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Richard Greil

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Kansas State University

Armando Marques-Guedes

UNL - New University of Lisbon

Case Western Reserve University

Merrill L Gassman

University of Illinois at Chicago

Santiago Arango Muñoz

Universidad de Antioquia

Dr Noore Alam Tufani

Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST)

Dr. A K M Mominul Islam

Bangladesh Agricultural University

Abdulrahman Bello (DVM, MSc, PhD)

Usmanu Danfodio University, Sokoto

Darwin H . Pangaribuan

The University Of Lampung

Universidad Nacional de Educación "Enrique Guzmán y Valle

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Papers by Richard Greil

Outcome of Patients With Early-Stage Infradiaphragmatic Hodgkin Lymphoma: A Comprehensive Analysis From the German Hodgkin Study Group

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2018

Purpose The prognostic effect of isolated infradiaphragmatic involvement in Hodgkin lymphoma (HL)... more Purpose The prognostic effect of isolated infradiaphragmatic involvement in Hodgkin lymphoma (HL) is controversial, and there are little data about patients treated with current therapies. Therefore, we performed a risk factor analysis to focus on isolated nodal infradiaphragmatic disease in patients treated within the German Hodgkin Study Group trials HD13 (clinical trial information: ISRCTN63474366) and HD14 (clinical trial information: ISRCTN04761296) for early-stage HL. Patients and Methods Characteristics and outcomes of patients who had infradiaphragmatic HL were compared with patients who had supradiaphragmatic disease. Progression-free survival (PFS) and overall survival (OS) were estimated according to Kaplan-Meier methods and were compared between groups using the log-rank test and Cox proportional hazards regression, which was also applied for multivariable analyses that adjusted for relevant baseline characteristics. Results Of 2,903 qualified patients, 223 (7.7%) were d...

Cytomegalovirus reactivation and its clinical impact in patients with solid tumors

Infectious Agents and Cancer, 2015

Targeted therapy in advanced metastatic colorectal cancer: Current concepts and perspectives

World Journal of Gastroenterology, 2014

The introduction of new cytotoxic substances as well as agents that target vascular endothelial g... more The introduction of new cytotoxic substances as well as agents that target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling has improved clinical outcome of patients with metastatic colorectal cancer (mCRC). In this review we summarize the most relevant clinical data on VEGF and EGFR targeting regimens in mCRC. The effects of available treatment strategies for mCRC are often temporary, with resistance and disease progression developing in most patients. Thus, new treatment strategies are urgently needed. Some GI peptides including gastrin and gastrin releasing peptide, certain growth factors such as insulin-like growth factor-I and II and neuropeptides such as growth hormone releasing hormone (GHRH) are implicated in the growth of CRC. Experimental investigations in CRC with antagonistic analogs of bombesin/gastrin-releasing peptide, GHRH, and with cytotoxic peptides that can be targeted to peptide receptors on tumors, are summarized in the second part of the review.

Reduced Treatment Intensity in Patients with Early-Stage Hodgkin's Lymphoma

New England Journal of Medicine, 2010

The Nationwide Austrian Aspergillus Registry: a prospective data collection on epidemiology, therapy and outcome of invasive mould infections in immunocompromised and/or immunosuppressed patients

International Journal of Antimicrobial Agents, 2010

HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Systemic effect of catumaxomab in a patient with metastasized colorectal cancer: a case report

BMC Cancer, 2013

Background Catumaxomab, the first anti-EpCAM antibody, was approved in 2009 for the treatment of ... more Background Catumaxomab, the first anti-EpCAM antibody, was approved in 2009 for the treatment of malignant ascites in cancer patients with EpCAM positive tumors. We consider this case of interest as treatment with catumaxomab not only prolonged the puncture-free interval but also showed a systemic effect in a patient with metastasized colorectal cancer by regression of a pulmonary metastasis. Case presentation We describe the case of a 78 year old patient initially diagnosed with locally advanced colon cancer and one synchronous liver metastasis in September 2010 who was treated by hemicolectomy and simultaneous atypical liver resection. During adjuvant chemotherapy the patient developed a peritoneal carcinomatosis with ascites in March 2011. Palliative chemotherapy was not well tolerated and therefore refused by the patient. Because of disease progression in June 2011 with one pulmonary metastasis and clinically predominant ascites an immunotherapy with intraperitoneal catumaxomab ...

Lenalidomide Maintenance Compared With Placebo in Responding Elderly Patients With Diffuse Large B-Cell Lymphoma Treated With First-Line Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone

Journal of Clinical Oncology, 2017

Purpose The standard treatment of patients with diffuse large B-cell lymphoma (DLBCL) is rituxima... more Purpose The standard treatment of patients with diffuse large B-cell lymphoma (DLBCL) is rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Lenalidomide, an immunomodulatory agent, has shown activity in DLBCL. This randomized phase III trial compared lenalidomide as maintenance therapy with placebo in elderly patients with DLBCL who achieved a complete response (CR) or partial response (PR) to R-CHOP induction. Methods Patients with previously untreated DLBCL or other aggressive B-cell lymphoma were 60 to 80 years old, had CR or PR after six or eight cycles of R-CHOP, and were randomly assigned to lenalidomide maintenance 25 mg/d or placebo for 21 days of every 28-day cycle for 24 months. The primary end point was progression-free survival (PFS). Results A total of 650 patients were randomly assigned. At the time of the primary analysis (December 2015), with a median follow-up of 39 months from random assignment, median PFS was not rea...

