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Competing Interests: Nadine Kutsch: Honoraria: AbbVie, AstraZeneca, BMS, Kite/Gilead; Research support: AstraZeneca, Gilead. travel grants: AbbVie, AstraZeneca, Beigene, Celgene, Janssen. Sandra Robrecht: Honoraria: AstraZeneca. Anna Fink: Research funding: AstraZeneca and Celgene, Travel grants: AbbVie. Elisabeth Lange: no COIs. Rudolf Weide: Personal fees from AstraZeneca, BeiGene, Biotest, CSL Behring, Daiichi Sankyo, Eisai, Gilead, Hexal, Incyte, Medac, Menarini‐Stemline, Pierre Fabre, Roche, SeaGen, Sobi, and Takeda. Our institution has received research funding from Amgen, Biotest, Celgene, CSL Behring, Daiichi Sankyo, Eisai, GSK, Hexal, Lilly, Medac, Mundipharma, Octapharma, Sobi, and Takeda. Michael G. Kiehl: no COIs. Martin Sökler: no COIs. Rudolf Schlag: no COIs. Ursula Vehling‐Kaiser: no COIs. Georg Köchling: no COIs. Christoph Plöger: no COIs. Michael Gregor: no COIs. Torben Plesner: advisory board: Celgene/BMS. Michael R. Clausen: no COIs. Ilske Oschlies: no COIs. Matthias Ritgen: grants from F. Hoffman‐La Roche; and personal fees from F. Hoffmann‐La Roche and AbbVie. Marco Herling: no COIs. Kirsten Fischer: Advisory Board: AbbVie, Roche, AstaZeneca, Honoraria: Roche, AstraZeneca, Travel Support: Roche. Hartmut Döhner: Advisory role with honoraria for AbbVie, AstraZeneca, Gilead, Janssen, Jazz, Pfizer, Servier, Stemline, Syndax; clinical research funding (to institution) from AbbVie, Astellas, Bristol Myers Squibb, Celgene, Jazz Pharmaceuticals, Kronos Bio, Servier. Clemens‐Martin Wendtner: Research grants, advisory boards and travel grants by Hoffmann‐La Roche, Janssen‐Cilag, AstraZeneca, AbbVie, BeiGene and GSK. Karl‐Anton Kreuzer: consultant or advisory board member, honoraria and research support by AbbVie, Amgen, F. Hoffmann‐LaRoche, Gilead, Janssen‐Cilag and Mundipharma. Stephan Stilgenbauer: Advisory board, honoraria, research support, travel support, speaker fees, trial participation: AbbVie, Amgen, AstraZeneca, BeiGene, BMS, Celgene, Gilead, GSK, Hoffmann‐La Roche, Janssen, Lilly, Novartis, Sunesis. Michael Hallek: Consultant or advisory board member, honoraria, and research support by AbbVie, Amgen, Celgene, F. Hoffmann‐LaRoche, Gilead, Janssen‐Cilag and Mundipharma. Sebastian Böttcher: research funding from Janssen and AbbVie; and honoraria from Roche, Janssen, AbbVie, Novartis, Becton Dickinson, AstraZeneca, and Sanofi. Wolfram Klapper: Research grants from Roche, Amgen, Janssen, InCyte Regeneraon, Takeda and advisory role (Roche) paid to my institution. All without relevance for the current manuscript. Barbara Eichhorst: Consultant or advisory board member, research support or travel support by AbbVie, AstraZeneca, Celgene, F. Hoffmann‐LaRoche, Gilead, Janssen‐Cilag.

Objective: To investigate the association between serum immunoglobulin G (IgG) concentrations and the incidence of infections in patients with chronic lymphocytic leukemia (CLL) and secondary immunodeficiency receiving treatment with Privigen., Materials and Methods: Data was analyzed from a non-interventional study conducted in 31 centers in Germany and 1 in Austria. Adult CLL patients with hypogammaglobulinemia and recurrent infections were allowed to enter the study upon signing informed consent, if a prior decision for treatment with Privigen had been made. All infections requiring an antimicrobial treatment were subject to analysis. Patients were stratified according to their mean post-baseline serum IgG trough levels in a group with lower IgG trough levels (≤ 5.0 g/L), and a group with higher IgG trough levels (> 5.0 g/L)., Results: Overall, 89 patients and 840 treatment cycles were analyzed. Up to 11 treatment cycles (average duration 29 days) were documented in each patient. In the group with higher IgG trough levels (> 5.0 g/L, N = 72), significantly fewer infections were observed than in the group with lower IgG trough levels (≤ 5.0 g/L, N = 17), including fewer severe and serious infections. The Privigen dosage was a major determinant of the post-baseline serum IgG levels. Overall tolerability of Privigen was assessed as very good or good in 91% of patients., Conclusion: This analysis confirms the association of serum IgG trough levels with the incidence of infections and highlights the importance of careful monitoring of IgG levels during treatment of secondary immunodeficiencies in CLL patients.

