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17 results on '"Bahce, I."'

1. The landscape of cell-free mitochondrial DNA in liquid biopsy for cancer detection

Author

van der Pol, Y, Moldovan, N, Ramaker, J, Bootsma, S, Lenos, KJ, Vermeulen, L, Sandhu, S, Bahce, I, Pegtel, DM, Wong, SQ, Dawson, S-J, Chandrananda, D, Mouliere, F, van der Pol, Y, Moldovan, N, Ramaker, J, Bootsma, S, Lenos, KJ, Vermeulen, L, Sandhu, S, Bahce, I, Pegtel, DM, Wong, SQ, Dawson, S-J, Chandrananda, D, and Mouliere, F

Abstract

BACKGROUND: Existing methods to detect tumor signal in liquid biopsy have focused on the analysis of nuclear cell-free DNA (cfDNA). However, non-nuclear cfDNA and in particular mitochondrial DNA (mtDNA) has been understudied. We hypothesize that an increase in mtDNA in plasma could reflect the presence of cancer, and that leveraging cell-free mtDNA could enhance cancer detection. RESULTS: We survey 203 healthy and 664 cancer plasma samples from three collection centers covering 12 cancer types with whole genome sequencing to catalogue the plasma mtDNA fraction. The mtDNA fraction is increased in individuals with cholangiocarcinoma, colorectal, liver, pancreatic, or prostate cancer, in comparison to that in healthy individuals. We detect almost no increase of mtDNA fraction in individuals with other cancer types. The mtDNA fraction in plasma correlates with the cfDNA tumor fraction as determined by somatic mutations and/or copy number aberrations. However, the mtDNA fraction is also elevated in a fraction of patients without an apparent increase in tumor-derived cfDNA. A predictive model integrating mtDNA and copy number analysis increases the area under the curve (AUC) from 0.73 when using copy number alterations alone to an AUC of 0.81. CONCLUSIONS: The mtDNA signal retrieved by whole genome sequencing has the potential to boost the detection of cancer when combined with other tumor-derived signals in liquid biopsies.