MDM2 promotor polymorphism and disease characteristics in CLL

Leukemia Research, 2010

CD18 (ITGB2) expression in chronic lymphocytic leukaemia is regulated by DNA methylation‐dependent and ‐independent mechanisms

British Journal of Haematology, 2014

Maintaining Bone Density in Patients Undergoing Treatment for Breast Cancer: Is There an Adjuvant Benefit?

Clinical Breast Cancer, 2009

Breast cancer is the most common cancer and the leading cause of cancer-related deaths among wome... more Breast cancer is the most common cancer and the leading cause of cancer-related deaths among women worldwide. 1 The annual global incidence of breast cancer is estimated to be > 1.3 million cases, and approximately 465,000 women die of this disease every year. Advances in technologies for early diagnosis and therapies for breast cancer have substantially improved survival and clinical outcomes in recent years, especially in the United States and other developed countries. 2 Treatment of breast cancer includes surgical resection and systemic therapy; chemotherapy is used extensively in the metastatic setting and in the treatment of hormone receptor-negative breast cancer, whereas hormonal (endocrine) therapy has become the standard adjuvant treatment option for hormone receptor-positive breast cancer. 2,3 Patients and Methods A systematic survey of published literature, recent reports at scientific congresses, and clinical trial registries was performed to identify key data pertaining to cancer therapy-associated bone loss

The CXCR4 and adhesion molecule expression of CD34+ hematopoietic cells mobilized by “on‐demand” addition of plerixafor to granulocyte–colony‐stimulating factor

Transfusion, 2014

BackgroundGranulocyte–colony‐stimulating factor (G‐CSF) is routinely used for mobilization of hem... more BackgroundGranulocyte–colony‐stimulating factor (G‐CSF) is routinely used for mobilization of hematopoietic stem and progenitor cells preceding autologous transplantation after high‐dose chemotherapy in hematologic malignancies. However, due to high mobilization failure rates, alternative mobilization strategies are required.Study Design and MethodsPatients who poorly mobilized CD34+ hematopoietic cells (HCs) with G‐CSF additionally received the CXCR4 antagonist plerixafor. The phenotype of CD34+ HCs collected after this plerixafor‐induced “rescue” mobilization, in regard to adhesion molecule and CD133, CD34, and CD38 expression in comparison to CD34+ HCs collected after traditional G‐CSF administration in good mobilizers, was analyzed flow cytometrically. To confirm previous studies in our patient cohort, the efficiency of mobilization and subsequent engraftment after this “on‐demand” plerixafor mobilization were analyzed.ResultsPronounced mobilization occurred after plerixafor adm...

Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial

The Lancet Oncology, 2011

Background Analysis of the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) ... more Background Analysis of the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) at 48 months' follow-up showed that addition of zoledronic acid to adjuvant endocrine therapy signifi cantly improved disease-free survival. We have now assessed long-term clinical effi cacy including disease-free survival and disease outcomes in patients receiving anastrozole or tamoxifen with or without zoledronic acid. Methods ABSCG-12 is a randomised, controlled, open-label, two-by-two factorial, multicentre trial in 1803 pre menopausal women with endocrine-receptor-positive early-stage (stage I-II) breast cancer receiving goserelin (3•6 mg every 28 days), comparing the effi cacy and safety of anastrozole (1 mg per day) or tamoxifen (20 mg per day) with or without zoledronic acid (4 mg every 6 months) for 3 years. Randomisation (1:1:1:1 ratio) was computerised and based on the Pocock and Simon minimisation method to balance the four treatment arms across eight prognostic variables (age, neoadjuvant chemotherapy, pathological tumour stage; lymph-node involvement, type of surgery or locoregional therapy, complete axillary dissection, intraoperative radiation therapy, and geographical region). Treatment allocation was not masked. The primary endpoint was disease-free survival (defi ned as disease recurrence or death) and analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00295646; follow-up is ongoing. Findings At a median follow-up of 62 months (range 0-114•4 months), more than 2 years after treatment completion, 186 disease-free survival events had been reported (53 events in 450 patients on tamoxifen alone, 57 in 453 patients on anastrozole alone, 36 in 450 patients on tamoxifen plus zoledronic acid, and 40 in 450 patients on anastrozole plus zoledronic acid). Zoledronic acid reduced risk of disease-free survival events overall (HR 0•68, 95% CI 0•51-0•91; p=0•009), although the diff erence was not signifi cant in the tamoxifen (HR 0•67, 95% CI 0•44-1•03; p=0•067) and anastrozole arms (HR 0•68, 95% CI 0•45-1•02; p=0•061) assessed separately. Zoledronic acid did not signifi cantly aff ect risk of death (30 deaths with zoledronic acid vs 43 deaths without; HR 0•67, 95% CI 0•41-1•07; p=0•09). There was no diff erence in disease-free survival between patients on tamoxifen alone versus anastrozole alone (HR 1•08, 95% CI 0•81-1•44; p=0•591), but overall survival was worse with anastrozole than with tamoxifen (46 vs 27 deaths; HR 1•75, 95% CI 1•08-2•83; p=0•02). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. Bone pain was reported in 601 patients (33%; 349 patients on zoledronic acid vs 252 not on the drug), fatigue in 361 (20%; 192 vs 169), headache in 280 (16%; 147 vs 133), and arthralgia in 266 (15%; 145 vs 121). Interpretation Addition of zoledronic acid improved disease-free survival in the patients taking anastrozole or tamoxifen. There was no diff erence in disease-free survival between patients receiving anastrozole and tamoxifen overall, but those on anastrozole alone had inferior overall survival. These data show persistent benefi ts with zoledronic acid and support its addition to adjuvant endocrine therapy in premenopausal patients with early-stage breast cancer. Funding AstraZeneca; Novartis.