Clinical trials in chronic myeloid leukemia (CML) are usually carried out in specialized centers whereas primary care for patients (pts) with CML is mainly provided by local oncology practices. The aim of this study was to assess treatment practices in pts with CML in the setting of private oncology practices in Germany. We collected data of 819 pts with a confirmed diagnosis (dx) of CML in 2013 or later from 43 practices. At dx, 84.2% (n=690) and 9.4% (n=77) of pts were in chronic or accelerated phase, 0.7% (n=6) had a blast crisis. Molecular monitoring was provided by EUTOS certified laboratories in 87.7% of pts. Typical BCR::ABL1 transcripts were detected in 86.6% (n=709). Molecular response was assessed after 2.8, 6.0, 9.4 and 12.9 m (mean) after start of treatment. Of the pts with available data, 11.1% did not achieve early molecular response and at 18 m, 83.7% had at least a major molecular response. 288 (35.2%) of pts switched to 2 nd line (2L) treatment after a mean of 21.0 months. Reasons for 2L treatment were side effects in 43.4% and suboptimal response or failure in 31.4% of pts. 106 pts went on to third line (3L) treatment. 36.8 % of pts switched to and 92.8 % of pts still on 3L treatment achieved BCR::ABL1 IS ≤1% at 12 m. In conclusion, in Germany pts with CML are routinely monitored by qPCR and good responses are achieved in the majority. Treatment changes are mainly due to adverse events rather than suboptimal responses., (© 2024. The Author(s).)

Overall survival (OS) of patients with metastatic breast cancer (MBC) has improved within controlled clinical trials. Whether these advances translate into improved OS in routine care is controversial. We therefore analyzed retrospectively unselected female patients from five oncology group practices and one university outpatient clinic, whose initial diagnosis of MBC was between 1995 and 2022. A total of 1610 patients with a median age of 63 years (23-100) were evaluated. In all, 82.9% had hormone-receptor-positive disease, and 23.8% were HER2-positive. Evaluation in time cohorts by initial MBC diagnosis date showed a continuous prolongation of median OS from 31.6 months (0.5-237.3+) (1995-2000) to 48.4 months (0.4-61.1+) (2018-2022) ( p = 0.003). Univariable analyses showed a significant dependence on the time cohort of diagnosis, metastatic status at initial diagnosis, age at metastasis, hormone and HER2 status, general condition, metastasis localization, and the number of affected organs. A multivariable analysis revealed a significant dependence of survival probability on receptor status, general condition, and number of metastatic sites, as well as the time between initial breast cancer diagnosis and the diagnosis date of MBC in months. In sum, OS of patients with MBC has improved continuously and significantly in routine care over the last 27 years.

Background: Eribulin, a halichondrin-class microtubule dynamics inhibitor, is a preferred treatment option for patients with advanced breast cancer who have been pretreated with an anthracycline and a taxane. Peripheral neuropathy (PN) is a common side effect of chemotherapies for breast cancer and other tumors. The Incidence and Resolution of Eribulin-Induced Peripheral Neuropathy (IRENE) noninterventional postauthorization safety study assessed the incidence and severity of PN in patients with breast cancer treated with eribulin., Patients and Methods: IRENE is an ongoing observational, single-arm, prospective, multicenter, cohort study. Adult patients (≥18 years of age) with locally advanced or metastatic breast cancer and disease progression after 1-2 prior chemotherapeutic regimen(s) for advanced disease were treated with eribulin. Patients with eribulin-induced PN (new-onset PN or worsening of preexisting PN) were monitored until death or resolution of PN. Primary endpoints included the incidence, severity, and time to resolution of eribulin-induced PN. Secondary endpoints included time to disease progression and safety., Results: In this interim analysis (data cutoff date: July 1, 2019), 67 (32.4%) patients experienced any grade eribulin-induced PN, and 12 (5.8%) patients experienced grade ≥3 eribulin-induced PN. Median time to resolution of eribulin-induced PN was not reached. Median time to disease progression was 4.6 months (95% CI, 4.0-6.5). Treatment-emergent adverse events (TEAEs) occurred in 195 (93.8%) patients and serious TEAEs occurred in 107 (51.4%) patients., Conclusion: The rates of any grade and grade ≥3 eribulin-induced PN observed in this real-world study were consistent with those observed in phase III randomized clinical trials. No new safety findings were observed., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Up to 30% of metastatic breast cancer (BC) patients develop brain metastases (BM). Prognosis of patients with BM is poor and long-term survival is rare. Identification of factors associated with long-term survival is important for improving treatment modalities., Patients and Methods: A total of 2889 patients of the national registry for BM in BC (BMBC) were available for this analysis. Long-term survival was defined as overall survival (OS) in the upper third of the failure curve resulting in a cut-off of 15 months. A total of 887 patients were categorized as long-term survivors., Results: Long-term survivors compared to other patients were younger at BC and BM diagnosis (median 48 versus 54 years and 53 versus 59 years), more often had HER2-positive tumors (59.1% versus 36.3%), less frequently luminal-like (29.1% versus 35.7%) or triple-negative breast cancer (TNBC) (11.9% versus 28.1%), showed better Eastern Cooperative Oncology Group (ECOG) performance status (PS) at the time of BM diagnosis (ECOG 0-1, 76.9% versus 51.0%), higher pathological complete remission rates after neoadjuvant chemotherapy (21.6% versus 13.7%) and lower number of BM (n = 1, BM 40.9% versus 25.4%; n = 2-3, BM 26.5% versus 26.7%; n ≥4, BM 32.6% versus 47.9%) (P < 0.001). Long-term survivors had leptomeningeal metastases (10.4% versus 17.5%) and extracranial metastases (ECM, 73.6% versus 82.5%) less frequently, and asymptomatic BM more often at the time of BM diagnosis (26.5% versus 20.1%), (P < 0.001). Median OS in long-term survivors was about two times higher than the cut-off of 15 months: 30.9 months [interquartile range (IQR) 30.3] overall, 33.9 months (IQR 37.1) in HER2-positive, 26.9 months (IQR 22.0) in luminal-like and 26.5 months (IQR 18.2) in TNBC patients., Conclusions: In our analysis, long-term survival of BC patients with BM was associated with better ECOG PS, younger age, HER2-positive subtype, lower number of BM and less extended visceral metastases. Patients with these clinical features might be more eligible for extended local brain and systemic treatment., Competing Interests: Disclosure IW received speaker’s honoraria from Astra Zeneca, Merck, Pfizer, Roche, Daiichi-Sankyo, Seagen, Gilead and Novartis. KL received speaker’s honoraria from Roche, Novartis, Pfizer, Exact Sciences, MSD, Eisai, Lilly, Seagen, AstraZeneca and Daiichy Sankyo. MS has received personal fees from AstraZeneca, BioNTech, Daiichi-Sankyo, Eisai, Lilly, MSD, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche and Seagen. His institution has received research funding from AstraZeneca, BioNTech, Eisai, Genentech, German Breast Group, Novartis, Palleos, Pantarhei Bioscience, Pierre Fabre and Seagen. In addition, he has a patent for EP 2390370 B1 and a patent for EP 2951317 B1 issued. SL reports grants, non-financial support and other from Daiichi-Sankyo, during the conduct of the study; grants and other from Abbvie, other from Amgen, grants and other from AstraZeneca, other from BMS, grants and other from Celgene, other from Eirgenix, other from Eisai Europe Ltd, other from GSK, grants, non-financial support and other from Immunomedics/Gilead, other from Lilly, other from Merck, grants from Molecular Health, grants, non-financial support and other from Novartis, grants, non-financial support and other from Pfizer, other from Pierre Fabre, other from Relay Therapeutics, grants, non-financial support and other from Roche, other from Sanofi, non-financial support and other from Seagen, other from Olema Pharmaceutics, outside the submitted work; In addition, SL has a patent EP14153692.0 pending, a patent EP21152186.9 pending, a patent EP15702464.7 issued, a patent EP19808852.8 pending and a patent Digital Ki67 Evaluator with royalties paid. CD reports advisory role for MSD Oncology, Daiichi-Sankyo, Molecular Health, AstraZeneca, Roche and Lilly; CD received research funding from Myriad Genetics, Roche and German Breast Group; CD owns following patents: VMScope digital pathology software, Patent WO2020109570A1, Patent WO2015114146A1, Patent WO2010076322A1. MT received personal fees from Agendia, Amgen, Art tempi, AstraZeneca, Aurikamed, Celgene, Daiichi-Sankyo, Eisai, Exact Sciences, Gilead Science, Grünenthal, GSK, Hexal, Lilly, MSD, Novartis, Onkowissen, Organon, Pfizer, Pierre Fabre, Roche, Seagen, Servier, Streamd Up!, Viatris, Vifor, trial funding from Exact Science and institutional trial honoraria from AstraZeneca, Celgene, Novartis, Roche. VM received speaker honoraria from Amgen, Astra Zeneca, Daiichi-Sankyo, Eisai, GSK, Pfizer, MSD, Medac, Novartis, Roche, Teva, Seagen, Onkowissen, high5 Oncology, Medscape, Gilead and Pierre Fabre; consultancy honoraria from Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Sanofi, Seagen and Gilead; Institutional research support from Novartis, Roche, Seagen, Genentech; travel grants: Roche, Pfizer, Daiichi-Sankyo, Gilead. RW received support for advisory, consultancy, speaker and travel grants from Agendia, Amgen, Aristo, AstraZeneca, Boeringer Ingelheim, Carl Zeiss, Celgene, Clinsol, Clovis Oncology, Daiichi-Sankyo, Eisai, Exact Sciences, Genomic Health, Gilead, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Mylan, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PINK, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Sanofi Genzyme, Seattle Genetics /Seagen, Stemline, Tesaro Bio, Teva, Veracyte and Viatris. TD received Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novartis, IOMEDICO and participated on a Data Safety Monitoring Board or Advisory Board for Novartis, IOMEDICO. All other authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with indolent B-cell non-Hodgkin lymphomas (B-NHLs) have an increased risk of infections which is caused by pathomechanisms of the diseases itself but also as a result of anti-tumor therapy. Especially the effects of anti-CD20 antibodies are well understood as these lead to decreased antibody production. Most studies regarding immunodeficiency in B-NHLs were conducted with multiple myeloma and chronic lymphocytic leukemia patients. As these studies not always represent the general population we collected and analyzed real world data from patients with indolent lymphomas and a control group (CG)., Results: Patients with B-NHLs undergoing therapy or who were regularly monitored in a watch and wait approach had, over the time of one year, an increased rate of infections compared to the CG of 145 healthy volunteers (mean: 11.66 vs. 7.13 infections per 1000 days). Consistent with this finding B-NHL patients received more antibiotic treatment (mean: 11.17 vs. 6.27 days) and were more often hospitalized than persons from the CG (mean: 5.19 vs. 0.99 days per 1000 days). Lymphoma patients without immunodeficiency had a lower infection rate than patients with non-symptomatic and symptomatic immunodeficiency (mean: 10.91 vs. 12.07 and 12.36 per 1000 days). The number of infections differed statistically significant for the subgroups and CG (7.13 per 1000 days). Patients with symptomatic immunodeficiency were mostly treated with regular immunoglobulin substitutions and infection rates were comparable to those of patients with asymptomatic immunodeficiency., Conclusions: Our data suggest the use of an approach with regular immune monitoring including the measurement of immunoglobulin levels and regular appointments for clinical assessment of all indolent lymphoma patients in order to identify patients with increased risk of infections. It also raises the question if patients with immunodeficiency should be treated more often with regular immunoglobulin substitution, but so far more studies are necessary to answer this question., (© 2023. The Author(s).)

Objective: Real-world evidence on the application of the granulocyte colony-stimulating factor lipegfilgrastim for the reduction of chemotherapy-induced neutropenia and febrile neutropenia (FN) is limited. The NADIR study aimed to evaluate effectiveness and safety of lipegfilgrastim as primary or secondary prophylaxis in patients with lung cancer undergoing chemotherapy in routine clinical practice., Methods: The non-interventional study NADIR (German Clinical Trials Register (DRKS) Number DRKS00005711) enrolled 156 patients with small-cell lung cancer (SCLC) and 145 patients with non-small-cell lung cancer (NSCLC), who received lipegfilgrastim during chemotherapy. Primary endpoint was the incidence of severe neutropenia (CTCAE grade 3/4) and FN. The analysis was stratified for age groups (≤65 years vs. >65 years)., Results: Approximately half of the patients were aged >65 years (SCLC 54.5%; NSCLC 46.9%). Intention of antineoplastic treatment was mostly palliative (SCLC 89.1%; NSCLC 73.1%). Patients with high FN risk (SCLC 44.9%; NSCLC 28.3%) mostly received lipegfilgrastim for primary prophylaxis (SCLC 81.4%; NSCLC 70.7%). FN was reported in 1.9% SCLC and 1.4% NSCLC patients. At least one severe neutropenia was documented in 30.1% SCLC and 17.9% NSCLC patients. For NSCLC patients aged >65 years, less severe neutropenia was reported as compared to younger patients (14.7% vs. 20.8%). Lipegfilgrastim-related adverse events were reported in 10.3% SCLC and 7.7% NSCLC patients., Conclusion: Lipegfilgrastim in routine clinical practice of patients with lung cancer showed similar effectiveness and safety as compared to the pivotal trial. Interestingly, in older patients severe neutropenia was reported less frequently. While most patients with high FN risk received lipegfilgrastim for primary prophylaxis as recommended, there are still 20-30% of patients at high FN risk without primary prophylaxis who could benefit from better adherence to guidelines.

