Publications by authors named "Carsten Bokemeyer"

500 Publications

Estimating Long-Term Survival Outcomes for Tumor-Agnostic Therapies: Larotrectinib Case Study.

Oncology 2021 Nov 29:1-6. Epub 2021 Nov 29.

The CHOICE Institute, University of Washington School of Pharmacy, Seattle, Washington, USA.

Background: Larotrectinib is a precision oncology treatment for solid tumors with neurotrophic tyrosine receptor kinase (NTRK) gene fusions. Larotrectinib efficacy has been evaluated in single-arm basket trials with limited follow-up and sample sizes at the initial regulatory approval due to the rarity of solid tumors with NTRK gene fusion.

Objectives: We aim to demonstrate that trends in progression-free survival (PFS) and overall survival (OS) in survival data with longer follow-up may be predicted from long-term survival estimates from survival data with shorter follow-up, including predictions for median survival when it is not observed in the trial.

Methods: Patient-level data were pooled from 3 clinical trials (NCT02122913, NCT02576431, and NCT02637687) using the 2018 and 2020 data cuts for the same subset of pediatric and adult patients. The Weibull distribution was selected for survival models. Survival predictions using 2018 data were compared to 2020 Kaplan-Meier (KM) curves.

Results: A total of 102 patients representing 15 tumor types were included in the analysis, with a mean age of 37 years. When comparing PFS from the 2018 survival prediction to observed 2020 KM data, the 12-month PFS rate was identical (66.6%). The 36-month PFS rate was lower for the 2018 prediction (35.3%) compared to 2020 KM data (44.4%). The median OS had not yet been reached in either data cut but was predicted to be 90 months using the 2018 data. When comparing OS from the 2018 survival prediction to the observed 2020 KM data, the 12-month OS rate was 89.0% and 86.6% and the 48-month OS rate was 67.2% and 63.0%, respectively.

Conclusion: Long-term PFS predictions deviated from observed PFS rates due to response differences across tumor types and heavy censoring towards the end of the survival curve. However, for OS, the 48-month survival prediction was consistent with the observed 2020 KM estimate.
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http://dx.doi.org/10.1159/000519767DOI Listing
November 2021

Need for additional professional psychosocial and spiritual support in patients with advanced diseases in the course of specialist palliative care - a longitudinal observational study.

BMC Palliat Care 2021 Nov 25;20(1):182. Epub 2021 Nov 25.

Palliative Care Unit, Department of Oncology, Hematology and BMT, University Medical Center Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Background: We investigated the need for additional professional support and associated factors in patients (pts) at initiation and in the course of in- and outpatient specialist palliative care (I-SPC/O-SPC).

Methods: Pts entering an urban SPC network consecutively completed questionnaires on psychosocial/spiritual problems and support needs within 72 h (T0) as well as within the first 6 weeks (T1) of SPC. Hierarchical linear regression analysis was used to investigate the impact of sociodemographic / disease-related variables, psychological / physical burden, social support, and SPC setting on the extent of support needs.

Results: Four hundred twenty-five pts (70 years, 48% female, 91% cancer, 67% O-SPC) answered at T0, and 167 at T1. At T0, main problems related to transportation, usual activities, and dependency (83-89%). At T1, most prevalent problems also related to transportation and usual activities and additionally to light housework (82-86%). At T0, support needs were highest for transportation, light housework, and usual activities (35-41%). Cross-sectional comparisons of SPC settings revealed higher problem scores in O-SPC compared to I-SPC at T0 (p = .039), but not at T1. Support need scores were higher in O-SPC at T0 (p < .001), but lower at T1 (p = .039). Longitudinal analyses showed a decrease of support need scores over time, independent from the SPC setting. At T0, higher distress (p = .047), anxiety/depression (p < .001), physical symptom burden (p < .001) and I-SPC (p < .001) were associated with higher support need scores (at T1: only higher distress, p = .037).

Conclusion: Need for additional professional psychosocial/spiritual support was identified in up to 40% of pts. with higher need at the beginning of O-SPC than of I-SPC. During SPC, this need decreased in both settings, but got lower in O-SPC than in I-SPC over time. Support need scores were not only associated with psychological, but also physical burden.
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http://dx.doi.org/10.1186/s12904-021-00880-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8613968PMC
November 2021

Bone Marrow-Resident Vδ1 T Cells Co-express TIGIT With PD-1, TIM-3 or CD39 in AML and Myeloma.

Front Med (Lausanne) 2021 8;8:763773. Epub 2021 Nov 8.

Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

γδ T cells represent a unique T cell subpopulation due to their ability to recognize cancer cells in a T cell receptor- (TCR) dependent manner, but also in a non-major histocompatibility complex- (MHC) restricted way via natural killer receptors (NKRs). Endowed with these features, they represent attractive effectors for immuno-therapeutic strategies with a better safety profile and a more favorable anti-tumor efficacy in comparison to conventional αβ T cells. Also, remarkable progress has been achieved re-activating exhausted T lymphocytes with inhibitors of co-regulatory receptors e.g., programmed cell death protein 1 (PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT) and of the adenosine pathway (CD39, CD73). Regarding γδ T cells, little evidence is available. This study aimed to immunophenotypically characterize γδ T cells from patients with diagnosed acute myeloid leukemia (AML) in comparison to patients with multiple myeloma (MM) and healthy donors (HD). The frequency, differentiation, activation, and exhaustion status of bone marrow- (BM) derived γδ T cells from patients with AML ( = 10) and MM ( = 11) were assessed in comparison to corresponding CD4 and CD8 T cells and peripheral blood- (PB) derived γδ T cells from HDs ( = 16) using multiparameter flow cytometry. BM-infiltrating Vδ1 T cells showed an increased terminally differentiated cell population (TEMRAs) in AML and MM in comparison to HDs with an aberrant subpopulation of CD27CD45RA cells. TIGIT, PD-1, TIM-3, and CD39 were more frequently expressed by γδ T cells in comparison to the corresponding CD4 T cell population, with expression levels that were similar to that on CD8 effector cells in both hematologic malignancies. In comparison to Vδ2 T cells, the increased frequency of PD-1-, TIGIT-, TIM-3, and CD39 cells was specifically observed on Vδ1 T cells and related to the TEMRA Vδ1 population with a significant co-expression of PD-1 and TIM-3 together with TIGIT. Our results revealed that BM-resident γδ T cells in AML and MM express TIGIT, PD-1, TIM-3 and CD39. As effector population for autologous and allogeneic strategies, inhibition of co-inhibitory receptors on especially Vδ1 γδ T cells may lead to re-invigoration that could further increase their cytotoxic potential.
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http://dx.doi.org/10.3389/fmed.2021.763773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606547PMC
November 2021

Acceptance and Benefits of Two Different Strategies to Timely Integrate Specialist Palliative Care into Routine Cancer Care - a Randomized Pilot Study.