A New Molecular Predictor of Distant Recurrence in ER-Positive, HER2-Negative Breast Cancer Adds Independent Information to Conventional Clinical Risk Factors

Clinical Cancer Research, 2011

Purpose: According to current guidelines, molecular tests predicting the outcome of breast cancer... more Purpose: According to current guidelines, molecular tests predicting the outcome of breast cancer patients can be used to assist in making treatment decisions after consideration of conventional markers. We developed and validated a gene expression signature predicting the likelihood of distant recurrence in patients with estrogen receptor (ER)–positive, HER2-negative breast cancer treated with adjuvant endocrine therapy. Experimental Design: RNA levels assessed by quantitative reverse transcriptase PCR in formalin-fixed, paraffin-embedded tumor tissue were used to calculate a risk score (Endopredict, EP) consisting of eight cancer-related and three reference genes. EP was combined with nodal status and tumor size into a comprehensive risk score, EPclin. Both prespecified risk scores including cutoff values to determine a risk group for each patient (low and high) were validated independently in patients from two large randomized phase III trials [Austrian Breast and Colorectal Canc...

The Austrian fulvestrant registry: results from a prospective observation of fulvestrant in postmenopausal patients with metastatic breast cancer

Breast Cancer Research and Treatment, 2008

Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone

Annals of Oncology, 2013

Background: PAM50 is a 50-gene test that is designed to identify intrinsic breast cancer subtypes... more Background: PAM50 is a 50-gene test that is designed to identify intrinsic breast cancer subtypes and generate a Risk of Recurrence (ROR) score. It has been developed to be carried out in qualified routine hospital pathology laboratories. Patients and Methods: One thousand four hundred seventy-eight postmenopausal women with estrogen receptor (ER)+ early breast cancer (EBC) treated with tamoxifen or tamoxifen followed by anastrozole from the prospective randomized ABCSG-8 trial were entered into this study. Patients did not receive adjuvant chemotherapy. RNA was extracted from paraffin blocks and analyzed using the PAM50 test. Both intrinsic subtype (luminal A/B, HER2-enriched, basal-like) and ROR score were calculated. The primary analysis was designed to test whether the continuous ROR score adds prognostic value in predicting distant recurrence (DR) over and above standard clinical variables. Results: In all tested subgroups, ROR score significantly adds prognostic information to the clinical predictor (P < 0.0001). PAM50 assigns an intrinsic subtype to all cases, and the luminal A cohort had a significantly lower ROR at 10 years compared with Luminal B (P < 0.0001). Significant and clinically relevant discrimination between low-and highrisk groups occurred also within all tested subgroups. Conclusion(s): The results of the primary analysis, in combination with recently published results from the ATAC trial, constitute Level 1 evidence for clinical validity of the PAM50 test for predicting the risk of DR in postmenopausal women with ER+ EBC. A 10-year metastasis risk of <3.5% in the ROR low category makes it unlikely that additional chemotherapy would improve this outcome-this finding could help to avoid unwarranted overtreatment.

