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Papers by Christoph Salat

Cancer Research, 2019

Background: In the pivotal BOLERO-2 trial, everolimus (EVE) + exemestane (EXE) more than doubled ... more Background: In the pivotal BOLERO-2 trial, everolimus (EVE) + exemestane (EXE) more than doubled the median progression-free survival (PFS) vs EXE alone in hormone receptor positive (HR+), human epidermal growth factor-receptor 2-negative (HER2-) advanced breast cancer (ABC) recurring/progressing on/after prior non-steroidal aromatase inhibitors (NSAIs). BRAWO is a German non-interventional study conducted in patients (pts) with HR+, HER2–ABC receiving EVE + EXE, according to Summary of Product Characteristics (SmPC), in routine clinical practice. Here we report the final PFS and safety results. Methods: This multicenter study documented 2100 pts between October 2012 and December 2017 across 341 sites in Germany. Postmenopausal women with HR+, HER2– ABC with recurrence or progression after a NSAI were included. Primary observation parameters included the evaluation of the effectiveness of EVE + EXE used in routine care for the entire pt group. Results: In the final analysis, out of ...

Journal of Clinical Oncology, 2014

1005 Background: We previously showed in participants with TNBC of the neoadjuvant phase II Gepar... more 1005 Background: We previously showed in participants with TNBC of the neoadjuvant phase II GeparSixto study (NCT01426880) that the addition of carboplatin can substantially improve the pCR rates f...

Journal of Clinical Oncology, 2014

510 Background: We have recently described tumor-infiltrating lymphocytes (TILs) as predictors of... more 510 Background: We have recently described tumor-infiltrating lymphocytes (TILs) as predictors of pathological complete response (pCR = ypT0ypN0) to neoadjuvant carboplatin-based chemotherapy in the GeparSixto breast cancer (BC) trial. To further dissect the immunological status in tumor tissue we have evaluated a total of 12 immunologically relevant genes, including T-cell markers, B-cell markers, chemokines and immunoregulatory factors, in 481 pretherapeutic FFPE samples. Methods: GeparSixto investigated the addition of carboplatin to a doxorubicin/taxane combination in HER2-positive (HER2+) or triple-negative (TN) primary BC. Trastuzumab and lapatinib were added for HER2+ disease and bevacizumab for TN disease. Expression of 12 immunologically relevant genes (CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21, IDO1, PD-1, PDL1, CTLA4, FOXP3) was evaluated by quantitative RT-PCR in 481 core biopsies. Results: All immune mRNA markers showed a strong positive correlation with each other and with the stromal lymp...

Annals of Oncology, 2018

Background In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-b... more Background In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD). Patients and methods Patients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA). Results A significantly better DFS (hazard ratio 0.56, 95% CI 0.34-0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) [odds ratio (OR) 2.60, 95% CI 1.26-5.37, P = 0.008]. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46-9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17-1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23-1.04, P = 0.059). Conclusions The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 2018

Human epidermal growth factor receptor 2 (HER2) is a central predictive biomarker in breast cance... more Human epidermal growth factor receptor 2 (HER2) is a central predictive biomarker in breast cancer. Inaccurate HER2 results in different laboratories could be as high as 20%. However, this statement is based on data generated more than 13 years ago and may not reflect the standards of modern diagnostic pathology. We compared central and local HER2 testing in a total of 1581 HER2-positive tumors from five clinical trials. We evaluated the clinical relevance for pathological complete response (pCR) and disease-free survival in a subgroup of 677 tumors, which received an anti-HER2 therapy. Over the period of 12 years, the discordance rate for HER2 decreased from 52.4 (GeparTrio) to 8.4% (GeparSepto). Discordance rates were significantly higher in hormone receptor (HR)-positive tumors (26.6%), compared to HR-negative tumors (16.3%, P<0.0001), which could be explained by a different distribution of HER2 mRNA levels in HR-positive and HR-negative tumors. pCR rates were significantly lo...

Oncotarget, Jan 27, 2018

Allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusions (DLI) may induce a... more Allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusions (DLI) may induce a graft-versus-tumor effect in pediatric sarcoma patients. Here, we describe general feasibility, toxicity and efficacy of DLI after allo-SCT. 4 of 8 patients responded. ES#4 had stable disease (SD) for 9 months after DLI and RMS#4 partial response for 8 months with combined hyperthermia/chemotherapy. In ES#4, DLI led to SD for 6 months and reverted residual disease before allo-SCT into complete remission. After DLI, ES#4 and RMS#4 developed acute GvHD (°III-°IV), ES#4 also developed chronic GvHD. 5 patients including ES#4 lived longer than expected. Median survival after allo-SCT was 2.3 years, post-relapse survival (PRS) was 13 months. Off note, HLA-mismatched DLI were associated with a trend towards increased survival after allo-SCT and increased PRS compared to HLA-matched DLI (23 versus 3 months). We studied eight adolescents and young adults (AYAs) with advanced Ewing sarcoma (ES#1-...

JAMA oncology, Jan 15, 2018

Patients with soft tissue sarcoma are at risk for local recurrence and distant metastases despite... more Patients with soft tissue sarcoma are at risk for local recurrence and distant metastases despite optimal local treatment. Preoperative anthracycline plus ifosfamide chemotherapy improves outcome in common histological subtypes. To analyze whether the previously reported improvement in local progression-free survival by adding regional hyperthermia to neoadjuvant chemotherapy translates into improved survival. Open-label, phase 3 randomized clinical trial to evaluate the efficacy and toxic effects of neoadjuvant chemotherapy plus regional hyperthermia. Adult patients (age ≥18 years) with localized soft tissue sarcoma (tumor ≥5 cm, French Federation Nationale des Centers de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep) were accrued across 9 centers (6, Germany; 1, Norway; 1, Austria; 1, United States) from July 1997 to November 2006. Follow-up ended December 2014. After stratification for tumor presentation and site, patients were randomly assigned to either neoadjuvant chemoth...