Published
2023

2. Detection and localization of early- and late-stage cancers using platelet RNA

Author

Veld, S., Arkani, M., Post, E., Antunes-Ferreira, M., D'Ambrosi, S., Vessies, D.C.L., Vermunt, L., Vancura, A., Muller, Mirte, Niemeijer, A.N., Tannous, J., Meijer, L.L., Large, T.Y. Le, Mantini, G., Wondergem, N.E., Heinhuis, K.M., Wilpe, S. van, Smits, Josien, Drees, E.E.E., Roos, E., Leurs, C.E., Fat, L.A. Tjon Kon, Lelij, E.J. van der, Dwarshuis, G., Kamphuis, M.J., Visser, Leonie N.C., Harting, R., Gregory, A., Schweiger, M.W., Wedekind, L.E., Ramaker, J., Zwaan, K., Verschueren, H., Bahce, I, Langen, A.J. de, Smit, E.F., Heuvel, M.M. van den, Hartemink, K.J., Kuijpers, M.J., Egbrink, M.G.A. Oude, Griffioen, A.W., Rossel, R., Hiltermann, T.J.N., Lee-Lewandrowski, E., Lewandrowski, K.B., Hamer, P.C., Kouwenhoven, M., Reijneveld, J.C., Leenders, W.P.J., Hoeben, A., Verdonck-de Leeuw, I.M., Leemans, C.Rene, Baatenburg de Jong, R.J., Terhaard, Chris H. J., Takes, R.P., Langendijk, J.A., Jager, S.C. de, Kraaijeveld, A.O., Pasterkamp, G., Smits, M., Schalken, J.A., Łapińska-Szumczyk, S., Łojkowska, A., Żaczek, A.J., Lokhorst, H., Donk, N. van de, Nijhof, I., Prins, H.J., Zijlstra, J.M., Idema, S., Baayen, J.C., Teunissen, C.E., Killestein, J., Besselink, M.G.H., Brammen, L., Bachleitner-Hofmann, T., Mateen, F., Plukker, J.T., Heger, M., Mast, Q. de, Lisman, T., Pegtel, D.M., Bogaard, H.J., Jassem, J., Supernat, A., Mehra, N., Gerritsen, W.R., Kroon, C.D. de, Lok, C. A. R., Piek, J.M.J., Steeghs, N., Houdt, W.J. van, Brakenhoff, R.H., Sonke, G.S., Verheul, H.M.W., Giovannetti, E., Kazemier, G., Sabrkhany, S., Schuuring, E., Sistermans, E.A., Veld, S., Arkani, M., Post, E., Antunes-Ferreira, M., D'Ambrosi, S., Vessies, D.C.L., Vermunt, L., Vancura, A., Muller, Mirte, Niemeijer, A.N., Tannous, J., Meijer, L.L., Large, T.Y. Le, Mantini, G., Wondergem, N.E., Heinhuis, K.M., Wilpe, S. van, Smits, Josien, Drees, E.E.E., Roos, E., Leurs, C.E., Fat, L.A. Tjon Kon, Lelij, E.J. van der, Dwarshuis, G., Kamphuis, M.J., Visser, Leonie N.C., Harting, R., Gregory, A., Schweiger, M.W., Wedekind, L.E., Ramaker, J., Zwaan, K., Verschueren, H., Bahce, I, Langen, A.J. de, Smit, E.F., Heuvel, M.M. van den, Hartemink, K.J., Kuijpers, M.J., Egbrink, M.G.A. Oude, Griffioen, A.W., Rossel, R., Hiltermann, T.J.N., Lee-Lewandrowski, E., Lewandrowski, K.B., Hamer, P.C., Kouwenhoven, M., Reijneveld, J.C., Leenders, W.P.J., Hoeben, A., Verdonck-de Leeuw, I.M., Leemans, C.Rene, Baatenburg de Jong, R.J., Terhaard, Chris H. J., Takes, R.P., Langendijk, J.A., Jager, S.C. de, Kraaijeveld, A.O., Pasterkamp, G., Smits, M., Schalken, J.A., Łapińska-Szumczyk, S., Łojkowska, A., Żaczek, A.J., Lokhorst, H., Donk, N. van de, Nijhof, I., Prins, H.J., Zijlstra, J.M., Idema, S., Baayen, J.C., Teunissen, C.E., Killestein, J., Besselink, M.G.H., Brammen, L., Bachleitner-Hofmann, T., Mateen, F., Plukker, J.T., Heger, M., Mast, Q. de, Lisman, T., Pegtel, D.M., Bogaard, H.J., Jassem, J., Supernat, A., Mehra, N., Gerritsen, W.R., Kroon, C.D. de, Lok, C. A. R., Piek, J.M.J., Steeghs, N., Houdt, W.J. van, Brakenhoff, R.H., Sonke, G.S., Verheul, H.M.W., Giovannetti, E., Kazemier, G., Sabrkhany, S., Schuuring, E., and Sistermans, E.A.

Abstract

Contains fulltext : 281792.pdf (Publisher’s version ) (Open Access), Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening.