A prospective multicenter pilot study to investigate the efficacy of pegylated Interferon-α2b and ribavirin in HBsAg+/HCV-RNA+ patients: The HEP-NET B/C coinfection trial

Zeitschrift für Gastroenterologie, 2008

Introduction Despite advances in adjuvant chemotherapy, 20-30% of patients in stages II-III color... more Introduction Despite advances in adjuvant chemotherapy, 20-30% of patients in stages II-III colorectal cancer will eventually relapse. Observational studies showed a reduction in relapse rate, colon cancer-specific mortality, and overall mortality by physical activity. Results from prospective randomized interventional studies to confirm these observational data are lacking. The aims of this prospective single-arm multicenter pilot study are to evaluate feasibility and safety of exercise training after adjuvant chemotherapy in colorectal cancer patients. Patients and methods The training was performed three times per week for 1 year and was increased gradually in three phases until reaching 18 metabolic equivalent task hours per week. Results Overall, 30 patients were included. The planned training intensity could be achieved in all three phases. Patients experienced a performance increase of median 35.5 watt, a weight-loss of a median of 3.0 kg, and a reduction in body fat content of median 1.0% during this exercise training. The analysis showed early study termination due to noncompliance in 10/30 patients (33.3%), disease progression in 4 patients (13.3%), and serious adverse events in 2 patients (6.7%). About half of patients (46.7%) completed the pilot study as planned. Biomarker analysis from 20 patients showed a non-significant reduction in insulin-like growth factor 1 (IGF-1), insulin-like growth factor 2 (IGF-2) and insulin-like growth factor binding protein 3 (IGF-BP3) levels, significant increases in adiponectin and leptin levels, and a nonsignificant increase in C-peptide levels. Conclusion Exercise training is feasible in patients with colorectal cancer after completion of adjuvant chemotherapy. The main problem encountered during the study was compliance. To improve compliance of exercise training, several measures were adapted for the upcoming prospective randomized ABCSG C08 Exercise II study.

Cardiotoxicity with rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in frontline treatment of patients with diffuse large B-cell lymphoma: A randomised phase-III stud...

European journal of cancer (Oxford, England : 1990), Jan 15, 2016

Chemoimmunotherapy containing rituximab, cyclophosphamide, doxorubicin, vincristine, and predniso... more Chemoimmunotherapy containing rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) is the standard treatment for diffuse large B-cell lymphoma (DLBCL). Doxorubicin may induce early and late cardiotoxicity. Non-pegylated liposomal (NPL) doxorubicin may reduce cardiotoxicity. Patients with untreated CD20+ DLBCL were randomised to conventional R-CHOP chemoimmunotherapy or rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone (R-COMP) with doxorubicin substituted by NPL-doxorubicin. Left ventricular ejection fraction (LVEF) and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels were measured before each treatment cycle and after the end of treatment. The mean LVEF of 178 and 158 measurements in the R-COMP and R-CHOP arms was 63.31% and 62.25%, respectively (P = 0.167). During treatment the LVEF measurements were below 50% in 10/218 (4.6%) in the R-COMP arm and 31/196 (15.8%) in the R-CHOP arm (P<0.001). Th...

The AKT 1 isoform plays a dominant role in the survival and chemoresistance of chronic lymphocytic leukaemia cells

British Journal of Haematology, 2015

A. (2012) A prognostic model to predict survival in 867 World Health Organization-defined essenti... more

Rituximab maintenance for patients with aggressive B-cell lymphoma in first remission: results of the randomized NHL13 trial

Haematologica, Jan 24, 2015

We investigated rituximab maintenance therapy in patients with diffuse large B-cell lymphoma (N=6... more We investigated rituximab maintenance therapy in patients with diffuse large B-cell lymphoma (N=662) or follicular lymphoma grade 3b (N=21) in first complete remission. Patients were randomised for rituximab maintenance (N=338) or observation (N=345). At a median follow-up of 45 months, event-free survival (primary endpoint) at 3 years was 80.4% for rituximab maintenance vs. 76.5% for observation. This difference was not significant for the intent to treat population (Likelihood ratio p=0.0670). The hazard ratio by treatment arm was 0.79 (95% confidence interval 0.57-1.08; p=0.1433). The secondary endpoint progression-free survival was also not met for the whole population (Likelihood ratio p=0.3646). Of note, rituximab maintenance was superior to observation when treatment arms only were compared (Hazard ratio: 0.62; 95% confidence interval 0.43-0.90; p=0.0120). Overall survival remained unchanged (92.0 vs. 90.3%). In subgroup analysis male patients benefitted from rituximab mainte...

CXCL12-induced VLA-4 activation is impaired in trisomy 12 chronic lymphocytic leukemia cells: a role for CCL21

Oncotarget, Jan 26, 2015

Homing to distinct lymphoid organs enables chronic lymphocytic leukemia (CLL) cells to receive pr... more Homing to distinct lymphoid organs enables chronic lymphocytic leukemia (CLL) cells to receive pro-survival and proliferative signals. Cytogenetic aberrations can significantly affect CLL cell compartmentalization. Trisomy 12 (tri12) defines a CLL subgroup with specific clinical features and increased levels of the negative prognostic marker CD49d, the α4-subunit of the integrin VLA-4, which is a key regulator of CLL cell homing to bone marrow (BM). Chemokine-induced inside-out VLA-4 activation, particularly via the CXCL12-CXCR4 axis, increases the arrest of various cell types on VCAM-1 presenting endothelium. Here, we demonstrate that high CD49d expression in tri12 CLL is accompanied by decreased CXCR4 expression. Dissecting functional consequences of these alterations, we observed that tri12 CLL cell homing to murine BM is not affected by CXCR4-CXCL12 blockage using AMD3100 or olaptesed pegol/NOX-A12. In line, CCL21-CCR7 rather than CXCL12-CXCR4 interactions triggered VLA-4-mediat...