Annals of Oncology, 2016

Objective: The prospective non-interventional study (NIS) NADIR was designed to evaluate both eff... more Objective: The prospective non-interventional study (NIS) NADIR was designed to evaluate both effectiveness and safety of prophylactic use of lipegfilgrastim (Lonquex ®), a glycopegylated granulocyte colony stimulating factor, in cancer patients with different tumor entities undergoing chemotherapy in routine clinical practice. The primary objective was incidence of severe neutropenia, febrile neutropenia (FN) and neutropenia-associated complications. Method: NADIR was a national, multicenter, prospective NIS. Results: Here, we present data on patients with Non-Hodgkin lymphoma (NHL). Final analysis comprised 337 NHL patients having received ≥1 administration of lipegfilgrastim. Primary prophylaxis with lipegfilgrastim was documented in 78.7% of patients with high risk to develop FN. In total, ≥1 severe neutropenia (grade 3/4) was reported in 115 (34.1%) patients and ≥1 event of FN documented in 15 (4.5%) patients. Grade 3/4 infections were reported in 22 (6.5%) patients overall. Most frequently reported adverse events (AEs) related to lipegfilgrastim in total were bone pain (5.4%), leukocytosis (2.1%), back pain (1.8%), platelet count decreased (1.2%) and myalgia (1.2%). Fatal serious AEs were documented in 9 (2.7%) patients; none were attributable to lipegfilgrastim. Conclusion: Prophylaxis or therapeutic intention with lipegfilgrastim in NHL patients in routine clinical practice showed similar effectiveness and safety as demonstrated in the pivotal trials.

Oncotarget, 2016

Background: TP53 mutations are frequent in breast cancer, however their clinical relevance in ter... more Background: TP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial. Methods: 450 pre-therapeutic, formalin-fixed, paraffin-embedded core biopsies from the phase II neoadjuvant GeparSixto trial that included HER2-positive and triple negative breast cancer (TNBC) were subjected to Sanger sequencing of exons 5-8 of the TP53 gene. TP53 status was correlated to response to neoadjuvant anthracycline/ taxane-based chemotherapy with or without carboplatin and trastuzumab/lapatinib in HER2-positive and bevacizumab in TNBC. p53 protein expression was evaluated by immunohistochemistry in the TNBC subgroup. Results: Of 450 breast cancer samples 297 (66.0%) were TP53 mutant. Mutations were significantly more frequent in TNBC (74.8%) compared to HER2-positive cancers (55.4%, P < 0.0001). Neither mutations nor different mutation types and effects were associated with pCR neither in the whole study group nor in molecular subtypes (P > 0.05 each). Missense mutations tended to be associated with a better survival compared to all other types of mutations in TNBC (P = 0.093) and in HER2-positive cancers (P = 0.071). In TNBC, missense mutations were also linked to higher numbers Priority Research Paper

The Breast, 2015

Lapatinib plus capecitabine (lapþcap) is approved as treatment for patients with human epidermal ... more Lapatinib plus capecitabine (lapþcap) is approved as treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), who have progressed on prior trastuzumab in the metastatic setting. We previously reported progression-free survival (PFS), overall survival (OS) and safety results from this open-label, multicentre, phase II study (VITAL; NCT01013740) conducted in women with HER2 positive MBC, to evaluate the efficacy and safety of lap plus vinorelbine (lapþvin), an important chemotherapy option for MBC, compared with lapþcap. In total, 112 patients were randomised 2:1 to treatment with lapþvin (N ¼ 75) or lapþcap (N ¼ 37). Results showed that the median PFS (primary endpoint) and OS (secondary endpoint) post-randomisation were comparable between treatment arms, with no new safety signals detected. Here, we assessed the final OS in this study at 40 months post-randomisation. At the time of final analyses, 24 (32%) patients were ongoing in the lapþvin arm, compared with 14 (38%) patients in the lapþcap arm (92% in both arms had discontinued treatment). Median OS in the lapþvin arm was 23.3 months (95% confidence intervals [CI]: 18.5, 31.1), compared with 20.3 months (95% CI: 16.4, 31.8) in the lapþcap arm. The median follow-up in the lapþvin arm was 18.86 months (95% CI: 10.68, 26.02), compared with 19.38 (95% CI: 25.56) months in the lapþcap arm. Similar rates of death (56e57%) were observed in both arms. The final OS was consistent with the previously reported data and suggest that lapþvin offers an effective treatment option for women with HER2-positive MBC.

Oncology research and treatment, 2015

The non-interventional study (NIS) NADIR was designed to assess the effectiveness and safety of l... more The non-interventional study (NIS) NADIR was designed to assess the effectiveness and safety of lipegfilgrastim, a novel glycopegylated granulocyte-colony stimulating factor, in reducing the risk of both febrile and severe neutropenia. Here, the interim analysis of NIS Nadir performed under real-world conditions at 80 oncology practices across Germany is reported. For a patient to be included, lipegfilgrastim at a subcutaneous single dose of 6 mg had to be administered during at least 1 cycle of the chemotherapy under consideration. The interim analysis included 224 patients. Median patient age was 61.1 years (interquartile range 51.2-70.2 years). Main tumor type was breast cancer followed by lung cancer, and non-Hodgkin's lymphoma (46.0, 13.4, and 10.7%, respectively). When lipegfilgrastim was given as primary prophylaxis, no patient developed febrile neutropenia (FN). 1.3% of patients developed FN when primary prophylaxis was withheld. Only 68.6% of patients undergoing chemoth...

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 22, 2014

Modulation of immunologic interactions in cancer tissue is a promising therapeutic strategy. To i... more Modulation of immunologic interactions in cancer tissue is a promising therapeutic strategy. To investigate the immunogenicity of human epidermal growth factor receptor 2 (HER2) -positive and triple-negative (TN) breast cancers (BCs), we evaluated tumor-infiltrating lymphocytes (TILs) and immunologically relevant genes in the neoadjuvant GeparSixto trial. GeparSixto investigated the effect of adding carboplatin (Cb) to an anthracycline-plus-taxane combination (PM) on pathologic complete response (pCR). A total of 580 tumors were evaluated before random assignment for stromal TILs and lymphocyte-predominant BC (LPBC). mRNA expression of immune-activating (CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21) as well as immunosuppressive factors (IDO1, PD-1, PD-L1, CTLA4, FOXP3) was measured in 481 tumors. Increased levels of stromal TILs predicted pCR in univariable (P < .001) and multivariable analyses (P < .001). pCR rate was 59.9% in LPBC and 33.8% for non-LPBC (P < .001). pCR rat...