Background/aim: Metastatic colorectal cancer (mCRC) is a heterogeneous disease with distinct molecular subtypes. The BRAF V600E -mutation found in approximately 8-12% of mCRC patients is associated with poor prognosis. Guideline recommendations for this population are mostly based on small cohorts due to lack of clinical data. This retrospective analysis was designed to evaluate (approved) therapeutic approaches and algorithms in BRAF V600E -mutant mCRC prior to approval of the targeted combination encorafenib plus cetuximab in Germany, Austria, and Switzerland., Patients and Methods: Anonymized data from BRAF V600E -mutant mCRC patients were analyzed retrospectively regarding 1 st -, 2 nd - and 3 rd -line treatment using descriptive statistics., Results: Forty-two patients were eligible for analysis (mean age 62.1 years, 47.6% female). At initial diagnosis, 20 patients (47.6%) were documented with right-sided tumors. Most patients (81.0%) were tested for BRAF before 1 st -line. Four patients (9.5%) showed high microsatellite instability (MSI-H). Based on 94 treatment lines, chemotherapy combined with targeted therapy (TT) was used mostly (61.7%), followed by chemotherapy alone (19.1%). Backbone therapies were most frequently FOLFOXIRI (27.7%), FOLFOX/CAPOX (22.3%), or FOLFIRI (20.2%). Anti-VEGF/VEGFR and anti-EGFR-treatments were used in 45.7% and 23.4% of patients, respectively. Across all treatment lines and types, the predominantly documented reason for discontinuation was lack of efficacy., Conclusion: Combined chemotherapy+TT (anti-VEGF/VEGFR and anti-EGFR) played a predominant role in BRAF V600E -mutated mCRC treatment prior to approval of the targeted combination encorafenib plus cetuximab. Since lack of efficacy was the major reason for treatment discontinuation, newly approved therapies including encorafenib plus cetuximab and - for MSI-H tumors - pembrolizumab represent urgently needed options for future mCRC patients., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: For several years now, medical students have also been taught general practice at academic medical teaching practices. Specialty practices have not yet been included in the curricular education. Since 1998, we have conducted a block seminar in hematology twice per semester for eighth-semester medical students. This block seminar was offered from 1998-2001 to students at the Philipps University in Marburg and since 2001 to students at the Johannes Gutenberg University in Mainz. Since 2010 our block seminar has been part of the curriculum at the Johannes Gutenberg University. Method: Standardized course evaluation by students who had attended our block seminar between January 2010 and March 2022. Courses that were held virtually due to corona were not included in the analysis. The questionnaire used to evaluate courses in the medical degree program at the Johannes Gutenberg University served as the evaluation instrument. Results: Since 1998 more than 1,000 students have attended our seminar. The systematic evaluation of the course by 500 students who participated in the curricular, classroom-based seminar sessions since 2010 shows that the highest ratings possible are given for practical relevance, learning atmosphere, teaching and effectiveness. Conclusion: High quality in teaching curricular courses to medical students at a specialty practice is possible. Insights into the possibilities connected with working in the outpatient setting at a medical practice broadens students' experience. This teaching format facilitates external university instructors in terms of teaching and, at the same time, relieves the university in terms of staff and financial budget., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Weide et al.)

Objective: Many preference-sensitive decisions have to be made in breast cancer care and little is known about the decision-making processes between breast cancer patients and the different health care professionals engaged in their treatment., Methods: All female breast cancer patients who underwent surgery in four German breast centers between 07/2016 and 12/2018 were invited to fill in a survey. The decision-making process was evaluated using the 9-item Shared Decision Making Questionnaire (SDM-Q-9) and a German measure to assess satisfaction with care (ZAPA). The higher the total score (0-100), the higher the experienced degree of participation and satisfaction, respectively. Participants were asked to separately rate consultations with their inpatient hospital doctors, outpatient gynecologists, outpatient oncologists and primary care providers. An overall mean score for the degree of participation and the satisfaction with care was calculated for each patient across all consultations assessed. Differences between the 4 treating physician groups were analyzed as well., Results: Of 1068 approached patients, 563 with a mean age of 62 and a standard deviation (SD) of 12.2 years filled in the survey (response rate: 53%). The overall SDM-Q-9 score was 73.8 (SD: 20.8). Older patients stated a higher level of participation than younger, different physician groups were rated quite similarly. Overall satisfaction with care was 87.4 (SD: 15.5)., Conclusions: Overall, patients reported to have experienced a high level of shared decision-making (SDM) and were quite satisfied with their treatment. However, we do not know whether non-responders might have had different experiences., (© 2022 John Wiley & Sons Ltd.)