Outcome of Patients With Early-Stage Infradiaphragmatic Hodgkin Lymphoma: A Comprehensive Analysis From the German Hodgkin Study Group

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2018

Purpose The prognostic effect of isolated infradiaphragmatic involvement in Hodgkin lymphoma (HL)... more Purpose The prognostic effect of isolated infradiaphragmatic involvement in Hodgkin lymphoma (HL) is controversial, and there are little data about patients treated with current therapies. Therefore, we performed a risk factor analysis to focus on isolated nodal infradiaphragmatic disease in patients treated within the German Hodgkin Study Group trials HD13 (clinical trial information: ISRCTN63474366) and HD14 (clinical trial information: ISRCTN04761296) for early-stage HL. Patients and Methods Characteristics and outcomes of patients who had infradiaphragmatic HL were compared with patients who had supradiaphragmatic disease. Progression-free survival (PFS) and overall survival (OS) were estimated according to Kaplan-Meier methods and were compared between groups using the log-rank test and Cox proportional hazards regression, which was also applied for multivariable analyses that adjusted for relevant baseline characteristics. Results Of 2,903 qualified patients, 223 (7.7%) were d...

Cytomegalovirus reactivation and its clinical impact in patients with solid tumors

Infectious Agents and Cancer, 2015

Targeted therapy in advanced metastatic colorectal cancer: Current concepts and perspectives

World Journal of Gastroenterology, 2014

The introduction of new cytotoxic substances as well as agents that target vascular endothelial g... more The introduction of new cytotoxic substances as well as agents that target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling has improved clinical outcome of patients with metastatic colorectal cancer (mCRC). In this review we summarize the most relevant clinical data on VEGF and EGFR targeting regimens in mCRC. The effects of available treatment strategies for mCRC are often temporary, with resistance and disease progression developing in most patients. Thus, new treatment strategies are urgently needed. Some GI peptides including gastrin and gastrin releasing peptide, certain growth factors such as insulin-like growth factor-I and II and neuropeptides such as growth hormone releasing hormone (GHRH) are implicated in the growth of CRC. Experimental investigations in CRC with antagonistic analogs of bombesin/gastrin-releasing peptide, GHRH, and with cytotoxic peptides that can be targeted to peptide receptors on tumors, are summarized in the second part of the review.

Reduced Treatment Intensity in Patients with Early-Stage Hodgkin's Lymphoma

New England Journal of Medicine, 2010

The Nationwide Austrian Aspergillus Registry: a prospective data collection on epidemiology, therapy and outcome of invasive mould infections in immunocompromised and/or immunosuppressed patients

International Journal of Antimicrobial Agents, 2010

HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Systemic effect of catumaxomab in a patient with metastasized colorectal cancer: a case report

BMC Cancer, 2013

Background Catumaxomab, the first anti-EpCAM antibody, was approved in 2009 for the treatment of ... more Background Catumaxomab, the first anti-EpCAM antibody, was approved in 2009 for the treatment of malignant ascites in cancer patients with EpCAM positive tumors. We consider this case of interest as treatment with catumaxomab not only prolonged the puncture-free interval but also showed a systemic effect in a patient with metastasized colorectal cancer by regression of a pulmonary metastasis. Case presentation We describe the case of a 78 year old patient initially diagnosed with locally advanced colon cancer and one synchronous liver metastasis in September 2010 who was treated by hemicolectomy and simultaneous atypical liver resection. During adjuvant chemotherapy the patient developed a peritoneal carcinomatosis with ascites in March 2011. Palliative chemotherapy was not well tolerated and therefore refused by the patient. Because of disease progression in June 2011 with one pulmonary metastasis and clinically predominant ascites an immunotherapy with intraperitoneal catumaxomab ...

Lenalidomide Maintenance Compared With Placebo in Responding Elderly Patients With Diffuse Large B-Cell Lymphoma Treated With First-Line Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone

Journal of Clinical Oncology, 2017

Purpose The standard treatment of patients with diffuse large B-cell lymphoma (DLBCL) is rituxima... more Purpose The standard treatment of patients with diffuse large B-cell lymphoma (DLBCL) is rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Lenalidomide, an immunomodulatory agent, has shown activity in DLBCL. This randomized phase III trial compared lenalidomide as maintenance therapy with placebo in elderly patients with DLBCL who achieved a complete response (CR) or partial response (PR) to R-CHOP induction. Methods Patients with previously untreated DLBCL or other aggressive B-cell lymphoma were 60 to 80 years old, had CR or PR after six or eight cycles of R-CHOP, and were randomly assigned to lenalidomide maintenance 25 mg/d or placebo for 21 days of every 28-day cycle for 24 months. The primary end point was progression-free survival (PFS). Results A total of 650 patients were randomly assigned. At the time of the primary analysis (December 2015), with a median follow-up of 39 months from random assignment, median PFS was not rea...