Cancer Research, 2013

Background: We have recently described a significantly increased pCR rate in triple-negative brea... more Background: We have recently described a significantly increased pCR rate in triple-negative breast cancer with addition of carboplatin to a non-pegylated liposomal doxorubicin/taxane (MC) combination in the neoadjuvant Geparsixto study (von Minckwitz et al, ASCO, 2013). Here we report the results of prospective biomarker analyses performed in Geparsixto. Methods: Geparsixto investigates the effect of adding carboplatin to MC for the treatment of patients with HER2+ve and triple-negative (TN) primary BC. All HER2+ve patients received trastuzumab and lapatinib, all TN patients received bevacizumab. As part of the central pathology assessment, we prospectively evaluated tumor-associated lymphocytes (TILs) in 580 core biopsies. We used the parameters stromal lymphocytes (strLy) and lymphocyte-predominant breast cancer (LPBC, ≥60%TILs) as previously described (Denkert et al, JCO, 2010). In addition, Ki67 (n = 588) was measured by immunohistochemistry and p53 mutations in Exons 5-8 (n = ...

DMW - Deutsche Medizinische Wochenschrift, 2002

The Lancet Oncology, 2014

Preclinical data suggest that triple-negative breast cancers are sensitive to interstrand crossli... more Preclinical data suggest that triple-negative breast cancers are sensitive to interstrand crosslinking agents, and that synergy may exist for the combination of a taxane, trastuzumab, and a platinum salt for HER2-positive breast cancer. We therefore aimed to assess the efficacy of the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive breast cancer. Patients with previously untreated, non-metastatic, stage II-III, triple-negative breast cancer and HER2-positive breast cancer were enrolled. Patients were treated for 18 weeks with paclitaxel (80 mg/m(2) once a week) and non-pegylated liposomal doxorubicin (20 mg/m(2) once a week). Patients with triple-negative breast cancer received simultaneous bevacizumab (15 mg/kg intravenously every 3 weeks). Patients with HER2-positive disease received simultaneous trastuzumab (8 mg/kg initial dose with subsequent doses of 6 mg/kg intravenously every 3 weeks) and lapatinib (750 mg daily). Patients were randomly assigned in a 1:1 ratio with dynamic allocation and minimisation, stratified by biological subtype and Ki-67 level to receive, at the same time as the backbone regimens, either carboplatin (AUC 1·5 [2·0 for the first 329 patients] once a week) or no carboplatin. The primary endpoint the proportion of patients who achieved a pathological complete response (defined as ypT0 ypN0), analysed for all patients who started treatment; a p value of less than 0·2 was deemed significant for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01426880. 296 patients were randomly assigned to receive carboplatin and 299 to no additional carboplatin, of whom 295 and 293 started treatment, respectively. In this final analysis, 129 patients (43·7%, 95% CI 38·1-49·4) in the carboplatin group achieved a pathological complete response, compared with 108 patients (36·9%, 31·3-42·4) without carboplatin (odds ratio 1·33, 95% CI 0·96-1·85; p=0·107). Of the patients with triple-negative breast cancer, 84 (53·2%, 54·4-60·9) of 158 patients achieved a pathological complete response with carboplatin, compared with 58 (36·9%, 29·4-44·5) of 157 without (p=0·005). Of the patients with HER2-positive tumours, 45 (32·8%, 25·0-40·7) of 137 patients achieved a pathological complete response with carboplatin compared with 50 (36·8%, 28·7-44·9) of 136 without (p=0·581; test for interaction p=0·015). Haematological and non-haematological toxic effects that were significantly more common in the carboplatin group than in the no-carboplatin group included grade 3 or 4 neutropenia (192 [65%] vs 79 [27%]), grade 3 or 4 anaemia (45 [15%] vs one [&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1%]), grade 3 or 4 thrombocytopenia (42 [14%] vs one [&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1%]), and grade 3 or 4 diarrhoea (51 [17%] vs 32 [11%]); carboplatin was more often associated with dose discontinuations (141 [48%] with carboplatin and 114 [39%] without carboplatin; p=0·031). The frequency of grade 3 or 4 haematological events decreased from 82% (n=135) to 70% (n=92) and grade 3 or 4 non-haematological events from 78% (n=128) to 59% (n=77) in the carboplatin arm when the dose of carboplatin was reduced from AUC 2·0 to 1·5. The addition of neoadjuvant carboplatin to a regimen of a taxane, an anthracycline, and targeted therapy significantly increases the proportion of patients achieving a pathological complete response. This regimen seems to increase responses in patients with triple-negative breast cancer, but not in those with HER2-positive breast cancer. GlaxoSmithKline, Roche, and Teva.

The Lancet Oncology, 2010

RDI and JV designed the study in collaboration with the European Society for Hyperthermic Oncolog... more RDI and JV designed the study in collaboration with the European Society for Hyperthermic Oncology (ESHO) and European Organisation for Research and Treatment of Cancer (EORTC). UM supervised data management and statistical analysis. All authors participated in the study implementation, data analysis, and interpretation of results. This report was principally drafted by RDI, LHL, JV, UM, and PH, and was critically reviewed and subsequently approved by each co-author.

Immunology, 2012

Adoptive transfer of T cells genetically modified with tumour-specific T-cell receptors (TCR) is ... more Adoptive transfer of T cells genetically modified with tumour-specific T-cell receptors (TCR) is a promising novel approach in the treatment of cancer. We have previously isolated an allorestricted MHC class I-restricted TCR with specificity for Formin-like protein 1 (FMNL1) with potent activity against chronic lymphocytic leukaemia cells. CD4 + T cells have been described to be highly important for tumour elimination although TCR derived from CD4 + T cells with anti-tumour reactivity have been only rarely described. In this study we aimed to isolate MHC class-II-restricted CD4 + T cells and TCR with specificity for leukaemia antigens. We used professional antigen-presenting cells pulsed with the leukaemiaassociated and tumour-associated antigen FMNL1 for stimulation of autologous T cells in vitro. We isolated two CD4 + HLA-DR-restricted T-cell clones and T-cell-derived TCR with so far unknown specificity but high reactivity against lymphoma cells and native malignant cells derived from HLA-matched patients with diverse leukaemias. Moreover, characterization of the TCR after TCR gene transfer revealed that specific characteristics of isolated TCR as reactivity in response to Toll-like receptors were transferable on effector cells. Our results have a major impact on the development of novel immunotherapies. They demonstrate that TCR with potent HLA-DR-restricted anti-leukaemic reactivity against so far undefined self-restricted antigens can be isolated from the healthy autorestricted CD4 + T-cell repertoire and these TCR are highly interesting candidate tools for novel immunotherapies.