Oncol Res Treat 2021 Nov 24. Epub 2021 Nov 24.

Background / Aims: To investigate the acceptance and benefits of two different strategies to timely integrate specialist palliative care (SPC) in routine cancer care: commonly recommended early SPC counselling versus an informational brochure plus SPC counselling upon patients' request.

Methods: Patients diagnosed with incurable cancer within the last 6-12 weeks were sequentially randomized. Endpoints were acceptance of the two strategies after 3 months as well as use of SPC counselling and psychosocial support, presence of advance directives, palliative care outcome (IPOS), psychosocial distress (DT) and after 3 and 6 months. In a qualitative part, SPC consultations were analyzed using content analysis.

Results: Overall, 43 patients received SPC counselling and 37 a brochure with SPC counselling on demand. In the brochure group, only one patient later registered for SPC counselling from own initiative. SPC timing was appropriate in 70% of patients (75% counselling / 61% brochure, n.s.). Sufficiency, helpfulness and relevance of information, provision of security and help with finding contacts for specific support were perceived adequate in both groups. No significant differences were found regarding potential effects of the interventions on IPOS or DT after 3 and 6 months. Use of psychosocial support was comparable between the groups and 4 patients had new advance directives (3 counselling / 1 brochure). Five key themes of SPC consultations were identified: symptoms, rapport, coping, illness understanding, and advance care planning.

Conclusions: Both SPC integration strategies were well accepted. However, patients seem not to benefit from a brochure in terms of initiating SPC counselling timely after a palliative cancer diagnosis.
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http://dx.doi.org/10.1159/000521077DOI Listing
November 2021

Current Treatment Approaches to Newly Diagnosed Multiple Myeloma.

Oncol Res Treat 2021 Nov 16:1-8. Epub 2021 Nov 16.

Department of Hematology, Oncology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Multiple myeloma is a so far incurable malignant plasma cell disorder. During the past 2 decades, treatment paradigms substantially changed when novel drugs were introduced initially in treatment of relapsed disease and subsequently also in first-line treatment.

Summary: Up to now, first-line treatment differs between patients initially classified as transplant eligible and those who are considered as nontransplant eligible. Transplant-eligible patients receive a primary proteasome inhibitor (PI)-based induction which is being combined with an immunomodulating agent and a CD38-directed monoclonal antibody followed by high-dose melphalan therapy and autologous stem cell transplantation with subsequent maintenance treatment with lenalidomide. Patients who are considered as nontransplant eligible receive upfront treatment preferentially with a continuous combination treatment either with a CD38-directed monoclonal antibody in combination with the immunomodulating agent lenalidomide or a lenalidomide-PI combination followed by lenalidomide maintenance. Key Messages: Primary goal of the initiated treatment is to induce a rapid and deep remission which ideally leads to an eradication of the residual plasma cell clone in sense of a minimal residual disease negativity. Achievement of long-term remission with limited toxicity despite continuous treatment strategies and maintenance or improvement of life-quality is key. Despite successful treatment options, specific difficult-to-treat subgroups, especially patients with high-risk myeloma remain with inferior prognosis and a clear unmet need for novel therapeutic strategies. Future concepts will evaluate cellular treatments and other innovative immunotherapies in first-line treatment in curative intention.
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http://dx.doi.org/10.1159/000520504DOI Listing
November 2021

Therapy of clinical stage IIA and IIB seminoma: a systematic review.

World J Urol 2021 Nov 15. Epub 2021 Nov 15.

II. Medical Clinic and Polyclinic, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

Purpose: The optimal treatment for clinical stage (CS) IIA/IIB seminomas is still controversial. We evaluated current treatment options.

Methods: A systematic review was performed. Only randomized clinical trials and comparative studies published from January 2010 until February 2021 were included. Search items included: seminoma, CS IIA, CS IIB and therapy. Outcome parameters were relapse rate (RR), relapse-free (RFS), overall and cancer-specific survival (OS, CSS). Additionally, acute and long-term side effects including secondary malignancies (SMs) were analyzed.

Results: Seven comparative studies (one prospective and six retrospective) were identified with a total of 5049 patients (CS IIA: 2840, CS IIB: 2209). The applied treatment modalities were radiotherapy (RT) (n = 3049; CS IIA: 1888, CSIIB: 1006, unknown: 155) and chemotherapy (CT) or no RT (n = 2000; CS IIA: 797, CS IIB: 1074, unknown: 129). In CS IIA, RRs ranged from 0% to 4.8% for RT and 0% for CT. Concerning CS IIB RRs of 9.5%-21.1% for RT and of 0%-14.2% for CT have been reported. 5-year OS ranged from 90 to 100%. Only two studies reported on treatment-related toxicities.

Conclusions: RT and CT are the most commonly applied treatments in CS IIA/B seminoma. In CS IIA seminomas, RRs after RT and CT are similar. However, in CS IIB, CT seems to be more effective. Survival rates of CS IIA/B seminomas are excellent. Consequently, long-term toxicities and SMs are important survivorship issues. Alternative treatment approaches, e.g., retroperitoneal lymph node dissection (RPLND) or dose-reduced sequential CT/RT are currently under prospective investigation.
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http://dx.doi.org/10.1007/s00345-021-03873-5DOI Listing
November 2021

Evaluation of an electronic psycho-oncological adaptive screening program (EPAS) with immediate patient feedback: findings from a German cluster intervention study.

J Cancer Surviv 2021 Nov 4. Epub 2021 Nov 4.

Department of Medical Psychology and Medical Sociology, University of Leipzig, Leipzig, Germany.

Purpose: Distress screening has become mandatory and essential in comprehensive cancer care. We evaluated an electronic psycho-oncological adaptive screening (EPAS) which assesses objective indicators of care needs and subjectively perceived care needs and subsequently provides patient feedback with individualized recommendations about psychosocial care services.