Background: Up to 40% of patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer develop brain metastases (BMs). Understanding of clinical features of these patients with HER2-positive breast cancer and BMs is vital., Patients and Methods: A total of 2948 patients from the Brain Metastases in Breast Cancer registry were available for this analysis, of whom 1311 had primary tumors with the HER2-positive subtype., Results: Patients with HER2-positive breast cancer and BMs were-when compared with HER2-negative patients-slightly younger at the time of breast cancer and BM diagnosis, had a higher pathologic complete response rate after neoadjuvant chemotherapy and a higher tumor grade. Furthermore, extracranial metastases at the time of BM diagnosis were less common in HER2-positive patients, when compared with HER2-negative patients. HER2-positive patients had more often BMs in the posterior fossa, but less commonly leptomeningeal metastases. The median overall survival (OS) in all HER2-positive patients was 13.2 months (95% confidence interval 11.4-14.4). The following factors were associated with shorter OS (multivariate analysis): older age at BM diagnosis [≥60 versus <60 years: hazard ratio (HR) 1.63, P < 0.001], lower Eastern Cooperative Oncology Group status (2-4 versus 0-1: HR 1.59, P < 0.001), higher number of BMs (2-3 versus 1: HR 1.30, P = 0.082; ≥4 versus 1: HR 1.51, P = 0.004; global P = 0.015), BMs in the fossa anterior (HR 1.71, P < 0.001), leptomeningeal metastases (HR 1.63, P = 0.012), symptomatic BMs at diagnosis (HR 1.35, P = 0.033) and extracranial metastases at diagnosis of BMs (HR 1.43, P = 0.020). The application of targeted therapy after the BM diagnosis (HR 0.62, P < 0.001) was associated with longer OS. HER2-positive/hormone receptor-positive patients showed longer OS than HER2-positive/hormone receptor-negative patients (median 14.3 versus 10.9 months; HR 0.86, P = 0.03), but no differences in progression-free survival were seen between both groups., Conclusions: We identified factors associated with the prognosis of HER2-positive patients with BMs. Further research is needed to understand the factors determining the longer survival of HER2-positive/hormone receptor-positive patients., Competing Interests: Disclosure MT serves on the advisory board for Amgen, AstraZeneca, AURIKAMED, Becton/Dickinson, Biom‘Up, Celgene, ClearCut, Clovis, Daiichi Sankyo, Eisai, Exact Sciences, Gilead Science, Lilly, MSD, Norgine, NeoDynamics, Novartis, Onkowissen, Pfizer, pfm Medical, Pierre-Fabre, Roche, RTI Surgical, Seagen and Sysmex; reports manuscript support from Amgen, Celgene, ClearCut, pfm medical, Roche and Servier; support for travel expenses from Amgen, Art Tempi, AstraZeneca, Celgene, Cleracut, Clovis, Connect Medica, Daiichi Sankyo, Eisai, Exact Sciences, Hexal, I-Med-Institute, Lilly, MCI, Medtronic, MSD, Norgine, Novartis, OmniaMed, Pfizer, pfm medical, Roche and RTI Surgical; support for congress expenses from Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Hexal, NeoDynamics, Novartis, Pfizer and Roche; support for speech expenses: Amgen, Art Tempi, AstraZeneca, Celgene, Clovis, Connect Medica, Eisai, Exact Sciences, Gilead Science, Hexal, I-Med-Institute, Jörg Eickeler, Lilly, MCI, Medtronic, MSD, Novartis, OmniaMed, Pfizer, pfm Medical, Roche, RTI Surgical, Seagen, Sysmex, Vifor and Viatris; trial funding support from Endomag and Exact Sciences. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Several scores have been developed in order to estimate the prognosis of patients with brain metastases (BM) by objective criteria. The aim of this analysis was to validate all three published graded-prognostic-assessment (GPA)-scores in a subcohort of 882 breast cancer (BC) patients with BM in the Brain Metastases in the German Breast Cancer (BMBC) registry. The median age at diagnosis of BM was 57 years. All in all, 22.3% of patients ( n = 197) had triple-negative, 33.4% ( n = 295) luminal A like, 25.1% ( n = 221) luminal B/HER2-enriched like and 19.2% ( n = 169) HER2 positive like BC. Age ≥60 years, evidence of extracranial metastases (ECM), higher number of BM, triple-negative subtype and low Karnofsky-Performance-Status (KPS) were all associated with worse overall survival (OS) in univariate analysis ( p < 0.001 each). All three GPA-scores were associated with OS. The breast-GPA showed the highest probability of classifying patients with survival above 12 months in the best prognostic group (specificity 68.7% compared with 48.1% for the updated breast-GPA and 21.8% for the original GPA). Sensitivities for predicting 3 months survival were very low for all scores. In this analysis, all GPA-scores showed only moderate diagnostic accuracy in predicting the OS of BC patients with BM.