Breast Cancer Research and Treatment, 2014

Lapatinib is approved in combination with capecitabine for treatment of patients with human epide... more Lapatinib is approved in combination with capecitabine for treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who have progressed on prior trastuzumab in the metastatic setting. Vinorelbine is an important chemotherapy option for MBC. We evaluated efficacy and safety of lapatinib plus vinorelbine, compared with lapatinib plus capecitabine, in women with HER2positive MBC. In this open-label, multicenter, phase II study, eligible patients (N = 112) were randomized 2:1 to lapatinib plus vinorelbine [(N = 75) 1,250 mg orally once daily (QD) continuously plus 20 mg/m 2 /day intravenously] or lapatinib plus capecitabine [(N = 37) 1,250 mg orally QD continuously plus 2,000 mg/m 2 /day orally, 2 doses]. The primary endpoint was progression-free survival (PFS). Other endpoints included overall survival (OS) and safety. Patients progressing within the study were given the option of crossover to the other treatment arm; time to second progression was an exploratory endpoint. Patient demographics, stratification, and prognostic factors were well balanced between treatments. Median PFS in both arms was 6.2 months [95 % confidence interval (CI) 4.2, 8.8 (lapatinib plus vinorelbine); 4.4, 8.3 (lapatinib plus capecitabine)]. Median OS on lapatinib plus vinorelbine was Electronic supplementary material The online version of this article (

Bone Marrow Transplantation, 2005

Veno-occlusive disease (VOD) is one of the most serious complications following hematopoietic ste... more Veno-occlusive disease (VOD) is one of the most serious complications following hematopoietic stem cell transplantation (HSCT) and is associated with a high mortality. We conducted a large trial on the clinical significance of protein C (PC) and procollagen III peptide (PNPIII) levels, which have been described as possible diagnostic markers of VOD. In total, 350 patients undergoing allogeneic HSCT were included. PC and PNPIII levels were analyzed prior to conditioning and weekly until 8 weeks after the HSCT. Signs of VOD and other transplantation-related complications (graft-versushost disease (GVHD), toxicity, microangiopathic hemolytic anemia, infection) were recorded weekly throughout the trial. Patients showed a significant drop of the PC levels in VOD (70.3 vs 96.3%, Po0.001) and with increasing severity of aGVHD. Steroids increased the PC levels (69.4% vs 109.4%, Po0.001). The highest PNPIII levels were registered in patients with VOD (mean 6.3 IU/ ml). Patients with aGVHD showed an elevation of PNPIII, especially patients with hepatic aGVHD. PC levels during conditioning do not predict VOD (98.5 vs 76.5%, NS). Although PC and PNPIII may play a role in the pathogenesis of VOD they cannot discriminate between complications with jaundice and are only of limited help in the differential diagnosis of VOD.

Bone Marrow Transplantation, 1997

Differential diagnosis of hepatic injury mainly includes veno-occlusive disease (VOD), acute graf... more Differential diagnosis of hepatic injury mainly includes veno-occlusive disease (VOD), acute graft-versus-host disease (aGVHD) of the liver, infections and toxic drug Plasminogen activator inhibitor 1 (PAI-1) and aminopropeptide of type III procollagen (PIIINP) have been effects. 1 Owing to different therapeutic consequences, accurate diagnosis is essential and the identification of a described as markers of hepatic veno-occlusive disease (VOD) after bone marrow transplantation (BMT). We marker would be helpful. Laboratory parameters such as plasminogen activator determined these parameters in two patients undergoing BMT and subsequent liver transplantation due to inhibitor 1 (PAI-1; 2,3) and the aminopropeptide of type III procollagen (PIIINP; 4-6) have been reported to be elevated VOD. Previously normal PAI-1 levels (maximum 30.0 ng/ml in patient 1, 23.7 ng/ml in patient 2) were elevated and possibly useful in diagnosing VOD. We determined these parameters in two bone marrow transplant recipients for the first time in both patients at the time of clinically diagnosed VOD on days 40 and 20, respectively (patient who developed VOD and underwent subsequent liver transplantation. 1: 317.5 ng/ml; patient 2: 317.2 ng/ml). Levels remained elevated until liver transplantation was performed on days 79 and 41, respectively. Baseline levels (day −8) of aminopropeptide of type III collagen (patient 1: 4.44 Patients and methods g/l; patient 2: 8.1 g/l) peaked at the time of BMT in both patients (155.0 g/l and 108.3 g/l). After an intermittent decrease at the time of discharge on day Case 1 32, a second elevation was observed in patient 1 when she was readmitted and presented with typical signs of A 39-year-old patient with acute myeloid leukemia was transplanted from her HLA-identical brother after con-VOD on day 40. In patient 2, PIIINP levels remained high until VOD was diagnosed (day 20) and liver trans-ditioning with busulfan (16 mg/kg over 4 days) and cyclophosphamide (200 mg/kg over 4 days) in April 1995. The plantation was performed. After liver transplantation, PAI-1 levels normalized in both patients and PIIINP patient received low-dose heparin (100 U/kg/day) as VOD prophylaxis starting on day −8. After an uncomplicated levels declined. Both patients died due to infectious complications and multiorgan failure on days 141 and 101, course the patient was discharged on day 32. On day 40 she was readmitted to hospital with hyperbilirubinemia (74.8 respectively. Whereas the early rise of PIIINP did not correlate with the clinical onset of VOD, the results mmol/l), ascites, right upper quadrant pain, hepatomegaly, elevation of liver enzymes, fever and impaired coagulation. emphasise the relevance of PAI-1 for diagnosing VOD. Keywords: veno-occlusive disease; bone marrow trans-The bilirubin level continued to rise. Transjugular liver biopsy was performed on day 47. Unfortunately insufficient plantation; liver transplantation; plasminogen activator inhibitor 1 (PAI-1); aminopropeptide of type III collagen material was obtained and the patient developed an intrahepatic hematoma precluding thrombolytic therapy. Treatment with PGE 2 (days 44-46 and 48-74) led to an improvement in the right upper quadrant pain and a Liver damage represents a key event in the most important decrease in liver enzymes, but the bilirubin continued to life-threatening complications following bone marrow rise. transplantation. In view of the growing numbers of high-On day 70, percutaneous liver biopsy confirmed the diagdose chemotherapy regimens and consecutive stem cell nosis of VOD. Liver transplantation was performed on day transplantations, an increasing rate of hepatic complications 79, when the bilirubin level was 1230.8 mmol/l. Histology can be expected. of the explanted organ confirmed the diagnosis of massive VOD. After improvement of liver function the patient developed pulmonary aspergillosis on day 105, pseudo