Published
2022

3. Detection and localization of early- and late-stage cancers using platelet RNA

Author

Veld, S., Arkani, M., Post, E., Antunes-Ferreira, M., D'Ambrosi, S., Vessies, D.C.L., Vermunt, L., Vancura, A., Muller, Mirte, Niemeijer, A.N., Tannous, J., Meijer, L.L., Large, T.Y. Le, Mantini, G., Wondergem, N.E., Heinhuis, K.M., Wilpe, S. van, Smits, Josien, Drees, E.E.E., Roos, E., Leurs, C.E., Fat, L.A. Tjon Kon, Lelij, E.J. van der, Dwarshuis, G., Kamphuis, M.J., Visser, Leonie N.C., Harting, R., Gregory, A., Schweiger, M.W., Wedekind, L.E., Ramaker, J., Zwaan, K., Verschueren, H., Bahce, I, Langen, A.J. de, Smit, E.F., Heuvel, M.M. van den, Hartemink, K.J., Kuijpers, M.J., Egbrink, M.G.A. Oude, Griffioen, A.W., Rossel, R., Hiltermann, T.J.N., Lee-Lewandrowski, E., Lewandrowski, K.B., Hamer, P.C., Kouwenhoven, M., Reijneveld, J.C., Leenders, W.P.J., Hoeben, A., Verdonck-de Leeuw, I.M., Leemans, C.Rene, Baatenburg de Jong, R.J., Terhaard, Chris H. J., Takes, R.P., Langendijk, J.A., Jager, S.C. de, Kraaijeveld, A.O., Pasterkamp, G., Smits, M., Schalken, J.A., Łapińska-Szumczyk, S., Łojkowska, A., Żaczek, A.J., Lokhorst, H., Donk, N. van de, Nijhof, I., Prins, H.J., Zijlstra, J.M., Idema, S., Baayen, J.C., Teunissen, C.E., Killestein, J., Besselink, M.G.H., Brammen, L., Bachleitner-Hofmann, T., Mateen, F., Plukker, J.T., Heger, M., Mast, Q. de, Lisman, T., Pegtel, D.M., Bogaard, H.J., Jassem, J., Supernat, A., Mehra, N., Gerritsen, W.R., Kroon, C.D. de, Lok, C. A. R., Piek, J.M.J., Steeghs, N., Houdt, W.J. van, Brakenhoff, R.H., Sonke, G.S., Verheul, H.M.W., Giovannetti, E., Kazemier, G., Sabrkhany, S., Schuuring, E., Sistermans, E.A., Veld, S., Arkani, M., Post, E., Antunes-Ferreira, M., D'Ambrosi, S., Vessies, D.C.L., Vermunt, L., Vancura, A., Muller, Mirte, Niemeijer, A.N., Tannous, J., Meijer, L.L., Large, T.Y. Le, Mantini, G., Wondergem, N.E., Heinhuis, K.M., Wilpe, S. van, Smits, Josien, Drees, E.E.E., Roos, E., Leurs, C.E., Fat, L.A. Tjon Kon, Lelij, E.J. van der, Dwarshuis, G., Kamphuis, M.J., Visser, Leonie N.C., Harting, R., Gregory, A., Schweiger, M.W., Wedekind, L.E., Ramaker, J., Zwaan, K., Verschueren, H., Bahce, I, Langen, A.J. de, Smit, E.F., Heuvel, M.M. van den, Hartemink, K.J., Kuijpers, M.J., Egbrink, M.G.A. Oude, Griffioen, A.W., Rossel, R., Hiltermann, T.J.N., Lee-Lewandrowski, E., Lewandrowski, K.B., Hamer, P.C., Kouwenhoven, M., Reijneveld, J.C., Leenders, W.P.J., Hoeben, A., Verdonck-de Leeuw, I.M., Leemans, C.Rene, Baatenburg de Jong, R.J., Terhaard, Chris H. J., Takes, R.P., Langendijk, J.A., Jager, S.C. de, Kraaijeveld, A.O., Pasterkamp, G., Smits, M., Schalken, J.A., Łapińska-Szumczyk, S., Łojkowska, A., Żaczek, A.J., Lokhorst, H., Donk, N. van de, Nijhof, I., Prins, H.J., Zijlstra, J.M., Idema, S., Baayen, J.C., Teunissen, C.E., Killestein, J., Besselink, M.G.H., Brammen, L., Bachleitner-Hofmann, T., Mateen, F., Plukker, J.T., Heger, M., Mast, Q. de, Lisman, T., Pegtel, D.M., Bogaard, H.J., Jassem, J., Supernat, A., Mehra, N., Gerritsen, W.R., Kroon, C.D. de, Lok, C. A. R., Piek, J.M.J., Steeghs, N., Houdt, W.J. van, Brakenhoff, R.H., Sonke, G.S., Verheul, H.M.W., Giovannetti, E., Kazemier, G., Sabrkhany, S., Schuuring, E., and Sistermans, E.A.