Background : Brain metastases (BM) have become a major challenge in patients with metastatic breast cancer. Methods : The aim of this analysis was to characterize patients with asymptomatic BM ( n = 580) in the overall cohort of 2589 patients with BM from our Brain Metastases in Breast Cancer Network Germany (BMBC) registry. Results : Compared to symptomatic patients, asymptomatic patients were slightly younger at diagnosis (median age: 55.5 vs. 57.0 years, p = 0.01), had a better performance status at diagnosis (Karnofsky index 80-100%: 68.4% vs. 57%, p < 0.001), a lower number of BM (>1 BM: 56% vs. 70%, p = 0.027), and a slightly smaller diameter of BM (median: 1.5 vs. 2.2 cm, p < 0.001). Asymptomatic patients were more likely to have extracranial metastases (86.7% vs. 81.5%, p = 0.003) but were less likely to have leptomeningeal metastasis (6.3% vs. 10.9%, p < 0.001). Asymptomatic patients underwent less intensive BM therapy but had a longer median overall survival (statistically significant for a cohort of HER2-positive patients) compared to symptomatic patients (10.4 vs. 6.9 months, p < 0.001). Conclusions : These analyses show a trend that asymptomatic patients have less severe metastatic brain disease and despite less intensive local BM therapy still have a better outcome (statistically significant for a cohort of HER2-positive patients) than patients who present with symptomatic BM, although a lead time bias of the earlier diagnosis cannot be ruled out. Our analysis is of clinical relevance in the context of potential trials examining the benefit of early detection and treatment of BM.

Background: The effects of intravenous immunoglobulin G replacement on perceived health and infection susceptibility of patients suffering from immunoglobulin G (IgG) deficiencies should be evaluated in a prospective analysis., Methods: Patients with symptomatic primary or secondary IgG deficiencies were interviewed prior to the first IgG infusion (t 0 ) and over the course of their treatment (t 1 - t 6 ). The respondents rated their current health using a 100 point scale (EQ-5D-5L), ranging from 0 ('worst imaginable health') to 100 ('best imaginable health'). The patients also provided information on the frequency of infections and of infections requiring antibiotics in the past 8 weeks. A healthy control group (CG) without oncologic diseases answered the questions once., Results: One hundred six patients with a median age of 65 years (21-85 years) were investigated. The median serum IgG concentration changed from 500 mg/dl (t 0 ) to 772 mg/dl (t 6 ). The mean number of infections and of infections requiring antibiotics decreased during IgG replacement significantly. Current health according to EQ-5D-5L improved from 57 (t 0 ) to 68 (t 6 ), compared to 73 in the CG., Conclusion: During the course of IgG replacement patients reported fewer and less severe infections. Their health assessment improved but still was inferior to the healthy CG.

Seven hundred and twenty-four CLL-outpatients with a median age of 67 (35-92) were analyzed. Four hundred and twenty-seven (59%) were male, 297 (41%) female. At diagnosis 556 (77%) were in Binet stage A, 91 (13%) stage B and 36 (5%) stage C. Forty-six percent received treatment during the evaluation period. Treatment consisted of purine analogs in 38%, alkylating agents in 96%, chemoimmunotherapy with anti-CD20 monoclonal antibodies in 63%, ibrutinib in 9%, venetoclax in 1% and idelalisib in 3%. 3% received allogeneic hematopoietic stem cell transplantation. Overall survival (OS) according to Binet stage was: A 13.9 years (0.1-37.4), B 9.2 years (1.4-29.3) and C 7.9 years (0.5-19.4) respectively. Median OS from the start of therapy improved over time; 1995-2001: 5.8 years, 2002-2008: 6.1 years and 2009-2017: median not reached. Survival of patients with CLL has improved in routine care and was strongly related to active disease, disease stage, performance status and whether therapy included an anti-CD20 monoclonal antibody.