MDM2 promotor polymorphism and disease characteristics in CLL

Leukemia Research, 2010

CD18 (ITGB2) expression in chronic lymphocytic leukaemia is regulated by DNA methylation‐dependent and ‐independent mechanisms

British Journal of Haematology, 2014

Maintaining Bone Density in Patients Undergoing Treatment for Breast Cancer: Is There an Adjuvant Benefit?

Clinical Breast Cancer, 2009

Breast cancer is the most common cancer and the leading cause of cancer-related deaths among wome... more Breast cancer is the most common cancer and the leading cause of cancer-related deaths among women worldwide. 1 The annual global incidence of breast cancer is estimated to be > 1.3 million cases, and approximately 465,000 women die of this disease every year. Advances in technologies for early diagnosis and therapies for breast cancer have substantially improved survival and clinical outcomes in recent years, especially in the United States and other developed countries. 2 Treatment of breast cancer includes surgical resection and systemic therapy; chemotherapy is used extensively in the metastatic setting and in the treatment of hormone receptor-negative breast cancer, whereas hormonal (endocrine) therapy has become the standard adjuvant treatment option for hormone receptor-positive breast cancer. 2,3 Patients and Methods A systematic survey of published literature, recent reports at scientific congresses, and clinical trial registries was performed to identify key data pertaining to cancer therapy-associated bone loss

The CXCR4 and adhesion molecule expression of CD34+ hematopoietic cells mobilized by “on‐demand” addition of plerixafor to granulocyte–colony‐stimulating factor

Transfusion, 2014

BackgroundGranulocyte–colony‐stimulating factor (G‐CSF) is routinely used for mobilization of hem... more BackgroundGranulocyte–colony‐stimulating factor (G‐CSF) is routinely used for mobilization of hematopoietic stem and progenitor cells preceding autologous transplantation after high‐dose chemotherapy in hematologic malignancies. However, due to high mobilization failure rates, alternative mobilization strategies are required.Study Design and MethodsPatients who poorly mobilized CD34+ hematopoietic cells (HCs) with G‐CSF additionally received the CXCR4 antagonist plerixafor. The phenotype of CD34+ HCs collected after this plerixafor‐induced “rescue” mobilization, in regard to adhesion molecule and CD133, CD34, and CD38 expression in comparison to CD34+ HCs collected after traditional G‐CSF administration in good mobilizers, was analyzed flow cytometrically. To confirm previous studies in our patient cohort, the efficiency of mobilization and subsequent engraftment after this “on‐demand” plerixafor mobilization were analyzed.ResultsPronounced mobilization occurred after plerixafor adm...

Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial

The Lancet Oncology, 2011

Background Analysis of the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) ... more Background Analysis of the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) at 48 months' follow-up showed that addition of zoledronic acid to adjuvant endocrine therapy signifi cantly improved disease-free survival. We have now assessed long-term clinical effi cacy including disease-free survival and disease outcomes in patients receiving anastrozole or tamoxifen with or without zoledronic acid. Methods ABSCG-12 is a randomised, controlled, open-label, two-by-two factorial, multicentre trial in 1803 pre menopausal women with endocrine-receptor-positive early-stage (stage I-II) breast cancer receiving goserelin (3•6 mg every 28 days), comparing the effi cacy and safety of anastrozole (1 mg per day) or tamoxifen (20 mg per day) with or without zoledronic acid (4 mg every 6 months) for 3 years. Randomisation (1:1:1:1 ratio) was computerised and based on the Pocock and Simon minimisation method to balance the four treatment arms across eight prognostic variables (age, neoadjuvant chemotherapy, pathological tumour stage; lymph-node involvement, type of surgery or locoregional therapy, complete axillary dissection, intraoperative radiation therapy, and geographical region). Treatment allocation was not masked. The primary endpoint was disease-free survival (defi ned as disease recurrence or death) and analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00295646; follow-up is ongoing. Findings At a median follow-up of 62 months (range 0-114•4 months), more than 2 years after treatment completion, 186 disease-free survival events had been reported (53 events in 450 patients on tamoxifen alone, 57 in 453 patients on anastrozole alone, 36 in 450 patients on tamoxifen plus zoledronic acid, and 40 in 450 patients on anastrozole plus zoledronic acid). Zoledronic acid reduced risk of disease-free survival events overall (HR 0•68, 95% CI 0•51-0•91; p=0•009), although the diff erence was not signifi cant in the tamoxifen (HR 0•67, 95% CI 0•44-1•03; p=0•067) and anastrozole arms (HR 0•68, 95% CI 0•45-1•02; p=0•061) assessed separately. Zoledronic acid did not signifi cantly aff ect risk of death (30 deaths with zoledronic acid vs 43 deaths without; HR 0•67, 95% CI 0•41-1•07; p=0•09). There was no diff erence in disease-free survival between patients on tamoxifen alone versus anastrozole alone (HR 1•08, 95% CI 0•81-1•44; p=0•591), but overall survival was worse with anastrozole than with tamoxifen (46 vs 27 deaths; HR 1•75, 95% CI 1•08-2•83; p=0•02). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. Bone pain was reported in 601 patients (33%; 349 patients on zoledronic acid vs 252 not on the drug), fatigue in 361 (20%; 192 vs 169), headache in 280 (16%; 147 vs 133), and arthralgia in 266 (15%; 145 vs 121). Interpretation Addition of zoledronic acid improved disease-free survival in the patients taking anastrozole or tamoxifen. There was no diff erence in disease-free survival between patients receiving anastrozole and tamoxifen overall, but those on anastrozole alone had inferior overall survival. These data show persistent benefi ts with zoledronic acid and support its addition to adjuvant endocrine therapy in premenopausal patients with early-stage breast cancer. Funding AstraZeneca; Novartis.