Methods: Patients were assessed within clusters, i.e., different oncological facilities of the competence network of the University Cancer Center Hamburg (UCCH). Patients in the intervention arm underwent the screening, controls received standard care. Patients were assessed at baseline (t0), 3-month (t1), and 6-month (t2) follow-up. Outcomes included information level and use of/access to nine psychosocial services at UCCH, well-being (GAD-7, PHQ-9, SF-8), and treatment satisfaction (SCCC). Conditional linear and logistic regressions were used to identify screening effects at t1 and t2.

Results: Of 1320 eligible patients across 11 clusters, 660 were included (50%). The average age was 60 years; 46% were female. The intervention was associated with increased information level for all psychosocial services at t1 and t2 (all p < .001), increased use in some of these services at t1 and t2, respectively (p ≤ .02), and better evaluation of access (e.g., more recommendations for services provided by physicians, p < .01). At t2, the intervention was associated with a lower level of satisfaction with disease-related information (p = .02).

Conclusions: EPAS may improve information about psychosocial services as well as utilization of and access to these services. The effect on information level seems not to be generalizable to other aspects of oncological care. Future studies should incorporate novel technologies and condense the procedure to its core factors.

Implications For Cancer Survivors: The screening may help to enhance self-management competencies among cancer survivors.

Trial Registration: The trial was retrospectively registered (2/2021) at ClinicalTrials.gov (number: NCT04749056).
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http://dx.doi.org/10.1007/s11764-021-01121-8DOI Listing
November 2021

Activity of New Synthetic (2-Chloroethylthio)-1,4-naphthoquinones in Prostate Cancer Cells.

Pharmaceuticals (Basel) 2021 Sep 22;14(10). Epub 2021 Sep 22.

Laboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, Germany.

Development of resistance to currently available standard therapies in advanced prostate cancer (PCa) emphasizes the need for novel therapeutic options. Here, we report the synthesis of new hybrid molecules consisting of 2-chloroethylthio and 1,4-naphthoquinone pharmacophores and describe their activity in PCa. In screening analyses, the introduction of one 2-chloroethylthio group improved the anticancer properties of 1,4-naphthoquinones, whereas the introduction of a second 2-chloroethylthio moiety rather decreased activity. Two most promising of the synthesized compounds, and , were highly active in different human PCa cell lines harboring varying resistance profiles at nanomolar concentrations. The generated data suggest that the compounds are capable of mitochondria targeting, cytotoxic ROS induction, and DNA damage, which resulted in apoptosis presumably executed in a caspase-dependent manner. The substances synergized with the clinically approved PARP inhibitor olaparib and resensitized AR-V7-expressing PCa cells to antiandrogen enzalutamide, as well as to a combination of enzalutamide and an AKT inhibitor. This was at least in part exerted via down-regulation of AR-V7 expression and inhibition of AR signaling. Mild antagonism was observed in combination with platinum- or taxane-based chemotherapy, which was putatively related to treatment-induced activation of p38, JNK1/2, ERK1/2, MEK1/2, and AKT, functioning as potential pro-survival factors. Thus, the synthesized (2-chloroethylthio)-1,4-naphthoquinone derivatives exhibit promising anticancer properties in vitro, suggesting their further development as potential therapeutics for the treatment of castration-resistant PCa.
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http://dx.doi.org/10.3390/ph14100949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540265PMC
September 2021

COVID-19 and seasonal influenza: a comparative analysis in patients with hematological malignancies.

Leuk Lymphoma 2021 Oct 20:1-8. Epub 2021 Oct 20.

Department of Oncology, Hematology and Bone Marrow Transplantation with Division of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The severity and mortality of COVID-19 and seasonal influenza were recently compared in the general population but not in patients with hematological malignancies. We analyzed the clinical courses of 79 patients with hematological malignancies and diagnosis of either SARS-CoV-2 ( = 29) or influenza A or B infections ( = 50) who were admitted or were already under treatment in the Department of Oncology, Hematology and Stem cell Transplantation at the University Medical Center Hamburg-Eppendorf, Germany, between 1 January 2012 and 31 January 2021. For COVID-19, we observed significantly higher rates of acute respiratory distress syndrome with 48% (14/29) compared to 14% (7/50) in the influenza group ( = 0.001) as well as a significantly higher virus-associated 90-day mortality (41% vs. 12%,  = 0.005). Based on our results, we conclude that infections with SARS-CoV-2 are more severe than influenza A or B in patients with hematological malignancies.
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http://dx.doi.org/10.1080/10428194.2021.1992626DOI Listing
October 2021

Mebendazole Mediates Proteasomal Degradation of GLI Transcription Factors in Acute Myeloid Leukemia.

Int J Mol Sci 2021 Oct 1;22(19). Epub 2021 Oct 1.

Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

The prognosis of elderly AML patients is still poor due to chemotherapy resistance. The Hedgehog (HH) pathway is important for leukemic transformation because of aberrant activation of GLI transcription factors. MBZ is a well-tolerated anthelmintic that exhibits strong antitumor effects. Herein, we show that MBZ induced strong, dose-dependent anti-leukemic effects on AML cells, including the sensitization of AML cells to chemotherapy with cytarabine. MBZ strongly reduced intracellular protein levels of GLI1/GLI2 transcription factors. Consequently, MBZ reduced the GLI promoter activity as observed in luciferase-based reporter assays in AML cell lines. Further analysis revealed that MBZ mediates its anti-leukemic effects by promoting the proteasomal degradation of GLI transcription factors via inhibition of HSP70/90 chaperone activity. Extensive molecular dynamics simulations were performed on the MBZ-HSP90 complex, showing a stable binding interaction at the ATP binding site. Importantly, two patients with refractory AML were treated with MBZ in an off-label setting and MBZ effectively reduced the GLI signaling activity in a modified plasma inhibitory assay, resulting in a decrease in peripheral blood blast counts in one patient. Our data prove that MBZ is an effective GLI inhibitor that should be evaluated in combination to conventional chemotherapy in the clinical setting.
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http://dx.doi.org/10.3390/ijms221910670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508953PMC
October 2021

Perceived Positive and Negative Life Changes in Testicular Cancer Survivors.

Medicina (Kaunas) 2021 Sep 20;57(9). Epub 2021 Sep 20.

Department of Medical Psychology and Medical Sociology, University Medical Center Leipzig, 04103 Leipzig, Germany.