Abstract

Contains fulltext : 281792.pdf (Publisher’s version ) (Open Access), Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening.

Published
2022

7. A nationwide population-based cohort study of surgical care for patients with superior sulcus tumors:Results from the Dutch Lung Cancer Audit for Surgery (DLCA-S)

Author

Winkelman, J. A., van der Woude, L., Heineman, D. J., Bahce, I., Damhuis, R. A., Mahtab, E. A.F., Hartemink, K. J., Senan, S., Maat, A. P.W.M., Braun, J., Paul, M. A., Dahele, M., Dickhoff, C., Winkelman, J. A., van der Woude, L., Heineman, D. J., Bahce, I., Damhuis, R. A., Mahtab, E. A.F., Hartemink, K. J., Senan, S., Maat, A. P.W.M., Braun, J., Paul, M. A., Dahele, M., and Dickhoff, C.

Abstract

Objectives: Data on national patterns of care for patients with superior sulcus tumors (SST) is currently lacking. We investigated the distribution of surgical care and outcome for patients with SST in the Netherlands. Material and methods: Data was retrieved from the Dutch Lung Cancer Audit for Surgery (DLCA-S) for all patients undergoing resection for clinical stage IIB-IV SST from 2012 to 2019. Because DLCA-S is not linked to survival data, survival for a separate cohort (2015–2017) was obtained from the Netherlands Cancer Registry (NCR). Results: In the study period, 181 patients had SST surgery, representing 1.03% (181/17488) of all lung cancer pulmonary resections. For 2015–2017, the SST resection rate was 14.4% (79/549), and patients with stage IIB/III SST treated with trimodality had a 3-year overall survival of 67.4%. 63.5% of patients were male, and median age was 60 years. Almost 3/4 of tumors were right sided. Surgery was performed in 20 hospitals, with average number of annual resections ranging from ≤ 1 (n = 17) to 9 (n = 1). 39.8% of resections were performed in 1 center and 63.5% in the 3 most active centers. 12.7% of resections were extended (e.g. vertebral resection). 85.1% of resections were complete (R0). Morbidity and 30-day mortality were 51.4% and 3.3% respectively. Despite treating patients with a higher ECOG performance score and more extended resections, the highest volume center had rates of morbidity/mortality, and length of hospital stay that were comparable to those of the medium volume (n = 2) and low-volume centers (n = 1). Conclusion: In the Netherlands, surgery for SST accounts for about 1% of all lung cancer pulmonary resections, the number of SST resections/hospital/year varies widely, with most centers performing an average of ≤ 1/year. Morbidity and mortality are acceptable and survival compares favourably with the literature. Although further centralisation is possible, it is unknown whether this will improve outcomes.

Published
2021

8. Effects of checkpoint inhibitors in advanced non-small cell lung cancer at population level from the National Immunotherapy Registry

Author

Smit, H.J., Aerts, J., Heuvel, M. van den, Hiltermann, T.J.N., Bahce, I., Smit, E.F., Dingemans, A.M., Hendriks, L.E., Stigt, J.A., Schramel, F.M., Tinteren, H. van, Groen, H.J.M., of, N.I.R. all participant, Smit, H.J., Aerts, J., Heuvel, M. van den, Hiltermann, T.J.N., Bahce, I., Smit, E.F., Dingemans, A.M., Hendriks, L.E., Stigt, J.A., Schramel, F.M., Tinteren, H. van, Groen, H.J.M., and of, N.I.R. all participant