A New Molecular Predictor of Distant Recurrence in ER-Positive, HER2-Negative Breast Cancer Adds Independent Information to Conventional Clinical Risk Factors

Clinical Cancer Research, 2011

Purpose: According to current guidelines, molecular tests predicting the outcome of breast cancer... more Purpose: According to current guidelines, molecular tests predicting the outcome of breast cancer patients can be used to assist in making treatment decisions after consideration of conventional markers. We developed and validated a gene expression signature predicting the likelihood of distant recurrence in patients with estrogen receptor (ER)–positive, HER2-negative breast cancer treated with adjuvant endocrine therapy. Experimental Design: RNA levels assessed by quantitative reverse transcriptase PCR in formalin-fixed, paraffin-embedded tumor tissue were used to calculate a risk score (Endopredict, EP) consisting of eight cancer-related and three reference genes. EP was combined with nodal status and tumor size into a comprehensive risk score, EPclin. Both prespecified risk scores including cutoff values to determine a risk group for each patient (low and high) were validated independently in patients from two large randomized phase III trials [Austrian Breast and Colorectal Canc...

The Austrian fulvestrant registry: results from a prospective observation of fulvestrant in postmenopausal patients with metastatic breast cancer

Breast Cancer Research and Treatment, 2008

Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone

Annals of Oncology, 2013

Background: PAM50 is a 50-gene test that is designed to identify intrinsic breast cancer subtypes... more Background: PAM50 is a 50-gene test that is designed to identify intrinsic breast cancer subtypes and generate a Risk of Recurrence (ROR) score. It has been developed to be carried out in qualified routine hospital pathology laboratories. Patients and Methods: One thousand four hundred seventy-eight postmenopausal women with estrogen receptor (ER)+ early breast cancer (EBC) treated with tamoxifen or tamoxifen followed by anastrozole from the prospective randomized ABCSG-8 trial were entered into this study. Patients did not receive adjuvant chemotherapy. RNA was extracted from paraffin blocks and analyzed using the PAM50 test. Both intrinsic subtype (luminal A/B, HER2-enriched, basal-like) and ROR score were calculated. The primary analysis was designed to test whether the continuous ROR score adds prognostic value in predicting distant recurrence (DR) over and above standard clinical variables. Results: In all tested subgroups, ROR score significantly adds prognostic information to the clinical predictor (P < 0.0001). PAM50 assigns an intrinsic subtype to all cases, and the luminal A cohort had a significantly lower ROR at 10 years compared with Luminal B (P < 0.0001). Significant and clinically relevant discrimination between low-and highrisk groups occurred also within all tested subgroups. Conclusion(s): The results of the primary analysis, in combination with recently published results from the ATAC trial, constitute Level 1 evidence for clinical validity of the PAM50 test for predicting the risk of DR in postmenopausal women with ER+ EBC. A 10-year metastasis risk of <3.5% in the ROR low category makes it unlikely that additional chemotherapy would improve this outcome-this finding could help to avoid unwarranted overtreatment.

A prospective multicenter pilot study to investigate the efficacy of pegylated Interferon-α2b and ribavirin in HBsAg+/HCV-RNA+ patients: The HEP-NET B/C coinfection trial