Despite a generally good prognosis, testicular cancer can be a life-altering event. We explored perceived positive and negative life changes after testicular cancer in terms of frequency, demographic and disease-related predictors, and associations with depression and anxiety. All testicular cancer survivors receiving follow-up care at two specialized outpatient treatment facilities were approached at follow-up visits or via mail. We assessed a total of = 164 patients (66% participation rate, mean time since diagnosis: 11.6 years, SD = 7.4) by the Posttraumatic Growth Inventory (PTGI, modified version assessing positive and negative changes for each of 21 items), Patient-Health-Questionnaire-9 (PHQ-9), and Generalized-Anxiety-Disorder-Scale-7 (GAD-7). We conducted controlled multivariate regression analyses. Most survivors (87%) reported at least one positive change (mean number: 7.2, SD = 5.0, possible range: 0-21). The most frequent perceived positive changes were greater appreciation of life (62%), changed priorities in life (62%), and ability rely on others (51%). At least one negative change was perceived by 33% (mean number of changes: 1.1, SD = 2.5). Negative changes were most frequent for decreases in self-reliance (14%), personal strength (11%), and ability to express emotions (9%). A higher socioeconomic status was associated with more positive changes (β = 0.25, 95% CI 0.08 to 0.42); no other association with demographic and disease-related predictors emerged. While positive life changes were not associated with depression (β = -0.05, 95% CI -0.17 to 0.07) and anxiety (β = 0.00, 95% CI -0.13 to 0.13), more negative life changes were significantly associated with higher depression (β = 0.15, 95% CI -0.03 to 0.27) and anxiety (β = 0.23, 95% CI 0.11 to 0.36). There was no significant interaction of positive and negative changes on depression or anxiety. Although positive life changes after testicular cancer are common, a significant number of survivors perceive negative changes in life domains that have been primarily investigated in terms of personal growth. Early identification of and psychosocial support for patients who perceive predominantly negative changes may contribute to prevention of prolonged symptoms of anxiety and depression.
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http://dx.doi.org/10.3390/medicina57090993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469336PMC
September 2021

Impact of Disease Evolution on Efficacy Outcomes From Larotrectinib in Patients With Locally Advanced or Metastatic Tropomyosin Receptor Kinase Fusion-Positive Solid Tumors.

JCO Precis Oncol 2021 13;5. Epub 2021 Sep 13.

Bayer Pharmaceuticals, Basel, Switzerland.

Neurotrophic tyrosine receptor kinase () gene fusions encode oncogenic, chimeric tropomyosin receptor kinase (TRK) proteins. Larotrectinib, an approved TRK inhibitor, is efficacious in locally advanced or metastatic (adv/met) TRK fusion cancer. We evaluated the time from initial diagnosis to locally advanced or metastatic disease and to initiation of larotrectinib treatment as well as larotrectinib impact on disease course.

Materials And Methods: Patients were grouped by prior lines of therapy (0, 1-2, and ≥ 3) and pre-larotrectinib duration of adv/met disease (short [< 3.5 months], medium [3.5 to < 15.7 months], and long [≥ 15.7 months]). Overall response rate (ORR), duration of response (DOR), and progression-free survival were assessed.

Results: One hundred sixty-four patients were evaluated. The median time from initial diagnosis to development of locally adv/met stage was 2.1 months; the duration of pre-larotrectinib adv/met disease was 7.3 months (n = 153). In patients with 0, 1-2, and ≥ 3 prior lines of therapy, the median time from diagnosis to adv/met stage was 0.9, 1.2, and 9.4 months, and 1.5, 5.8, and 29.0 months from adv/met disease to larotrectinib initiation, respectively. Clinical outcomes were independent of line of therapy (ORR: 86%, 63%, and 80%, respectively; median DOR: 27.6, not reached, and 32.9 months), and similar across subgroups of short, medium, and long duration of pre-larotrectinib adv/met disease status (ORR: 88%, 65%, and 69%, respectively; median DOR: not reached, 27.6, and 32.9 months).

Conclusion: The short time from initial diagnosis to adv/met stage before larotrectinib suggests that gene fusion does not generally have a positive prognostic value. Patients on larotrectinib had high, sustained ORR, independent of number of prior therapies or duration of adv/met disease, suggesting that the effect of TRK inhibition in molecularly selected patients is independent of prior treatments or disease course.
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http://dx.doi.org/10.1200/PO.21.00089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457788PMC
September 2021

Bacitracin and Rutin Regulate Tissue Factor Production in Inflammatory Monocytes and Acute Myeloid Leukemia Blasts.

Cancers (Basel) 2021 Aug 4;13(16). Epub 2021 Aug 4.

II. Medizinische Klinik und Poliklinik, Universitätsklinikum Eppendorf, 20246 Hamburg, Germany.

Aberrant expression of tissue factor (TF) by transformed myeloblasts and inflammatory monocytes drives coagulation activation in acute myeloid leukemia (AML). Although regulation of TF procoagulant activity (PCA) involves thiol-disulfide exchange reactions, the specific role of protein disulfide isomerase (PDI) and other thiol isomerases in AML-associated TF biology is unclear. THP1 cells and peripheral blood mononuclear cells (PBMCs) from healthy controls or AML patients were analyzed for thiol isomerase-dependent TF production under various experimental conditions. Total cellular and membrane TF antigen, TF PCA and TF mRNA were analyzed by ELISA, flow cytometry, clotting or Xa generation assay and qPCR, respectively. PBMCs and THP1 cells showed significant insulin reductase activity, which was inhibited by bacitracin or rutin. Co-incubation with these thiol isomerase inhibitors prevented LPS-induced TF production by CD14-positive monocytes and constitutive TF expression by THP1 cells and AML blasts. Downregulation of the TF antigen was mainly restricted to the cryptic pool of TF, efficiently preventing phosphatidylserine-dependent TF activation by daunorubicin, and at least partially regulated on the mRNA level in LPS-stimulated monocytes. Our study thus delineates a complex role of thiol isomerases in the regulation of myeloid TF PCA, with PDI being a promising therapeutic target in the management of AML-associated coagulopathies.
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http://dx.doi.org/10.3390/cancers13163941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393688PMC
August 2021

Gender-specific problems and needs of family caregivers during specialist inpatient palliative care: a qualitative study on experiences of family caregivers and healthcare professionals.

