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  • American Association for Cancer Research (AACR)  (6)
  • 1
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 6 ( 2017-03-15), p. 1461-1470
    Abstract: Purpose: Tumor heterogeneity is a hallmark of pancreatic ductal adenocarcinoma (PDAC). It determines tumor biology including tumor cellularity (i.e., amount of neoplastic cells and arrangement into clusters), which is related to the proliferative capacity and differentiation and the degree of desmoplasia among others. Given the close relation of tumor differentiation with differences in progression and therapy response or, e.g., the recently reported protective role of tumor stroma, we aimed at the noninvasive detection of PDAC groups, relevant for future personalized approaches. We hypothesized that histologic differences in PDAC tissue composition are detectable by the noninvasive diffusion weighted- (DW-) MRI-derived apparent diffusion coefficient (ADC) parameter. Experimental design: PDAC cellularity was quantified histologically and correlated with the ADC parameter and survival in genetically engineered mouse models and human patients. Results: Histologic analysis showed an inverse relationship of tumor cellularity and stroma content. Low tumor cellularity correlated with a significantly prolonged mean survival time (PDAClow = 21.93 months vs. PDACmed = 12.7 months; log-rank P & lt; 0.001; HR = 2.23; CI, 1.41–3.53). Multivariate analysis using the Cox regression method confirmed tumor cellularity as an independent prognostic marker (P = 0.034; HR = 1.73; CI, 1.04–2.89). Tumor cellularity showed a strong negative correlation with the ADC parameter in murine (r = −0.84; CI, −0.90– −0.75) and human (r = −0.79; CI, −0.90 to −0.56) PDAC and high preoperative ADC values correlated with prolonged survival (ADChigh = 41.7 months; ADClow = 14.77 months; log rank, P = 0.040) in PDAC patients. Conclusions: This study identifies high tumor cellularity as a negative prognostic factor in PDAC and supports the ADC parameter for the noninvasive identification of PDAC groups. Clin Cancer Res; 23(6); 1461–70. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 2
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 2 ( 2018-01-15), p. 351-359
    Abstract: Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with a dismal prognosis and poor therapeutic response to current chemotherapy regimens in unselected patient populations. Recently, it has been shown that PDAC may be stratified into functionally and therapeutically relevant molecular subgroups and that some of these subtypes can be recapitulated by IHC for KRT81 [quasi-mesenchymal (QM)/squamous/basal-like] and HNF1A (non-QM, overlap with exocrine/ADEX subtype). Experimental Design: We validated the different outcome of the HNF1A/KRT81 PDAC subtypes in two independent cohorts of surgically treated patients and examined the treatment response to chemotherapy in a third cohort of unresectable patients. The first two cohorts included 262 and 130 patients, respectively, and the third independent cohort comprised advanced-stage PDAC patients who were treated with either FOLFIRINOX (64 patients) or gemcitabine (61 patients). Results: In both cohorts with resected PDAC, the HNF1A-positive subtype showed the best, the KRT81-positive subtype the worst, and the double-negative subtype an intermediate survival (P & lt; 0.013 and P & lt; 0.009, respectively). In the chemotherapy cohort, the survival difference between the double-negative and the HNF1A-positive subtype was lost, whereas the dismal prognosis of KRT81-positive PDAC patients was retained (P & lt; 0.021). Patients with a KRT81-positive subtype did not benefit from FOLFIRINOX therapy, whereas those with HNF1A-positive tumors responded better compared with gemcitabine-based treatment (P & lt; 0.038). Conclusions: IHC stratification recapitulating molecular subtypes of PDAC using HNF1A and KRT81 is associated with significantly different outcomes and responses to chemotherapy. These results may pave the way toward future pretherapeutic biomarker-based stratification of PDAC patients. Clin Cancer Res; 24(2); 351–9. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 3
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 11 ( 2014-06-01), p. 2984-2993