Cancer Research, 2019

Background: In the pivotal BOLERO-2 trial, everolimus (EVE) + exemestane (EXE) more than doubled ... more Background: In the pivotal BOLERO-2 trial, everolimus (EVE) + exemestane (EXE) more than doubled the median progression-free survival (PFS) vs EXE alone in hormone receptor positive (HR+), human epidermal growth factor-receptor 2-negative (HER2-) advanced breast cancer (ABC) recurring/progressing on/after prior non-steroidal aromatase inhibitors (NSAIs). BRAWO is a German non-interventional study conducted in patients (pts) with HR+, HER2–ABC receiving EVE + EXE, according to Summary of Product Characteristics (SmPC), in routine clinical practice. Here we report the final PFS and safety results. Methods: This multicenter study documented 2100 pts between October 2012 and December 2017 across 341 sites in Germany. Postmenopausal women with HR+, HER2– ABC with recurrence or progression after a NSAI were included. Primary observation parameters included the evaluation of the effectiveness of EVE + EXE used in routine care for the entire pt group. Results: In the final analysis, out of ...

Journal of Clinical Oncology, 2014

1005 Background: We previously showed in participants with TNBC of the neoadjuvant phase II Gepar... more 1005 Background: We previously showed in participants with TNBC of the neoadjuvant phase II GeparSixto study (NCT01426880) that the addition of carboplatin can substantially improve the pCR rates f...

Journal of Clinical Oncology, 2014

510 Background: We have recently described tumor-infiltrating lymphocytes (TILs) as predictors of... more 510 Background: We have recently described tumor-infiltrating lymphocytes (TILs) as predictors of pathological complete response (pCR = ypT0ypN0) to neoadjuvant carboplatin-based chemotherapy in the GeparSixto breast cancer (BC) trial. To further dissect the immunological status in tumor tissue we have evaluated a total of 12 immunologically relevant genes, including T-cell markers, B-cell markers, chemokines and immunoregulatory factors, in 481 pretherapeutic FFPE samples. Methods: GeparSixto investigated the addition of carboplatin to a doxorubicin/taxane combination in HER2-positive (HER2+) or triple-negative (TN) primary BC. Trastuzumab and lapatinib were added for HER2+ disease and bevacizumab for TN disease. Expression of 12 immunologically relevant genes (CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21, IDO1, PD-1, PDL1, CTLA4, FOXP3) was evaluated by quantitative RT-PCR in 481 core biopsies. Results: All immune mRNA markers showed a strong positive correlation with each other and with the stromal lymp...

Annals of Oncology, 2018

Background In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-b... more Background In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD). Patients and methods Patients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA). Results A significantly better DFS (hazard ratio 0.56, 95% CI 0.34-0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) [odds ratio (OR) 2.60, 95% CI 1.26-5.37, P = 0.008]. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46-9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17-1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23-1.04, P = 0.059). Conclusions The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 2018

Human epidermal growth factor receptor 2 (HER2) is a central predictive biomarker in breast cance... more Human epidermal growth factor receptor 2 (HER2) is a central predictive biomarker in breast cancer. Inaccurate HER2 results in different laboratories could be as high as 20%. However, this statement is based on data generated more than 13 years ago and may not reflect the standards of modern diagnostic pathology. We compared central and local HER2 testing in a total of 1581 HER2-positive tumors from five clinical trials. We evaluated the clinical relevance for pathological complete response (pCR) and disease-free survival in a subgroup of 677 tumors, which received an anti-HER2 therapy. Over the period of 12 years, the discordance rate for HER2 decreased from 52.4 (GeparTrio) to 8.4% (GeparSepto). Discordance rates were significantly higher in hormone receptor (HR)-positive tumors (26.6%), compared to HR-negative tumors (16.3%, P<0.0001), which could be explained by a different distribution of HER2 mRNA levels in HR-positive and HR-negative tumors. pCR rates were significantly lo...

Oncotarget, Jan 27, 2018

Allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusions (DLI) may induce a... more Allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusions (DLI) may induce a graft-versus-tumor effect in pediatric sarcoma patients. Here, we describe general feasibility, toxicity and efficacy of DLI after allo-SCT. 4 of 8 patients responded. ES#4 had stable disease (SD) for 9 months after DLI and RMS#4 partial response for 8 months with combined hyperthermia/chemotherapy. In ES#4, DLI led to SD for 6 months and reverted residual disease before allo-SCT into complete remission. After DLI, ES#4 and RMS#4 developed acute GvHD (°III-°IV), ES#4 also developed chronic GvHD. 5 patients including ES#4 lived longer than expected. Median survival after allo-SCT was 2.3 years, post-relapse survival (PRS) was 13 months. Off note, HLA-mismatched DLI were associated with a trend towards increased survival after allo-SCT and increased PRS compared to HLA-matched DLI (23 versus 3 months). We studied eight adolescents and young adults (AYAs) with advanced Ewing sarcoma (ES#1-...

JAMA oncology, Jan 15, 2018

Patients with soft tissue sarcoma are at risk for local recurrence and distant metastases despite... more Patients with soft tissue sarcoma are at risk for local recurrence and distant metastases despite optimal local treatment. Preoperative anthracycline plus ifosfamide chemotherapy improves outcome in common histological subtypes. To analyze whether the previously reported improvement in local progression-free survival by adding regional hyperthermia to neoadjuvant chemotherapy translates into improved survival. Open-label, phase 3 randomized clinical trial to evaluate the efficacy and toxic effects of neoadjuvant chemotherapy plus regional hyperthermia. Adult patients (age ≥18 years) with localized soft tissue sarcoma (tumor ≥5 cm, French Federation Nationale des Centers de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep) were accrued across 9 centers (6, Germany; 1, Norway; 1, Austria; 1, United States) from July 1997 to November 2006. Follow-up ended December 2014. After stratification for tumor presentation and site, patients were randomly assigned to either neoadjuvant chemoth...