Ann Palliat Med 2021 Aug 16;10(8):8571-8583. Epub 2021 Aug 16.

Palliative Care Unit, Department of Oncology, Hematology and BMT, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Previous studies have demonstrated gender-specific impacts on symptoms and problems of patients receiving palliative care; however, there is limited knowledge about the impact of gender on the problems and needs of their family caregivers (FCs).

Methods: Using a qualitative design, semi-structured interviews with FCs and healthcare professionals (HCPs) of a specialist palliative care inpatient ward were conducted. Themes and categories were identified using qualitative content analysis, with data coded using MAXQDA.

Results: Ten FCs (6 female, 4 male) and 16 HCPs (8 female, 8 male) were interviewed. Analysis revealed seven main categories of gendered problems and needs: role as FC, physical and emotional burden, self-care and coping strategies, adaptation to new life circumstances, interaction with the palliative care team, use of psychosocial or care-related support, as well as advance care planning and caregiving after inpatient palliative care. Stronger identification with the caregiver role, less consideration of own needs, and more active utilization of professional and informal support were ascribed to female FCs. With regard to male FCs, respondents had the impression of better self-caring strategies, less expressiveness of emotions, less involvement in care and more target-oriented interactions with the palliative care team.

Conclusions: Gender has a relevant impact on roles, coping, communication and support as well as psychosocial needs of FCs of patients receiving palliative care. These gender-related aspects have to be taken into account during palliative care including care for FCs.
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http://dx.doi.org/10.21037/apm-20-2553DOI Listing
August 2021

Molecular- and cytogenetic characterization of the associated (1;14) in a nodal marginal zone B-cell lymphoma case.

Leuk Lymphoma 2021 Aug 18:1-5. Epub 2021 Aug 18.

Department of Oncology and Hematology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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http://dx.doi.org/10.1080/10428194.2021.1966783DOI Listing
August 2021

AXL Inhibition Represents a Novel Therapeutic Approach in Negative Myeloproliferative Neoplasms.

Hemasphere 2021 Sep 11;5(9):e630. Epub 2021 Aug 11.

Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, Germany.

negative myeloproliferative neoplasms (MPNs) consist of essential thrombocythemia, polycythemia vera, and myelofibrosis. The majority of patients harbor the -activating mutation V617F. JAK2 inhibitors were shown to reduce symptom burden and splenomegaly in MPN patients. However, treatment options are limited after failure of JAK2 inhibitors. AXL, a member of the TAM family of receptor tyrosine kinases, mediates survival and therapy resistance of different myeloid cancers including acute myeloid leukemia and chronic myeloid leukemia. We studied the relevance of AXL as a target in MPN using primary patient cells and preclinical disease models. We found that AXL is abundantly activated in MPN cells and that its ligand growth arrest-specific gene 6 is upregulated in MPN patients. Pharmacologic and genetic blockade of AXL impaired viability, decreased proliferation and increased apoptosis of MPN cells. Interestingly, ruxolitinib treatment induced increased phosphorylation of AXL indicating that activation of AXL might mediate resistance to ruxolitinib. Consistently, the AXL inhibitor bemcentinib exerted additive effects with ruxolitinib via impaired STAT3, STAT5, and AKT signaling. Both agents had activity when employed alone and exerted an additive effect on survival and splenomegaly in vivo. Moreover, bemcentinib treatment normalized red blood cell count and hemoglobin levels in vivo. Thus, our data indicate that AXL inhibition represents a novel treatment option in MPN warranting clinical investigation.
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http://dx.doi.org/10.1097/HS9.0000000000000630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357258PMC
September 2021

Post-Vaccination Anti-SARS-CoV-2-Antibody Response in Patients with Multiple Myeloma Correlates with Low CD19+ B-Lymphocyte Count and Anti-CD38 Treatment.

Cancers (Basel) 2021 Jul 28;13(15). Epub 2021 Jul 28.

University Cancer Center Hamburg, Department of Oncology, Hematology and Bone Marrow Transplantation, Section of Pneumology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.

Few data are available regarding the efficacy of anti-SARS-CoV-2 vaccines in patients with hematological malignancies, and particular, plasma cell neoplasia. This ongoing single-center study aimed to describe the level of post-vaccination anti-SARS-CoV-2-antibodies depending on B lymphocyte count, current therapy, and remission status of patients with multiple myeloma and related plasma cell dyscrasia, after the first dose of anti-SARS-CoV-2 vaccination. The 82 patients included in this study received SARS-CoV-2 vaccines (including mRNA- and vector-based vaccines) as a routine measure. After the first vaccination, a positive SARS-CoV-2 spike protein antibody titer (SP-AbT) was detected in 23% of assessable patients. SARS-CoV-2 SP-AbT was significantly higher in patients with higher CD19+ B lymphocyte counts. A cut-off value of ≥30 CD19+ B cells/µL was significantly positive correlating with higher SARS-CoV-2 SP-AbT. In contrast, current treatment with anti-CD38-antibodies has led to significantly reduced SP-AbT titers. Furthermore, in multivariable linear regression, higher age and insufficiently controlled disease significantly correlated negatively with SARS-CoV-2 SP-AbT. Conversely, treatment with immunomodulatory drugs did not harm the development of antibody titers. Based on our results, the majority of myeloma patients respond poorly after receiving the first dose of any anti-SARS-CoV-2 vaccination and need booster vaccination.
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http://dx.doi.org/10.3390/cancers13153800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345197PMC
July 2021

Clinical and Biological Characteristics of Medullary and Extramedullary Plasma Cell Dyscrasias.

Biology (Basel) 2021 Jul 6;10(7). Epub 2021 Jul 6.

Clinic of Hematology and Stem Cell Transplantation, HELIOS Clinic Berlin-Buch, 13125 Berlin, Germany.

