.
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  35. Start
    22209
    Prefix
    Ipilimumab (BMS) Combination of Cetuximab, Radiation and Ipilimumab in first line PULA HNSCC–[27] Ipilimumab plus NivolumabCheckMate651&714[28, 29] Tremelimumab (AstraZeneca)Tremelimumab plus DurvalumabKestrel[30] anti-PD-1 PembrolizumabCombination with Chemo and Radiation and Pembrolizumab–[31] Nivolumab Ipilimumab plus NivolumabCheckMate651&714[28, 29] Nivolumab plus ChemotherapyCheckmate 227
    Exact
    [32]
    Suffix
    Induction of Chemo plus Nivolumab followed by surgery (similar to neoadjuvant)Optima2[33] anti-PD-L1DurvalumabDurvalumab plus TremelimumabKestrel[30] Fig. 4. As demonstrated also in different studies, the three stains in A (clone 28.8), B (clone 22C3) and D (clone SP263) stain differently, but the same amount of tumor cells (staining counted irrespectively the strength).
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  36. Start
    22298
    Prefix
    –[27] Ipilimumab plus NivolumabCheckMate651&714[28, 29] Tremelimumab (AstraZeneca)Tremelimumab plus DurvalumabKestrel[30] anti-PD-1 PembrolizumabCombination with Chemo and Radiation and Pembrolizumab–[31] Nivolumab Ipilimumab plus NivolumabCheckMate651&714[28, 29] Nivolumab plus ChemotherapyCheckmate 227[32] Induction of Chemo plus Nivolumab followed by surgery (similar to neoadjuvant)Optima2
    Exact
    [33]
    Suffix
    anti-PD-L1DurvalumabDurvalumab plus TremelimumabKestrel[30] Fig. 4. As demonstrated also in different studies, the three stains in A (clone 28.8), B (clone 22C3) and D (clone SP263) stain differently, but the same amount of tumor cells (staining counted irrespectively the strength).
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  37. Start
    22357
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    (AstraZeneca)Tremelimumab plus DurvalumabKestrel[30] anti-PD-1 PembrolizumabCombination with Chemo and Radiation and Pembrolizumab–[31] Nivolumab Ipilimumab plus NivolumabCheckMate651&714[28, 29] Nivolumab plus ChemotherapyCheckmate 227[32] Induction of Chemo plus Nivolumab followed by surgery (similar to neoadjuvant)Optima2[33] anti-PD-L1DurvalumabDurvalumab plus TremelimumabKestrel
    Exact
    [30]
    Suffix
    Fig. 4. As demonstrated also in different studies, the three stains in A (clone 28.8), B (clone 22C3) and D (clone SP263) stain differently, but the same amount of tumor cells (staining counted irrespectively the strength).
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  38. Start
    23612
    Prefix
    Harmonization studies of different working groups, the antibody clones: 28.8, 22C3 and SP263 are staining more equally with differences in intensity. The clone SP142 stained significantly less tumor cells but highlight more immune cells
    Exact
    [25, 26]
    Suffix
    (see figure 3). Next, cut-off values of 1 % are extremely uneasy to read in histological section with a high proportion of tumor tissue. Therefore, Agilent / Dako and MSD organized training work-shops for pathologists.
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  39. Start
    24044
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    Due to high costs for the testing kits for the described antibodies (e. g. reagents only DAKO / Agilent: ~3150 € / 50 Table 3. Antibodies to test for PD-L1 immunohistochemistry (adjusted from S.Kintsler et al.
    Exact
    [34]
    Suffix
    ) CharacteristicAgilentAgilentVentanaVentanaCell SignallingAbcamZytomedQuartettMerck TypemMomRabmRabmRabmRabmMomRabmRabpolyclRab Clone28.822C3SP142SP263E1L3N28.8Cal10 QR1 Efficacy concordant++–+++++–
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