    Abstract: Purpose: To determine the value of diffusion-weighted MRI (DWI-MRI) for pretherapeutic imaging of fluorodeoxyglucose (FDG)-avid lymphoma and lymphoma with variable FDG avidity. Experimental Design: Treatment-naïve patients with lymphoma who were referred for whole-body staging were included in this prospective study. Group A included patients with FDG-avid lymphoma (e.g., Hodgkin, diffuse large B-cell, and follicular lymphoma), whereas Group B included patients with lymphoma of variable FDG avidity [e.g., extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT)]. All patients underwent DWI-MRI and 18F-FDG- positron emission tomography/computed tomography (PET/CT). Region-based sensitivity and agreement with Ann Arbor staging, relative to the reference standard, were calculated for DWI-MRI, and, in Group B, also 18F-FDG-PET/CT and contrast-enhanced (CE-) CT. Results: In Group A (100 patients), DWI-MRI had a region-based sensitivity of 97%, and with regard to staging, agreed with the reference standard in 94 of 100 patients (κ, 0.92). In Group B (40 patients; 38 MALT lymphomas and 2 small lymphocytic lymphomas/chronic lymphocytic leukemias), DWI-MRI, 18F-FDG-PET/CT, and CE-CT had region-based sensitivities of 94.4%, 60.9%, and 70.7%, respectively. With regard to staging in Group B, DWI-MRI, 18F-FDG-PET/CT, and CE-CT agreed with the reference standard in 37 of 40, 26 of 40, and 24 of 40 patients, with κ values of 0.89, 0.52, and 0.43, respectively. Conclusions: In patients with FDG-avid lymphoma, DWI-MRI seems to be only slightly inferior to 18F-FDG-PET/CT with regard to pretherapeutic regional assessment and staging. In patients with lymphoma subtypes that show a variable FDG avidity (e.g., MALT lymphoma), DWI-MRI seems to be superior to both 18F-FDG-PET/CT and CE-CT. Clin Cancer Res; 20(11); 2984–93. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. P4-01-03-P4-01-03
    Abstract: Aim: The prognostic value of circulating tumor cells (CTCs) in the adjuvant setting has recently been demonstrated in the SUCCESS A Study (Rack et al. JNCI 2014). As breast carcinomas depend on partly different pathways for progression, the relevance of CTCs could differ between molecular intrinsic subtypes of breast cancer. Aim of this study was therefore to analyze the prognostic impact of CTCs in molecular subtypes of a large patient cohort. Methods: Within the adjuvant SUCCESS A Study, patients were treated either with 5-Flourouracil, Epirubicin and Cyclophosphamid (FEC) followed by Docetaxel (D) or with FEC followed by D and Gemcitabine (DG). There was no restriction with regard to molecular subtype, however a high recurrence risk was required for study entry. In addition patients were assessed prospectively for the presence of CTCs before chemotherapy. Molecular subtypes were defined as: triple negative (TN), hormone receptor positive and grading 1/2 (LUM A like), hormone receptor positive and grading 3 (LUM B like), HER2 positive (HER2 like). We studied whether the addition of CTC status (0 CTC vs & gt; 0 CTCs) to well-known predictors such as age, BMI, tumor size, lymph node status improved the prediction of overall survival (OS) and disease free survival (DFS) across all patients and especially within molecular subtypes using likelihood ratio tests, which compared multivariable Cox regression models with and without CTC and the interaction between CTC and molecular subtype. Results: Information about molecular subtype and CTCs was available in a total of 1994 patients. At least one CTC was seen in 422 (21.2%) of patients. 383 (19.2%) were TN, 798 were LUM A like (40.0%), 328 (16.4%) were LUM B like (16.4%) and 485 (24.3%) were HER2 like. The effect of CTC on overall survival had a HR of 2.50 (95%: 1.75 to 3.58) for the entire cohort. However as the effect was different across subtypes (p=0.04, likelihood ratio test), subtype specific HR were calculated. The effects on OS were most prominent in LUM B like patients (HR=3.96; 95%CI: 1.93 to 8.14) and LUM A like patients (HR=3.57; 95%CI: 1.81 to 7.03), less strong in HER2 like (HR=2.35; 95%CI: 1.04 to 5.32) and not present in TN patients (HR=1.18; 95%CI: 0.62 to 2.24). CTC status had a clear effect on DFS as well (HR=1.93, 95%CI: 1.48 to 2.52). It could not be shown that this effect was different across subtypes (p=0.07, likelihood ratio test). However, the effect size was similarly distributed like the ones for OS. Conclusion: With regard to OS the prognostic effect of CTCs in this study cohort seems most prominent in patients with hormone receptor positive disease. It is still significant in HER2 positive, but not in TN breast cancer patients. Results with regard to DFS trended into the same direction, differences within subgroups could however not be shown, possibly due to power reasons. Citation Format: Wolfgang Janni, Andreas Schneeweiss, Lothar Häberle, Peter A Fasching, Lukas Schwentner, Mahdi Rezai, Jörn Hilfrich, Hans Tesch, Georg Heinrich, Helmut Forstbauer, Thomas Friedl, Fabienne Schochter, Susanne Albrecht, Bernadette Jäger, Julia Jückstöck, Tanja Fehm, Volkmar Müller, Klaus Friese, Werner Lichtenegger, Matthias B Beckmann, Brigitte Rack. Prognostic relevance of circulating tumor cells across different molecular subgroups in the adjuvant SUCCESS-A study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-01-03.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 21, No. 11 ( 2015-06-01), p. 2506-2513