Extramedullary plasma cell (PC) disorders may occur as extramedullary disease in multiple myeloma (MM-EMD) or as primary extramedullary plasmocytoma (pEMP)/solitary osseous plasmocytoma (SOP). In this study, we aimed to obtain insights into the molecular mechanisms of extramedullary spread of clonal PC. Clinical and biological characteristics of 87 patients with MM-EMD ( = 49), pEMP/SOP ( = 20) and classical MM ( = 18) were analyzed by using immunohistochemistry (CXCR4, CD31, CD44 and CD81 staining) and cytoplasmic immunoglobulin staining combined with fluorescence hybridization (cIg-FISH). High expression of CD44, a cell-surface glycoprotein involved in cell-cell interactions, was significantly enriched in MM-EMD (90%) . pEMP/SOP (27%) or classical MM (33%) ( < 0.001). In addition, 1q21 amplification by clonal PC occurred at a similar frequency of MM-EMD (33%), pEMP/SOP (57%) and classical MM (44%). Conversely, del(17p13), t(4;14) and t(14;16) were completely absent in pEMP/SOP. Besides this, 1q21 amplification was identified in 64% of not paraskeletal samples from MM-EMD or pEMP compared to 9% of SOP or paraskeletal MM-EMD/pEMP and 44% of classical MM samples, respectively ( = 0.02). Expression of molecules involved in homing and cytogenetic aberrations differ between MM with or without EMD and pEMP/SOP.
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http://dx.doi.org/10.3390/biology10070629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301115PMC
July 2021

The BET bromodomain inhibitor ZEN-3365 targets the Hedgehog signaling pathway in acute myeloid leukemia.

Ann Hematol 2021 Dec 1;100(12):2933-2941. Epub 2021 Aug 1.

Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Modern cancer therapies increased the survival rates of acute myeloid leukemia (AML) patients tremendously. However, the complexity of the disease and the identification of new targets require the adaptation of treatment protocols to reduce side effects and increase benefit for the patients. One key regulator of leukemogenesis and chemotherapy resistance in AML is the Hedgehog (HH) signaling pathway. It is deregulated in numerous cancer entities and inhibition of its downstream transcription factors GLI translates into anti-leukemic effects. One major regulator of GLI is BRD4, a BET family member with epigenetic functions. We investigated the effect of ZEN-3365, a novel BRD4 inhibitor, on AML cells in regard to the HH pathway. We show that ZEN-3365 alone or in combination with GANT-61 reduced GLI promoter activity, cell proliferation and colony formation in AML cell lines and primary cells. Our findings strongly support the evaluation of the BRD4 inhibitor ZEN-3365 as a new therapeutic option in AML.
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http://dx.doi.org/10.1007/s00277-021-04602-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8592969PMC
December 2021

Lorlatinib Induces Durable Disease Stabilization in a Pancreatic Cancer Patient with a ROS1 p.L1950F Mutation: Case Report.

Oncol Res Treat 2021 28;44(9):495-502. Epub 2021 Jul 28.

Department of Hematology, Oncology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Introduction: The prognosis of pancreatic cancer has improved only modestly in recent years. This is partly due to the lack of development in precision oncology including immune oncology in this entity. Rearrangements of the proto-oncogene tyrosine protein kinase ROS1 gene represent driver alterations found especially in lung cancer. Tyrosine kinase inhibitors (TKI) with activity against ROS1 including lorlatinib substantially improved the outcome of this patient population. Anecdotal evidence reports treatment of pancreatic cancer harboring ROS1 fusions with ROS1 TKI, but data concerning treatment of patients with ROS1 point mutations are lacking.

Case Presentation: This case describes a pancreatic cancer patient harboring a ROS1 point mutation that occurred without an underlying ROS1 rearrangement and thus not in the resistance situation. The heavily pretreated patient showed a strong decrease of the tumor biomarkers (CA19-9 and CEA) and radiologically a durable stable disease to the targeted treatment with lorlatinib, thereby achieving a progression-free survival of 12 months.

Conclusion: Our data are the first to show a clinical benefit from targeted treatment with ROS1 TKI in a cancer patient with a thus far undescribed ROS1 point mutation without a concomitant ROS1 rearrangement. Furthermore, they indicate that ROS1 could be an oncogenic driver in pancreatic cancer. This subgroup could be eligible for targeted treatments, which may contribute to the urgently needed improvement in patient outcome.
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http://dx.doi.org/10.1159/000517616DOI Listing
October 2021

The developmental origin of cancers defines basic principles of cisplatin resistance.

Cancer Lett 2021 Oct 25;519:199-210. Epub 2021 Jul 25.

Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Universitätsstraße 1, 40225 Düsseldorf, Germany. Electronic address:

Cisplatin-based chemotherapy has been used for more than four decades as a standard therapeutic option in several tumor entities. However, being a multifaceted and heterogeneous phenomenon, inherent or acquired resistance to cisplatin remains a major obstacle during the treatment of several solid malignancies and inevitably results in disease progression. Hence, we felt there was an urgent need to evaluate common mechanisms between multifarious cancer entities to identify patient-specific therapeutic strategies. We found joint molecular and (epi)genetic resistance mechanisms and specific cisplatin-induced mutational signatures that depended on the developmental origin (endo-, meso-, ectoderm) of the tumor tissue. Based on the findings of thirteen tumor entities, we identified three resistance groups, where Group 1 (endodermal origin) prominently indicates NRF2-pathway activation, Group 2 (mesodermal origin, primordial germ cells) shares elevated DNA repair mechanisms and decreased apoptosis induction, and Group 3 (ectodermal and paraxial mesodermal origin) commonly presents deregulated apoptosis induction and alternating pathways as the main cisplatin-induced resistance mechanisms. This review further proposes potential and novel therapeutic strategies to improve the outcome of cisplatin-based chemotherapy.
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http://dx.doi.org/10.1016/j.canlet.2021.07.037DOI Listing
October 2021

PD-L1 targeting and subclonal immune escape mediated by PD-L1 mutations in metastatic colorectal cancer.

J Immunother Cancer 2021 07;9(7)

Department of Oncology and Hematology, Bone Marrow Transplantation with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Background: In patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), immune checkpoint blockade is ineffective, and combinatorial approaches enhancing immunogenicity need exploration.

Methods: We treated 43 patients with predominantly microsatellite stable wild-type mCRC on a phase II trial combining chemotherapy with the epidermal growth factor receptor antibody cetuximab and the programmed cell death ligand 1 (PD-L1) antibody avelumab. We performed next-generation gene panel sequencing for mutational typing of tumors and liquid biopsy monitoring as well as digital droplet PCR to confirm individual mutations. Translational analyses included tissue immunohistochemistry, multispectral imaging and repertoire sequencing of tumor-infiltrating T cells. Detected PD-L1 mutations were mechanistically validated in CRISPR/Cas9-generated cell models using qRT-PCR, immunoblotting, flow cytometry, complement-dependent cytotoxicity assay, antibody-dependent cytotoxicity by natural killer cell degranulation assay and LDH release assay as well as live cell imaging of T cell mediated tumor cell killing.