Zeitschrift für Gastroenterologie, 2008

Introduction Despite advances in adjuvant chemotherapy, 20-30% of patients in stages II-III color... more Introduction Despite advances in adjuvant chemotherapy, 20-30% of patients in stages II-III colorectal cancer will eventually relapse. Observational studies showed a reduction in relapse rate, colon cancer-specific mortality, and overall mortality by physical activity. Results from prospective randomized interventional studies to confirm these observational data are lacking. The aims of this prospective single-arm multicenter pilot study are to evaluate feasibility and safety of exercise training after adjuvant chemotherapy in colorectal cancer patients. Patients and methods The training was performed three times per week for 1 year and was increased gradually in three phases until reaching 18 metabolic equivalent task hours per week. Results Overall, 30 patients were included. The planned training intensity could be achieved in all three phases. Patients experienced a performance increase of median 35.5 watt, a weight-loss of a median of 3.0 kg, and a reduction in body fat content of median 1.0% during this exercise training. The analysis showed early study termination due to noncompliance in 10/30 patients (33.3%), disease progression in 4 patients (13.3%), and serious adverse events in 2 patients (6.7%). About half of patients (46.7%) completed the pilot study as planned. Biomarker analysis from 20 patients showed a non-significant reduction in insulin-like growth factor 1 (IGF-1), insulin-like growth factor 2 (IGF-2) and insulin-like growth factor binding protein 3 (IGF-BP3) levels, significant increases in adiponectin and leptin levels, and a nonsignificant increase in C-peptide levels. Conclusion Exercise training is feasible in patients with colorectal cancer after completion of adjuvant chemotherapy. The main problem encountered during the study was compliance. To improve compliance of exercise training, several measures were adapted for the upcoming prospective randomized ABCSG C08 Exercise II study.

Cardiotoxicity with rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in frontline treatment of patients with diffuse large B-cell lymphoma: A randomised phase-III stud...

European journal of cancer (Oxford, England : 1990), Jan 15, 2016

Chemoimmunotherapy containing rituximab, cyclophosphamide, doxorubicin, vincristine, and predniso... more Chemoimmunotherapy containing rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) is the standard treatment for diffuse large B-cell lymphoma (DLBCL). Doxorubicin may induce early and late cardiotoxicity. Non-pegylated liposomal (NPL) doxorubicin may reduce cardiotoxicity. Patients with untreated CD20+ DLBCL were randomised to conventional R-CHOP chemoimmunotherapy or rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone (R-COMP) with doxorubicin substituted by NPL-doxorubicin. Left ventricular ejection fraction (LVEF) and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels were measured before each treatment cycle and after the end of treatment. The mean LVEF of 178 and 158 measurements in the R-COMP and R-CHOP arms was 63.31% and 62.25%, respectively (P = 0.167). During treatment the LVEF measurements were below 50% in 10/218 (4.6%) in the R-COMP arm and 31/196 (15.8%) in the R-CHOP arm (P<0.001). Th...

The AKT 1 isoform plays a dominant role in the survival and chemoresistance of chronic lymphocytic leukaemia cells

British Journal of Haematology, 2015

A. (2012) A prognostic model to predict survival in 867 World Health Organization-defined essenti... more

Rituximab maintenance for patients with aggressive B-cell lymphoma in first remission: results of the randomized NHL13 trial

Haematologica, Jan 24, 2015

We investigated rituximab maintenance therapy in patients with diffuse large B-cell lymphoma (N=6... more We investigated rituximab maintenance therapy in patients with diffuse large B-cell lymphoma (N=662) or follicular lymphoma grade 3b (N=21) in first complete remission. Patients were randomised for rituximab maintenance (N=338) or observation (N=345). At a median follow-up of 45 months, event-free survival (primary endpoint) at 3 years was 80.4% for rituximab maintenance vs. 76.5% for observation. This difference was not significant for the intent to treat population (Likelihood ratio p=0.0670). The hazard ratio by treatment arm was 0.79 (95% confidence interval 0.57-1.08; p=0.1433). The secondary endpoint progression-free survival was also not met for the whole population (Likelihood ratio p=0.3646). Of note, rituximab maintenance was superior to observation when treatment arms only were compared (Hazard ratio: 0.62; 95% confidence interval 0.43-0.90; p=0.0120). Overall survival remained unchanged (92.0 vs. 90.3%). In subgroup analysis male patients benefitted from rituximab mainte...

CXCL12-induced VLA-4 activation is impaired in trisomy 12 chronic lymphocytic leukemia cells: a role for CCL21

Oncotarget, Jan 26, 2015

Homing to distinct lymphoid organs enables chronic lymphocytic leukemia (CLL) cells to receive pr... more Homing to distinct lymphoid organs enables chronic lymphocytic leukemia (CLL) cells to receive pro-survival and proliferative signals. Cytogenetic aberrations can significantly affect CLL cell compartmentalization. Trisomy 12 (tri12) defines a CLL subgroup with specific clinical features and increased levels of the negative prognostic marker CD49d, the α4-subunit of the integrin VLA-4, which is a key regulator of CLL cell homing to bone marrow (BM). Chemokine-induced inside-out VLA-4 activation, particularly via the CXCL12-CXCR4 axis, increases the arrest of various cell types on VCAM-1 presenting endothelium. Here, we demonstrate that high CD49d expression in tri12 CLL is accompanied by decreased CXCR4 expression. Dissecting functional consequences of these alterations, we observed that tri12 CLL cell homing to murine BM is not affected by CXCR4-CXCL12 blockage using AMD3100 or olaptesed pegol/NOX-A12. In line, CCL21-CCR7 rather than CXCL12-CXCR4 interactions triggered VLA-4-mediat...