Abstract

Contains fulltext : 229865.pdf (Publisher’s version ) (Open Access), OBJECTIVE: Phase III studies of checkpoint inhibitors changed the therapeutic landscape for lung cancer. In 2015 the Dutch Society of Chest Physicians (NVALT) introduced a national immunotherapy registry for patients with lung cancer; quality standards for hospitals were implemented. At population level we studied clinical benefit in daily practice and in patients who are underrepresented in phase III trials. MATERIALS AND METHODS: From the initial introduction of checkpoint inhibitors in the Netherlands patients were centrally registered. Educational programs and quality control were provided under supervision of NVALT. The largest immunotherapy providing hospitals were compared to hospitals who provided less checkpoint inhibitors as marker of experience. Patients characteristics, treatment and side effects, response rate and survival were studied. RESULTS: A total of 2676 patients were registered, 2302 with follow up data were evaluated. Between October 2015 and December 2017 a gradual increase from 12 to 30 qualified hospitals showed no major toxicity differences. Toxicity led to a hospital admission rate of 9.1 with an average duration of 10.4 days. Overall tumor response was 21.8 % and median overall survival 12.6 months. Overall survival was not significantly different for patients aged ≥ 75 years, those having brain metastases or selected auto-immune diseases before start checkpoint inhibitors compared to younger patients or those without, respectively. Survival outcomes were worse in patients with PS 2+, non-smokers, and patients who received any palliative radiotherapy (HR 2.1, 95 % CI 1.7-2.7; 1.3, 95 % CI 1.0-1.6 and 1.2, 95 % CI 1.1-1.4, respectively). CONCLUSIONS: Changes in the therapeutic landscape did not lead to major differences in quality of care between hospitals. Elderly patients, those with brain metastases or selected auto-immune disease underrepresented in clinical trials did not do worse on checkpoint inhibitors, except for those with PS 2 +

Published
2020

9. Effects of checkpoint inhibitors in advanced non-small cell lung cancer at population level from the National Immunotherapy Registry

Author

Smit, H.J., Aerts, J., Heuvel, M. van den, Hiltermann, T.J.N., Bahce, I., Smit, E.F., Dingemans, A.M., Hendriks, L.E., Stigt, J.A., Schramel, F.M., Tinteren, H. van, Groen, H.J.M., of, N.I.R. all participant, Smit, H.J., Aerts, J., Heuvel, M. van den, Hiltermann, T.J.N., Bahce, I., Smit, E.F., Dingemans, A.M., Hendriks, L.E., Stigt, J.A., Schramel, F.M., Tinteren, H. van, Groen, H.J.M., and of, N.I.R. all participant

Abstract

Contains fulltext : 229865.pdf (Publisher’s version ) (Open Access), OBJECTIVE: Phase III studies of checkpoint inhibitors changed the therapeutic landscape for lung cancer. In 2015 the Dutch Society of Chest Physicians (NVALT) introduced a national immunotherapy registry for patients with lung cancer; quality standards for hospitals were implemented. At population level we studied clinical benefit in daily practice and in patients who are underrepresented in phase III trials. MATERIALS AND METHODS: From the initial introduction of checkpoint inhibitors in the Netherlands patients were centrally registered. Educational programs and quality control were provided under supervision of NVALT. The largest immunotherapy providing hospitals were compared to hospitals who provided less checkpoint inhibitors as marker of experience. Patients characteristics, treatment and side effects, response rate and survival were studied. RESULTS: A total of 2676 patients were registered, 2302 with follow up data were evaluated. Between October 2015 and December 2017 a gradual increase from 12 to 30 qualified hospitals showed no major toxicity differences. Toxicity led to a hospital admission rate of 9.1 with an average duration of 10.4 days. Overall tumor response was 21.8 % and median overall survival 12.6 months. Overall survival was not significantly different for patients aged ≥ 75 years, those having brain metastases or selected auto-immune diseases before start checkpoint inhibitors compared to younger patients or those without, respectively. Survival outcomes were worse in patients with PS 2+, non-smokers, and patients who received any palliative radiotherapy (HR 2.1, 95 % CI 1.7-2.7; 1.3, 95 % CI 1.0-1.6 and 1.2, 95 % CI 1.1-1.4, respectively). CONCLUSIONS: Changes in the therapeutic landscape did not lead to major differences in quality of care between hospitals. Elderly patients, those with brain metastases or selected auto-immune disease underrepresented in clinical trials did not do worse on checkpoint inhibitors, except for those with PS 2 +