Results: Circulating tumor DNA showed rapid clearance in the majority of patients mirroring a high rate of early tumor shrinkage. In 3 of 13 patients expressing the high-affinity Fcγ receptor 3a (FcγR3a), tumor subclones with mutations were selected that led to loss of tumor PD-L1 by nonsense-mediated RNA decay in K162fs and protein degradation in L88S. As a consequence, avelumab binding and antibody-dependent cytotoxicity were impaired, while T cell killing of these variant clones was increased. Interestingly, mutant subclones showed slow selection dynamics reversing on avelumab withdrawal and patients with such subclones had above-average treatment benefit. This suggested that the mutations mediated resistance to direct antitumor effects of avelumab, while at the same time loss of PD-L1 reduced biological fitness by enhanced T cell killing limiting subclonal expansion.

Conclusion: The addition of avelumab to standard treatment appeared feasible and safe. mutations mediate subclonal immune escape to avelumab in some patients with mCRC expressing high-affinity FcγR3a, which may be a subset experiencing most selective pressure. Future trials evaluating the addition of avelumab to standard treatment in MSS mCRC are warranted especially in this patient subpopulation.

Trial Registration Number: NCT03174405.
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http://dx.doi.org/10.1136/jitc-2021-002844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317124PMC
July 2021

Patient assessment and feasibility of treatment in older patients with cancer: results from the IN-GHO Registry.

J Cancer Res Clin Oncol 2021 Nov 26;147(11):3183-3194. Epub 2021 Jul 26.

Department of Haematology, Oncology, Department of Palliative Care, University Hospital Jena, Am Klinikum 1, 07747, Jena, Germany.

Purpose: Predicting feasibility of treatment in older patients with cancer is a major clinical task. The Initiative Geriatrische Hämatologie und Onkologie (IN-GHO) registry prospectively collected data on the comprehensive geriatric assessment (CGA), physician's and patient's-self assessment of fitness for treatment, and the course of treatment in patients within a treatment decision aged ≥ 70 years.

Patients And Methods: The registry included 3169 patients from 93 centres and evaluated clinical course and treatment outcomes 2-3 and 6 months after initial assessment. Fitness for treatment was classified as fit, compromised and frail according to results of a CGA, and in addition by an experienced physician's and by patient's itself. Feasibility of treatment (termed IN-GHO-FIT) was defined as a composite endpoint, including willingness to undergo the same treatment again in retrospect, no modification or unplanned termination of treatment, and no early mortality (within 90 days).

Results: CGA classified 30.0% as fit, 35.8% as compromised, and 34.2% as frail. Physician's and patient's-self assessment classified 61.8%/52.3% as fit, 34.2%/42.4% as compromised, and 3.9%/5.3%, as frail, respectively. Survival status at day 180 was available in 2072 patients, of which 625 (30.2%) had died. After 2-3 months, feasibility of treatment could be assessed in 1984 patients. 62.8% fulfilled IN-GHO®-FIT criteria. Multivariable analysis identified physician's assessment as the single most important item regarding feasibility of treatment.

Conclusion: Geriatricians were involved in 2% of patients only. Classification of fitness for treatment by CGA, and physician's or patient's-self assessment showed marked discrepancies. For the prediction of feasibility of treatment no single item was superior to physician's assessment. However CGA was not performed by trained geriatricians.
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http://dx.doi.org/10.1007/s00432-021-03714-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484105PMC
November 2021

Immune thrombocytopenic purpura after vaccination with COVID-19 vaccine (ChAdOx1 nCov-19).

Blood 2021 09;138(11):996-999

Division of Pneumology, Department of Oncology, Hematology, and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and.

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http://dx.doi.org/10.1182/blood.2021012790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313798PMC
September 2021

Outcome of a Real-World Patient Cohort with Secondary CNS Lymphoma Treated with High-Intensity Chemoimmunotherapy and Autologous Stem Cell Transplantation.

Oncol Res Treat 2021 21;44(7-8):375-381. Epub 2021 Jul 21.

Department of Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Aggressive non-Hodgkin lymphomas with secondary central nervous system (CNS) involvement bear a dismal prognosis. Optimal treatment remains so far unclear, and effective treatment options remain an unmet clinical need. Remission rates are in general low, resulting in rapid relapses and palliative care in the majority of patients. High-intensity treatment combining effective CNS-directed chemoimmunotherapy with autologous stem cell transplantation was shown in a recent phase 2 trial to induce durable remissions. Here, we report the outcome of the first real-world patient cohort treated according to the published protocol.

Methods: We retrospectively identified 17 HIV-negative lymphoma patients with secondary CNS involvement, either at first diagnosis or at relapse of lymphoma, treated according to the study protocol published by Ferreri et al. [J Clin Oncol. 2015] at two university medical centers in Germany. Treatment consisted of four cycles of chemoimmunotherapy with a consolidating autologous stem cell transplantation. Adverse events and overall outcome were assessed.

Results: Five patients had CNS involvement at first diagnosis and 12 patients at relapse of lymphoma. A complete response was achieved in 9 patients. Median survival was 11 months. Five patients died of septic complications and 4 patients succumbed to progression or relapse of disease.

Conclusions: The outcome of our real-world cohort emphasizes the possible toxic character of the treatment protocol by Ferreri et al. [J Clin Oncol. 2015]. Further improvement in treatment regimens is still an unmet need.
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http://dx.doi.org/10.1159/000517531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495762PMC
September 2021

Monocyte activation and acquired autoimmune protein S deficiency promote disseminated intravascular coagulation in a patient with primary antiphospholipid syndrome.

Res Pract Thromb Haemost 2021 Jul 28;5(5):e12559. Epub 2021 Jun 28.

Department of Hematology and Oncology University Cancer Center Hamburg (UCCH) University Medical Center Eppendorf Hamburg Germany.