Annals of Oncology, 2016

Objective: The prospective non-interventional study (NIS) NADIR was designed to evaluate both eff... more Objective: The prospective non-interventional study (NIS) NADIR was designed to evaluate both effectiveness and safety of prophylactic use of lipegfilgrastim (Lonquex ®), a glycopegylated granulocyte colony stimulating factor, in cancer patients with different tumor entities undergoing chemotherapy in routine clinical practice. The primary objective was incidence of severe neutropenia, febrile neutropenia (FN) and neutropenia-associated complications. Method: NADIR was a national, multicenter, prospective NIS. Results: Here, we present data on patients with Non-Hodgkin lymphoma (NHL). Final analysis comprised 337 NHL patients having received ≥1 administration of lipegfilgrastim. Primary prophylaxis with lipegfilgrastim was documented in 78.7% of patients with high risk to develop FN. In total, ≥1 severe neutropenia (grade 3/4) was reported in 115 (34.1%) patients and ≥1 event of FN documented in 15 (4.5%) patients. Grade 3/4 infections were reported in 22 (6.5%) patients overall. Most frequently reported adverse events (AEs) related to lipegfilgrastim in total were bone pain (5.4%), leukocytosis (2.1%), back pain (1.8%), platelet count decreased (1.2%) and myalgia (1.2%). Fatal serious AEs were documented in 9 (2.7%) patients; none were attributable to lipegfilgrastim. Conclusion: Prophylaxis or therapeutic intention with lipegfilgrastim in NHL patients in routine clinical practice showed similar effectiveness and safety as demonstrated in the pivotal trials.

Oncotarget, 2016

Background: TP53 mutations are frequent in breast cancer, however their clinical relevance in ter... more Background: TP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial. Methods: 450 pre-therapeutic, formalin-fixed, paraffin-embedded core biopsies from the phase II neoadjuvant GeparSixto trial that included HER2-positive and triple negative breast cancer (TNBC) were subjected to Sanger sequencing of exons 5-8 of the TP53 gene. TP53 status was correlated to response to neoadjuvant anthracycline/ taxane-based chemotherapy with or without carboplatin and trastuzumab/lapatinib in HER2-positive and bevacizumab in TNBC. p53 protein expression was evaluated by immunohistochemistry in the TNBC subgroup. Results: Of 450 breast cancer samples 297 (66.0%) were TP53 mutant. Mutations were significantly more frequent in TNBC (74.8%) compared to HER2-positive cancers (55.4%, P < 0.0001). Neither mutations nor different mutation types and effects were associated with pCR neither in the whole study group nor in molecular subtypes (P > 0.05 each). Missense mutations tended to be associated with a better survival compared to all other types of mutations in TNBC (P = 0.093) and in HER2-positive cancers (P = 0.071). In TNBC, missense mutations were also linked to higher numbers Priority Research Paper

The Breast, 2015

Lapatinib plus capecitabine (lapþcap) is approved as treatment for patients with human epidermal ... more Lapatinib plus capecitabine (lapþcap) is approved as treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), who have progressed on prior trastuzumab in the metastatic setting. We previously reported progression-free survival (PFS), overall survival (OS) and safety results from this open-label, multicentre, phase II study (VITAL; NCT01013740) conducted in women with HER2 positive MBC, to evaluate the efficacy and safety of lap plus vinorelbine (lapþvin), an important chemotherapy option for MBC, compared with lapþcap. In total, 112 patients were randomised 2:1 to treatment with lapþvin (N ¼ 75) or lapþcap (N ¼ 37). Results showed that the median PFS (primary endpoint) and OS (secondary endpoint) post-randomisation were comparable between treatment arms, with no new safety signals detected. Here, we assessed the final OS in this study at 40 months post-randomisation. At the time of final analyses, 24 (32%) patients were ongoing in the lapþvin arm, compared with 14 (38%) patients in the lapþcap arm (92% in both arms had discontinued treatment). Median OS in the lapþvin arm was 23.3 months (95% confidence intervals [CI]: 18.5, 31.1), compared with 20.3 months (95% CI: 16.4, 31.8) in the lapþcap arm. The median follow-up in the lapþvin arm was 18.86 months (95% CI: 10.68, 26.02), compared with 19.38 (95% CI: 25.56) months in the lapþcap arm. Similar rates of death (56e57%) were observed in both arms. The final OS was consistent with the previously reported data and suggest that lapþvin offers an effective treatment option for women with HER2-positive MBC.

Oncology research and treatment, 2015

The non-interventional study (NIS) NADIR was designed to assess the effectiveness and safety of l... more The non-interventional study (NIS) NADIR was designed to assess the effectiveness and safety of lipegfilgrastim, a novel glycopegylated granulocyte-colony stimulating factor, in reducing the risk of both febrile and severe neutropenia. Here, the interim analysis of NIS Nadir performed under real-world conditions at 80 oncology practices across Germany is reported. For a patient to be included, lipegfilgrastim at a subcutaneous single dose of 6 mg had to be administered during at least 1 cycle of the chemotherapy under consideration. The interim analysis included 224 patients. Median patient age was 61.1 years (interquartile range 51.2-70.2 years). Main tumor type was breast cancer followed by lung cancer, and non-Hodgkin's lymphoma (46.0, 13.4, and 10.7%, respectively). When lipegfilgrastim was given as primary prophylaxis, no patient developed febrile neutropenia (FN). 1.3% of patients developed FN when primary prophylaxis was withheld. Only 68.6% of patients undergoing chemoth...

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 22, 2014

Modulation of immunologic interactions in cancer tissue is a promising therapeutic strategy. To i... more Modulation of immunologic interactions in cancer tissue is a promising therapeutic strategy. To investigate the immunogenicity of human epidermal growth factor receptor 2 (HER2) -positive and triple-negative (TN) breast cancers (BCs), we evaluated tumor-infiltrating lymphocytes (TILs) and immunologically relevant genes in the neoadjuvant GeparSixto trial. GeparSixto investigated the effect of adding carboplatin (Cb) to an anthracycline-plus-taxane combination (PM) on pathologic complete response (pCR). A total of 580 tumors were evaluated before random assignment for stromal TILs and lymphocyte-predominant BC (LPBC). mRNA expression of immune-activating (CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21) as well as immunosuppressive factors (IDO1, PD-1, PD-L1, CTLA4, FOXP3) was measured in 481 tumors. Increased levels of stromal TILs predicted pCR in univariable (P < .001) and multivariable analyses (P < .001). pCR rate was 59.9% in LPBC and 33.8% for non-LPBC (P < .001). pCR rat...