Published
2020

10. Effects of checkpoint inhibitors in advanced non-small cell lung cancer at population level from the National Immunotherapy Registry

Author

Smit, H.J., Aerts, J., Heuvel, M. van den, Hiltermann, T.J.N., Bahce, I., Smit, E.F., Dingemans, A.M., Hendriks, L.E., Stigt, J.A., Schramel, F.M., Tinteren, H. van, Groen, H.J.M., of, N.I.R. all participant, Smit, H.J., Aerts, J., Heuvel, M. van den, Hiltermann, T.J.N., Bahce, I., Smit, E.F., Dingemans, A.M., Hendriks, L.E., Stigt, J.A., Schramel, F.M., Tinteren, H. van, Groen, H.J.M., and of, N.I.R. all participant

Abstract

Contains fulltext : 229865.pdf (Publisher’s version ) (Open Access), OBJECTIVE: Phase III studies of checkpoint inhibitors changed the therapeutic landscape for lung cancer. In 2015 the Dutch Society of Chest Physicians (NVALT) introduced a national immunotherapy registry for patients with lung cancer; quality standards for hospitals were implemented. At population level we studied clinical benefit in daily practice and in patients who are underrepresented in phase III trials. MATERIALS AND METHODS: From the initial introduction of checkpoint inhibitors in the Netherlands patients were centrally registered. Educational programs and quality control were provided under supervision of NVALT. The largest immunotherapy providing hospitals were compared to hospitals who provided less checkpoint inhibitors as marker of experience. Patients characteristics, treatment and side effects, response rate and survival were studied. RESULTS: A total of 2676 patients were registered, 2302 with follow up data were evaluated. Between October 2015 and December 2017 a gradual increase from 12 to 30 qualified hospitals showed no major toxicity differences. Toxicity led to a hospital admission rate of 9.1 with an average duration of 10.4 days. Overall tumor response was 21.8 % and median overall survival 12.6 months. Overall survival was not significantly different for patients aged ≥ 75 years, those having brain metastases or selected auto-immune diseases before start checkpoint inhibitors compared to younger patients or those without, respectively. Survival outcomes were worse in patients with PS 2+, non-smokers, and patients who received any palliative radiotherapy (HR 2.1, 95 % CI 1.7-2.7; 1.3, 95 % CI 1.0-1.6 and 1.2, 95 % CI 1.1-1.4, respectively). CONCLUSIONS: Changes in the therapeutic landscape did not lead to major differences in quality of care between hospitals. Elderly patients, those with brain metastases or selected auto-immune disease underrepresented in clinical trials did not do worse on checkpoint inhibitors, except for those with PS 2 +

Published
2020

11. ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib

Author

Thunnissen, E., Lissenberg-Witte, B., I, van den Heuvel, M. M., Monkhorst, K., Skov, B. G., Sorensen, J. B., Mellemgaard, A., Dingemans, A. M. C., Speel, E. J. M., de Langen, A. J., Hashemi, S. M. S., Bahce, I, van der Drift, M. A., Looijen-Salamon, M. G., Gosney, J., Postmus, P. E., Samii, S. M. S., Duplaquet, F., Weynand, B., Durando, X., Penault-Llorca, F., Finn, S., Grady, A. O., Oz, B., Akyurek, N., Buettner, R., Wolf, J., Bubendorf, L., Duin, S., Marondel, I, Heukamp, L. C., Timens, W., Schuuring, E. M. D., Pauwels, P., Smit, E. F., Thunnissen, E., Lissenberg-Witte, B., I, van den Heuvel, M. M., Monkhorst, K., Skov, B. G., Sorensen, J. B., Mellemgaard, A., Dingemans, A. M. C., Speel, E. J. M., de Langen, A. J., Hashemi, S. M. S., Bahce, I, van der Drift, M. A., Looijen-Salamon, M. G., Gosney, J., Postmus, P. E., Samii, S. M. S., Duplaquet, F., Weynand, B., Durando, X., Penault-Llorca, F., Finn, S., Grady, A. O., Oz, B., Akyurek, N., Buettner, R., Wolf, J., Bubendorf, L., Duin, S., Marondel, I, Heukamp, L. C., Timens, W., Schuuring, E. M. D., Pauwels, P., and Smit, E. F.