    Abstract: Purpose: To determine the value of diffusion-weighted MRI (DWI-MRI) for treatment response assessment in 2-[18F]fluoro-2-deoxy-D-glucose (FDG)–avid lymphoma. Experimental Design: Patients with FDG-avid Hodgkin (HL) or non-Hodgkin lymphoma (NHL) at pretherapeutic 18F-FDG-PET/CT, who had also undergone pretherapeutic whole-body DWI-MRI, were included in this prospective study. Depending on the histologic lymphoma subtype, patients received different systemic treatment regimens, and follow-up DWI-MRI and 18F-FDG-PET/CT were performed at one or more time points, depending on the clinical course. For each follow-up DWI-MRI, region-based rates of agreement, and rates of agreement in terms of treatment response (complete remission, partial remission, stable disease, or progressive disease), relative to the corresponding 18F-FDG-PET/CT, were calculated. Results: Sixty-four patients were included: 10 with HL, 22 with aggressive NHL, and 32 with indolent NHL. The overall region-based agreement of DWI-MRI with 18F-FDG-PET/CT was 99.4%. For the 51 interim examinations (performed after 1–3 therapy cycles), region-based agreement of DWI-MRI with 18F-FDG-PET/CT was 99.2%, and for the 48 end-of-treatment examinations, agreement was 99.8%. No significant differences, in terms of region-based agreement between DWI-MRI and 18F-FDG-PET/CT, were observed between the three lymphoma groups (HL, aggressive NHL, indolent NHL; P = 0.25), or between interim and end-of-treatment examinations (P = 0.21). With regard to treatment response assessment, DWI-MRI agreed with 18F-FDG-PET/CT in 99 of 102 follow-up examinations (97.1%), with a κ value of 0.94 (P & lt; 0.0001). Conclusions: In patients with FDG-avid lymphoma, DWI-MRI may be a feasible alternative to 18F-FDG-PET/CT for follow-up and treatment response assessment. Clin Cancer Res; 21(11); 2506–13. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Library Location Call Number Volume/Issue/Year Availability
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  • 6
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. P4-11-21-P4-11-21
    Abstract: Aim: The prognostic value of CTCs at primary diagnosis has recently been confirmed by the SUCCESS A Study (Rack et al. JNCI 2014). Key questions on the role of adjuvant bisphosphonate treatment, including patient populations deriving benefit and optimal timing/scheduling of therapy are still controversial. Aim of this study was therefore to evaluate CTCs in the context of two different zoledronate regimens. Methods: The SUCCESS A trial is a large, randomized, open-label, 2x2 factorial design Phase III study in patients with high risk breast cancer (stage N1 or T2–T4 or grade 3 or age ≤ 35 or hormone-receptor negative). Patients were first randomized to adjuvant chemotherapy treatment with 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide (FEC) followed by either 3 cycles of Docetaxel or 3 cycles of Gemcitabine-Docetaxel. In addition, patients were randomized to 2 years vs. 5 years of zoledronate treatment. CTC status 5 years after primary diagnosis was assessed using the FDA-approved CellSearch System (Veridex, USA), and CTC positivity was defined as ≥ 1 CTC. We studied the influence of zoledronate treatment duration on CTC prevalence at 5 years in addition to well-known patient and tumour characteristics using a multiple logistic regression analysis on the ITT population. Results: Data on CTC status at 5 years after primary diagnosis were available for 728 (19.4%) out of 3754 randomized patients. 310 patients had been randomized to 2 years of zoledronate treatment and 418 patients had been randomized to 5 years of zoledronate treatment. In these patients a difference in CTC positivity after 5 years could not be shown between patients randomized to 2 or 5 years of zoledronate (p = 0.13, Wald test). The adjusted odds ratio for 2 years vs 5 years was 0.65 (95%CI: 0.37 to 1.13). Conclusions: The final survival analysis of the SUCCESS A trial will give further insight, whether CTCs can be used as early predictive marker for the efficacy of adjuvant zoledronate treatment. Citation Format: Brigitte Rack, Peter A Fasching, Lothar Häberle, Thomas Friedl, Mahdi Rezai, Jörn Hilfrich, Hans Tesch, Georg Heinrich, Helmut Forstbauer, Julia Neugebauer, Elisabeth Trapp, Susanne Albrecht, Bernadette Jäger, Tanja Fehm, Volkmar Müller, Andreas Schneeweiss, Klaus Friese, Werner Lichtenegger, Matthias W Beckmann, Wolfgang Janni. Prevalence of circulating tumor cells (CTCs) after five years of zoledronate treatment in the adjuvant SUCCESS-A study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-21.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
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