Cancer Research, 2013

Background: We have recently described a significantly increased pCR rate in triple-negative brea... more Background: We have recently described a significantly increased pCR rate in triple-negative breast cancer with addition of carboplatin to a non-pegylated liposomal doxorubicin/taxane (MC) combination in the neoadjuvant Geparsixto study (von Minckwitz et al, ASCO, 2013). Here we report the results of prospective biomarker analyses performed in Geparsixto. Methods: Geparsixto investigates the effect of adding carboplatin to MC for the treatment of patients with HER2+ve and triple-negative (TN) primary BC. All HER2+ve patients received trastuzumab and lapatinib, all TN patients received bevacizumab. As part of the central pathology assessment, we prospectively evaluated tumor-associated lymphocytes (TILs) in 580 core biopsies. We used the parameters stromal lymphocytes (strLy) and lymphocyte-predominant breast cancer (LPBC, ≥60%TILs) as previously described (Denkert et al, JCO, 2010). In addition, Ki67 (n = 588) was measured by immunohistochemistry and p53 mutations in Exons 5-8 (n = ...

DMW - Deutsche Medizinische Wochenschrift, 2002

The Lancet Oncology, 2014

Preclinical data suggest that triple-negative breast cancers are sensitive to interstrand crossli... more Preclinical data suggest that triple-negative breast cancers are sensitive to interstrand crosslinking agents, and that synergy may exist for the combination of a taxane, trastuzumab, and a platinum salt for HER2-positive breast cancer. We therefore aimed to assess the efficacy of the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive breast cancer. Patients with previously untreated, non-metastatic, stage II-III, triple-negative breast cancer and HER2-positive breast cancer were enrolled. Patients were treated for 18 weeks with paclitaxel (80 mg/m(2) once a week) and non-pegylated liposomal doxorubicin (20 mg/m(2) once a week). Patients with triple-negative breast cancer received simultaneous bevacizumab (15 mg/kg intravenously every 3 weeks). Patients with HER2-positive disease received simultaneous trastuzumab (8 mg/kg initial dose with subsequent doses of 6 mg/kg intravenously every 3 weeks) and lapatinib (750 mg daily). Patients were randomly assigned in a 1:1 ratio with dynamic allocation and minimisation, stratified by biological subtype and Ki-67 level to receive, at the same time as the backbone regimens, either carboplatin (AUC 1·5 [2·0 for the first 329 patients] once a week) or no carboplatin. The primary endpoint the proportion of patients who achieved a pathological complete response (defined as ypT0 ypN0), analysed for all patients who started treatment; a p value of less than 0·2 was deemed significant for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01426880. 296 patients were randomly assigned to receive carboplatin and 299 to no additional carboplatin, of whom 295 and 293 started treatment, respectively. In this final analysis, 129 patients (43·7%, 95% CI 38·1-49·4) in the carboplatin group achieved a pathological complete response, compared with 108 patients (36·9%, 31·3-42·4) without carboplatin (odds ratio 1·33, 95% CI 0·96-1·85; p=0·107). Of the patients with triple-negative breast cancer, 84 (53·2%, 54·4-60·9) of 158 patients achieved a pathological complete response with carboplatin, compared with 58 (36·9%, 29·4-44·5) of 157 without (p=0·005). Of the patients with HER2-positive tumours, 45 (32·8%, 25·0-40·7) of 137 patients achieved a pathological complete response with carboplatin compared with 50 (36·8%, 28·7-44·9) of 136 without (p=0·581; test for interaction p=0·015). Haematological and non-haematological toxic effects that were significantly more common in the carboplatin group than in the no-carboplatin group included grade 3 or 4 neutropenia (192 [65%] vs 79 [27%]), grade 3 or 4 anaemia (45 [15%] vs one [&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1%]), grade 3 or 4 thrombocytopenia (42 [14%] vs one [&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1%]), and grade 3 or 4 diarrhoea (51 [17%] vs 32 [11%]); carboplatin was more often associated with dose discontinuations (141 [48%] with carboplatin and 114 [39%] without carboplatin; p=0·031). The frequency of grade 3 or 4 haematological events decreased from 82% (n=135) to 70% (n=92) and grade 3 or 4 non-haematological events from 78% (n=128) to 59% (n=77) in the carboplatin arm when the dose of carboplatin was reduced from AUC 2·0 to 1·5. The addition of neoadjuvant carboplatin to a regimen of a taxane, an anthracycline, and targeted therapy significantly increases the proportion of patients achieving a pathological complete response. This regimen seems to increase responses in patients with triple-negative breast cancer, but not in those with HER2-positive breast cancer. GlaxoSmithKline, Roche, and Teva.

The Lancet Oncology, 2010

RDI and JV designed the study in collaboration with the European Society for Hyperthermic Oncolog... more RDI and JV designed the study in collaboration with the European Society for Hyperthermic Oncology (ESHO) and European Organisation for Research and Treatment of Cancer (EORTC). UM supervised data management and statistical analysis. All authors participated in the study implementation, data analysis, and interpretation of results. This report was principally drafted by RDI, LHL, JV, UM, and PH, and was critically reviewed and subsequently approved by each co-author.

Immunology, 2012

Adoptive transfer of T cells genetically modified with tumour-specific T-cell receptors (TCR) is ... more Adoptive transfer of T cells genetically modified with tumour-specific T-cell receptors (TCR) is a promising novel approach in the treatment of cancer. We have previously isolated an allorestricted MHC class I-restricted TCR with specificity for Formin-like protein 1 (FMNL1) with potent activity against chronic lymphocytic leukaemia cells. CD4 + T cells have been described to be highly important for tumour elimination although TCR derived from CD4 + T cells with anti-tumour reactivity have been only rarely described. In this study we aimed to isolate MHC class-II-restricted CD4 + T cells and TCR with specificity for leukaemia antigens. We used professional antigen-presenting cells pulsed with the leukaemiaassociated and tumour-associated antigen FMNL1 for stimulation of autologous T cells in vitro. We isolated two CD4 + HLA-DR-restricted T-cell clones and T-cell-derived TCR with so far unknown specificity but high reactivity against lymphoma cells and native malignant cells derived from HLA-matched patients with diverse leukaemias. Moreover, characterization of the TCR after TCR gene transfer revealed that specific characteristics of isolated TCR as reactivity in response to Toll-like receptors were transferable on effector cells. Our results have a major impact on the development of novel immunotherapies. They demonstrate that TCR with potent HLA-DR-restricted anti-leukaemic reactivity against so far undefined self-restricted antigens can be isolated from the healthy autorestricted CD4 + T-cell repertoire and these TCR are highly interesting candidate tools for novel immunotherapies.