Autoimmune protein S (PS) deficiency is a highly thrombotic, potentially life-threatening disorder. Its pathophysiological relevance in the context of primary antiphospholipid syndrome (APS) is unclear. Here, we report the case of a 76-year-old woman, who presented with a painful reticular skin erythema caused by microvascular thromboses. Disseminated intravascular coagulation (DIC) with consumptive coagulopathy was controlled only by continuous anticoagulation. While significantly elevated IgM antibodies to cardiolipin and β-glycoprotein-I were consistent with primary APS, a function-blocking PS autoantibody of the IgG isotype was detected. Robust microvesicle (MV)-associated tissue factor (TF) procoagulant activity (PCA) was isolated from patient plasma. Moreover, patient IgG, but not IgM, induced expression of TF PCA and release of TF-bearing MVs by peripheral blood mononuclear cells from healthy donors. In primary APS, induction of monocyte TF in combination with an acquired PS inhibitor may provoke a deleterious imbalance of procoagulant and anticoagulant pathways with evolution of thrombotic DIC.
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http://dx.doi.org/10.1002/rth2.12559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265818PMC
July 2021

Impact of geography on prognostic outcomes of 21,509 patients with metastatic colorectal cancer enrolled in clinical trials: an ARCAD database analysis.

Ther Adv Med Oncol 2021 30;13:17588359211020547. Epub 2021 Jun 30.

Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France.

Background: Benchmarking international cancer survival differences is necessary to evaluate and improve healthcare systems. Our aim was to assess the potential regional differences in outcomes among patients with metastatic colorectal cancer (mCRC) participating in international randomized clinical trials (RCTs).

Design: Countries were grouped into 11 regions according to the World Health Organization and the EUROCARE model. Meta-analyses based on individual patient data were used to synthesize data across studies and regions and to conduct comparisons for outcomes in a two-stage random-effects model after adjusting for age, sex, performance status, and time period. We used mCRC patients enrolled in the first-line RCTs from the ARCAD database, which provided enrolling country information. There were 21,509 patients in 27 RCTs included across the 11 regions.

Results: Main outcomes were overall survival (OS) and progression-free survival (PFS). Compared with other regions, patients from the United Kingdom (UK) and Ireland were proportionaly over-represented, older, with higher performance status, more frequently male, and more commonly not treated with biological therapies. Cohorts from central Europe and the United States (USA) had significantly longer OS compared with those from UK and Ireland ( = 0.0034 and  < 0.001, respectively), with median difference of 3-4 months. The survival deficits in the UK and Ireland cohorts were, at most, 15% at 1 year. No evidence of a regional disparity was observed for PFS. Among those treated without biological therapies, patients from the UK and Ireland had shorter OS than central Europe patients ( < 0.001).

Conclusions: Significant international disparities in the OS of cohorts of mCRC patients enrolled in RCTs were found. Survival of mCRC patients included in RCTs was consistently lower in the UK and Ireland regions than in central Europe, southern Europe, and the USA, potentially attributed to greater overall population representation, delayed diagnosis, and reduced availability of therapies.
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http://dx.doi.org/10.1177/17588359211020547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252342PMC
June 2021

Prognostic and Predictive Impact of Primary Tumor Sidedness for Previously Untreated Advanced Colorectal Cancer.

J Natl Cancer Inst 2021 Jun 1. Epub 2021 Jun 1.

Department of Gastrointestinal Onocology, Keck School of Medicine at USC, Los Angeles, CA, USA.

Background: Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the impact of PTS on outcomes of mCRC patients.

Methods: PTS data of 9,277 mCRC patients from 12 first-line randomized trials in the ARCAD database were pooled. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status, prior radiation/chemo, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (cetuximab plus chemotherapy vs. chemotherapy alone). All statistical tests were 2-sided.

Results: Compared to right-sided metastatic colorectal cancer patients (n = 2421, 26.1%), left-sided metastatic colorectal cancer patients (n = 6856, 73.9%) had better OS (median = 21.6 v 15.9 months; adjusted hazard ratio [HRadj] = 0.71, 95% confidence interval [CI] = 0.67-0.76, P<.001) and PFS (median = 8.6 v 7.5 months; HRadj = 0.80, 95% CI = 0.75-0.84, P<.001). Interaction between PTS and KRAS mutation was statistically significant (Pinteraction<.001): left-sidedness was associated with better prognosis among KRAS wild-type (WT) (OS HRadj = 0.59, 95% CI = 0.53-0.66; PFS HRadj =0.68, 95% CI = 0.61-0.75), but not among KRAS mutated tumors. Among KRAS-WT tumors, survival benefit from anti-EGFR was confirmed for left-sidedness (OS HRadj = 0.85, 95% CI = 0.75-0.97, P = .01; PFS HRadj = 0.77, 95% CI = 0.67-0.88, P<.001), but not for right-sidedness.

Conclusions: The prognostic value of PTS is restricted to the KRAS-WT population. PTS is predictive of anti-EGFR efficacy, with a statistically significant improvement of survival for left-sidedness mCRC patients. These results suggest treatment choice in mCRC should be based on both PTS and KRAS status.
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http://dx.doi.org/10.1093/jnci/djab112DOI Listing
June 2021

Developing a Framework for the Health Technology Assessment of Histology-independent Precision Oncology Therapies.

Appl Health Econ Health Policy 2021 09 24;19(5):625-634. Epub 2021 May 24.

London School of Hygiene and Tropical Medicine, London, UK.

The arrival of precision oncology is challenging the evidence standards under which technologies are evaluated for regulatory approval as well as for health technology assessment (HTA) purposes. Several key concepts are discussed to highlight the source of the challenges in evaluating these products, particularly those impacting the HTA of histology-independent therapies. These include the basket trial design, high uncertainty in (potentially substantial) benefits for histology-independent therapies, and the inability to identify and quantify benefits of standard of care in daily practice when the biomarker is not currently used in practice. There is little precedent for a technology with the unique mixture of challenges for HTA of histology-independent therapies and they will be evaluated using standard HTA, as there currently is no evidence suggesting the standard HTA framework is not appropriate. A number of questions proposed to help guide HTA bodies when assessing the appropriateness of local processes to optimally evaluate histology-independent therapies. Pragmatic solutions are further proposed to decrease uncertainty in the benefits of histology independent therapies as well as fill gaps in comparative evidence. The proposed solutions ensure a consistent and streamlined approach to evaluation across histology-independent products, although with varying strengths and limitations. Alongside these solutions, sponsors should engage early with HTA bodies/payers and regulatory agencies through parallel/joint scientific advice to facilitate the integration of both regulatory and HTA perspectives into one clinical development programme, potentially reconciling evidence requirements.
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http://dx.doi.org/10.1007/s40258-021-00654-4DOI Listing
September 2021
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