Abstract

Objective: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH +). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC) +). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases. Materials and methods: In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH. Results: Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC + /FISH +) and 16 discordant (ALK IHC + /FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78-7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR = 4.5; 95% CI = 1.2-15.9; p = 0.010. Conclusion: ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines.

Published
2019

12. ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib

Author

Thunnissen, E., Lissenberg-Witte, B., I, van den Heuvel, M. M., Monkhorst, K., Skov, B. G., Sorensen, J. B., Mellemgaard, A., Dingemans, A. M. C., Speel, E. J. M., de Langen, A. J., Hashemi, S. M. S., Bahce, I, van der Drift, M. A., Looijen-Salamon, M. G., Gosney, J., Postmus, P. E., Samii, S. M. S., Duplaquet, F., Weynand, B., Durando, X., Penault-Llorca, F., Finn, S., Grady, A. O., Oz, B., Akyurek, N., Buettner, R., Wolf, J., Bubendorf, L., Duin, S., Marondel, I, Heukamp, L. C., Timens, W., Schuuring, E. M. D., Pauwels, P., Smit, E. F., Thunnissen, E., Lissenberg-Witte, B., I, van den Heuvel, M. M., Monkhorst, K., Skov, B. G., Sorensen, J. B., Mellemgaard, A., Dingemans, A. M. C., Speel, E. J. M., de Langen, A. J., Hashemi, S. M. S., Bahce, I, van der Drift, M. A., Looijen-Salamon, M. G., Gosney, J., Postmus, P. E., Samii, S. M. S., Duplaquet, F., Weynand, B., Durando, X., Penault-Llorca, F., Finn, S., Grady, A. O., Oz, B., Akyurek, N., Buettner, R., Wolf, J., Bubendorf, L., Duin, S., Marondel, I, Heukamp, L. C., Timens, W., Schuuring, E. M. D., Pauwels, P., and Smit, E. F.

Abstract

Objective: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH +). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC) +). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases. Materials and methods: In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH. Results: Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC + /FISH +) and 16 discordant (ALK IHC + /FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78-7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR = 4.5; 95% CI = 1.2-15.9; p = 0.010. Conclusion: ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines.

Published
2019

13. ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib

Author

Thunnissen, E., Lissenberg-Witte, B. I., van den Heuvel, M. M., Monkhorst, K., Skov, B. G., Sørensen, J. B., Mellemgaard, A., Dingemans, A. M.C., Speel, E. J.M., de Langen, A. J., Hashemi, S. M.S., Bahce, I., van der Drift, M. A., Looijen-Salamon, M. G., Gosney, J., Postmus, P. E., Samii, S. M.S., Duplaquet, F., Weynand, B., Durando, X., Penault-Llorca, F., Finn, S., Grady, A. O., Oz, B., Akyurek, N., Buettner, R., Wolf, J., Bubendorf, L., Duin, S., Marondel, I., Heukamp, L. C., Timens, W., Schuuring, E. M.D., Pauwels, P., Smit, E. F., Thunnissen, E., Lissenberg-Witte, B. I., van den Heuvel, M. M., Monkhorst, K., Skov, B. G., Sørensen, J. B., Mellemgaard, A., Dingemans, A. M.C., Speel, E. J.M., de Langen, A. J., Hashemi, S. M.S., Bahce, I., van der Drift, M. A., Looijen-Salamon, M. G., Gosney, J., Postmus, P. E., Samii, S. M.S., Duplaquet, F., Weynand, B., Durando, X., Penault-Llorca, F., Finn, S., Grady, A. O., Oz, B., Akyurek, N., Buettner, R., Wolf, J., Bubendorf, L., Duin, S., Marondel, I., Heukamp, L. C., Timens, W., Schuuring, E. M.D., Pauwels, P., and Smit, E. F.