Breast Cancer Research and Treatment, 2014

Lapatinib is approved in combination with capecitabine for treatment of patients with human epide... more Lapatinib is approved in combination with capecitabine for treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who have progressed on prior trastuzumab in the metastatic setting. Vinorelbine is an important chemotherapy option for MBC. We evaluated efficacy and safety of lapatinib plus vinorelbine, compared with lapatinib plus capecitabine, in women with HER2positive MBC. In this open-label, multicenter, phase II study, eligible patients (N = 112) were randomized 2:1 to lapatinib plus vinorelbine [(N = 75) 1,250 mg orally once daily (QD) continuously plus 20 mg/m 2 /day intravenously] or lapatinib plus capecitabine [(N = 37) 1,250 mg orally QD continuously plus 2,000 mg/m 2 /day orally, 2 doses]. The primary endpoint was progression-free survival (PFS). Other endpoints included overall survival (OS) and safety. Patients progressing within the study were given the option of crossover to the other treatment arm; time to second progression was an exploratory endpoint. Patient demographics, stratification, and prognostic factors were well balanced between treatments. Median PFS in both arms was 6.2 months [95 % confidence interval (CI) 4.2, 8.8 (lapatinib plus vinorelbine); 4.4, 8.3 (lapatinib plus capecitabine)]. Median OS on lapatinib plus vinorelbine was Electronic supplementary material The online version of this article (

Bone Marrow Transplantation, 2005

Veno-occlusive disease (VOD) is one of the most serious complications following hematopoietic ste... more Veno-occlusive disease (VOD) is one of the most serious complications following hematopoietic stem cell transplantation (HSCT) and is associated with a high mortality. We conducted a large trial on the clinical significance of protein C (PC) and procollagen III peptide (PNPIII) levels, which have been described as possible diagnostic markers of VOD. In total, 350 patients undergoing allogeneic HSCT were included. PC and PNPIII levels were analyzed prior to conditioning and weekly until 8 weeks after the HSCT. Signs of VOD and other transplantation-related complications (graft-versushost disease (GVHD), toxicity, microangiopathic hemolytic anemia, infection) were recorded weekly throughout the trial. Patients showed a significant drop of the PC levels in VOD (70.3 vs 96.3%, Po0.001) and with increasing severity of aGVHD. Steroids increased the PC levels (69.4% vs 109.4%, Po0.001). The highest PNPIII levels were registered in patients with VOD (mean 6.3 IU/ ml). Patients with aGVHD showed an elevation of PNPIII, especially patients with hepatic aGVHD. PC levels during conditioning do not predict VOD (98.5 vs 76.5%, NS). Although PC and PNPIII may play a role in the pathogenesis of VOD they cannot discriminate between complications with jaundice and are only of limited help in the differential diagnosis of VOD.

Bone Marrow Transplantation, 1997

Differential diagnosis of hepatic injury mainly includes veno-occlusive disease (VOD), acute graf... more Differential diagnosis of hepatic injury mainly includes veno-occlusive disease (VOD), acute graft-versus-host disease (aGVHD) of the liver, infections and toxic drug Plasminogen activator inhibitor 1 (PAI-1) and aminopropeptide of type III procollagen (PIIINP) have been effects. 1 Owing to different therapeutic consequences, accurate diagnosis is essential and the identification of a described as markers of hepatic veno-occlusive disease (VOD) after bone marrow transplantation (BMT). We marker would be helpful. Laboratory parameters such as plasminogen activator determined these parameters in two patients undergoing BMT and subsequent liver transplantation due to inhibitor 1 (PAI-1; 2,3) and the aminopropeptide of type III procollagen (PIIINP; 4-6) have been reported to be elevated VOD. Previously normal PAI-1 levels (maximum 30.0 ng/ml in patient 1, 23.7 ng/ml in patient 2) were elevated and possibly useful in diagnosing VOD. We determined these parameters in two bone marrow transplant recipients for the first time in both patients at the time of clinically diagnosed VOD on days 40 and 20, respectively (patient who developed VOD and underwent subsequent liver transplantation. 1: 317.5 ng/ml; patient 2: 317.2 ng/ml). Levels remained elevated until liver transplantation was performed on days 79 and 41, respectively. Baseline levels (day −8) of aminopropeptide of type III collagen (patient 1: 4.44 Patients and methods g/l; patient 2: 8.1 g/l) peaked at the time of BMT in both patients (155.0 g/l and 108.3 g/l). After an intermittent decrease at the time of discharge on day Case 1 32, a second elevation was observed in patient 1 when she was readmitted and presented with typical signs of A 39-year-old patient with acute myeloid leukemia was transplanted from her HLA-identical brother after con-VOD on day 40. In patient 2, PIIINP levels remained high until VOD was diagnosed (day 20) and liver trans-ditioning with busulfan (16 mg/kg over 4 days) and cyclophosphamide (200 mg/kg over 4 days) in April 1995. The plantation was performed. After liver transplantation, PAI-1 levels normalized in both patients and PIIINP patient received low-dose heparin (100 U/kg/day) as VOD prophylaxis starting on day −8. After an uncomplicated levels declined. Both patients died due to infectious complications and multiorgan failure on days 141 and 101, course the patient was discharged on day 32. On day 40 she was readmitted to hospital with hyperbilirubinemia (74.8 respectively. Whereas the early rise of PIIINP did not correlate with the clinical onset of VOD, the results mmol/l), ascites, right upper quadrant pain, hepatomegaly, elevation of liver enzymes, fever and impaired coagulation. emphasise the relevance of PAI-1 for diagnosing VOD. Keywords: veno-occlusive disease; bone marrow trans-The bilirubin level continued to rise. Transjugular liver biopsy was performed on day 47. Unfortunately insufficient plantation; liver transplantation; plasminogen activator inhibitor 1 (PAI-1); aminopropeptide of type III collagen material was obtained and the patient developed an intrahepatic hematoma precluding thrombolytic therapy. Treatment with PGE 2 (days 44-46 and 48-74) led to an improvement in the right upper quadrant pain and a Liver damage represents a key event in the most important decrease in liver enzymes, but the bilirubin continued to life-threatening complications following bone marrow rise. transplantation. In view of the growing numbers of high-On day 70, percutaneous liver biopsy confirmed the diagdose chemotherapy regimens and consecutive stem cell nosis of VOD. Liver transplantation was performed on day transplantations, an increasing rate of hepatic complications 79, when the bilirubin level was 1230.8 mmol/l. Histology can be expected. of the explanted organ confirmed the diagnosis of massive VOD. After improvement of liver function the patient developed pulmonary aspergillosis on day 105, pseudo