Abstract

Objective: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases. Materials and methods: In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH. Results: Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC+/FISH+) and 16 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78–7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2–15.9; p=0.010. Conclusion: ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines.

Published
2019

14. Crizotinib-Treated ALK Immunopositive Metastasized NSCLC is Associated with an Unfavorable Prognosis when FISH Negative

Author

Thunnissen, E., Lissenberg-Witte, B., Van den Heuvel, M., Monkhorst, K., Skov, B., Sorensen, J., Mellemgaard, A., Dingemans, A., Speel, E., De langen, J., Hashemi, S., Bahce, I., Van Der Drift, M., Buettner, R., Salomon, M. Looijen, Gosney, J., Postmus, P. E., Samii, S., Duplaquet, F., Weynand, B., Durando, X., Penault-Llorca, F., Finn, S., Oz, B., Akyurek, N., Wolf, J., Bubendorf, L., Hiemstra, A., Duin, S., Marondel, L., Timens, W., Schuuring, E., Pauwels, P., Smit, E., Thunnissen, E., Lissenberg-Witte, B., Van den Heuvel, M., Monkhorst, K., Skov, B., Sorensen, J., Mellemgaard, A., Dingemans, A., Speel, E., De langen, J., Hashemi, S., Bahce, I., Van Der Drift, M., Buettner, R., Salomon, M. Looijen, Gosney, J., Postmus, P. E., Samii, S., Duplaquet, F., Weynand, B., Durando, X., Penault-Llorca, F., Finn, S., Oz, B., Akyurek, N., Wolf, J., Bubendorf, L., Hiemstra, A., Duin, S., Marondel, L., Timens, W., Schuuring, E., Pauwels, P., and Smit, E.

Published
2018

15. Crizotinib-Treated ALK Immunopositive Metastasized NSCLC is Associated with an Unfavorable Prognosis when FISH Negative

Author

Thunnissen, E., Lissenberg-Witte, B., Van den Heuvel, M., Monkhorst, K., Skov, B., Sorensen, J., Mellemgaard, A., Dingemans, A., Speel, E., De langen, J., Hashemi, S., Bahce, I., Van Der Drift, M., Buettner, R., Salomon, M. Looijen, Gosney, J., Postmus, P. E., Samii, S., Duplaquet, F., Weynand, B., Durando, X., Penault-Llorca, F., Finn, S., Oz, B., Akyurek, N., Wolf, J., Bubendorf, L., Hiemstra, A., Duin, S., Marondel, L., Timens, W., Schuuring, E., Pauwels, P., Smit, E., Thunnissen, E., Lissenberg-Witte, B., Van den Heuvel, M., Monkhorst, K., Skov, B., Sorensen, J., Mellemgaard, A., Dingemans, A., Speel, E., De langen, J., Hashemi, S., Bahce, I., Van Der Drift, M., Buettner, R., Salomon, M. Looijen, Gosney, J., Postmus, P. E., Samii, S., Duplaquet, F., Weynand, B., Durando, X., Penault-Llorca, F., Finn, S., Oz, B., Akyurek, N., Wolf, J., Bubendorf, L., Hiemstra, A., Duin, S., Marondel, L., Timens, W., Schuuring, E., Pauwels, P., and Smit, E.

Published
2018

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