Fludarabine, cyclophosphamide and rituximab (FCR) was compared to bendamustine and rituximab (BR) in an international, randomized, open label, phase 3 trial in 561 previously untreated, fit patients with chronic lymphocytic leukemia (CLL) without del (17p). Primary endpoint was progression free survival (PFS). The final primary endpoint analysis after 37.1 months median follow up failed to show the non-inferiority of BR as compared with FCR. With extended median follow up of 58.2 months, median PFS was 42.3 months in BR-treated patients versus 57.6 months for FCR-treated patients (Hazard Ratio [HR] 1.593; 95% CI 1.271-1.996; p < 0.0001). For patients > 65 years, median PFS was 48.5 months with BR versus 57.9 months with FCR without reaching statistical significance (HR 1.352; 95% CI 0.912-2.006; p = 0.134). Median OS was not reached for both arms with 5-year OS rates of 80.1% vs 80.9%, respectively (HR 1.108; 95% CI 0.755-1.627; p = 0.599). No statistically significant difference was found in the time to secondary malignancy between the 2 groups (at 5 years, 86.6% free from secondary malignancies in the BR group vs 83.8% in the FCR group [HR 0.801; 95% CI 0.507-1.267; p = 0.344]). In patients >65 years secondary neoplasia occurred more frequently after FCR treatment [28 of 86 (32.6%) patients] as compared with BR [18 of 107 (16.8%) patients; p = 0.011]. Health-related quality of life was similar in both treatments. Despite the improved PFS for FCR, OS did not differ. These results also suggest an increase in secondary neoplasia associated with FCR in elderly fit CLL patients., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Purpose: Immunomodulatory drugs (IMIDS) have changed the treatment and outcome of patients suffering from multiple myeloma. However, with the oral administration adherence becomes an issue. Since there is no "gold standard" in measuring adherence, we assessed the adherence of myeloma patients with the help of different data sources., Methods: All patients who have been receiving IMIDS for at least 3 months were eligible. Computer assisted personal interviews of patients and, if possible, their caregivers were carried out. Attending oncologists evaluated the patient's adherence with the help of a standardized questionnaire. In addition, a retrospective analysis of prescription data was conducted. All data were analyzed statistically using SPSS., Results: One hundred myeloma patients, 35% female, 65% male, with a median age of 70 years (37-86) were interviewed. Prescription data could be evaluated in terms of adherence in 78 patients (78%), 56 caregivers could be questioned (56%). Ninety-seven percent of patients rated themselves as adherent in taking IMIDS. Data from treating oncologists, caregivers and prescriptions supported this result. IMID therapies were rated as very effective and significant, toxicities were acceptable and dosing regimens simple/uncomplicated., Conclusions: Myeloma patients seem to be highly adherent to IMID treatments.

Purpose: Primary (PID) and secondary immune deficiencies (SID) represent diverse groups of diagnoses, yet both can be effectively treated with intravenous immunoglobulin (IVIG) replacement therapy. Guidelines for the use of IVIG in SID vary due to the paucity of data. The objective was to analyze available IVIG Privigen® (IgPro10, CSL Behring, Bern, Switzerland) data on Efficiency Index (EI) and pharmacokinetic (PK) parameters in patients with PID and SID., Methods: Three Privigen® studies (NCT00168025, NCT00322556, and the observational study IgPro10&#95;5001) were used to identify patients with PID and SID meeting the qualifying criteria for the PK analysis. PK properties of IVIG were estimated using a population PK model based on a standard two-compartment PK model. Immunoglobulin G (IgG) EI was calculated as the gain in serum IgG level per unit external IgG dose., Results: A similar IVIG dose-serum IgG concentration relationship was observed in patients with PID (N = 90) and SID (N = 91). IgG EI was inversely proportional to the endogenous IgG concentration and comparable in PID (slope = -1.079) and SID (slope = -2.12)., Conclusions: These findings indicate that the disposition of Privigen® is similar during IgG replacement therapy in PID and SID. The results contribute to the understanding of IVIG treatment of SID and may support an evidence-based approach for the use of IVIG in SID in the future., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Brain metastases (BMs) have a major impact on life expectancy and quality of life for many breast cancer patients. Knowledge about treatment patterns and outcomes is limited., Methods: We analysed clinical data of 1712 patients diagnosed with BMs from breast cancer between January 2000 and December 2016 at 80 institutions., Results: Median age at diagnosis of BMs was 56 years (22-90 years). About 47.8% (n = 732) of patients had HER2-positive, 21.4% (n = 328) had triple-negative and 30.8% (n = 471) had hormone receptor (HR)-positive, HER2-negative (luminal-like) primary tumours. The proportion of patients with HER2-positive BMs decreased comparing the years 2000-2009 with 2010-2015 (51%-44%), whereas the percentage of patients with luminal-like tumours increased (28%-34%; p = 0.0331). Patients with BMs in the posterior fossa were more often HER2 positive (n = 169/314, 53.8%) than those diagnosed with triple-negative (n = 65/314, 20.7%) or luminal-like primary breast cancer (n = 80/314, 25.5%), (p < 0.0001). Median overall survival (OS) time after development of BMs for the overall cohort was 7.4 months (95% confidence interval [CI]: 6.7-8.0 months). One-year survival rate was 37.7% (95% CI: 35.2-40.1). Patients with HER2-positive tumours had the longest median OS of 11.6 months (95% CI: 10.0-13.4) compared with 5.9 months (95% CI: 5.0-7.2) for patients with luminal-like and 4.6 months (95% CI: 3.9-5.4) for patients with triple-negative tumours. Patients with HER2-positive tumours who received anti-HER2 treatment had longer median OS than those without (17.1 months versus 7.2 months, p < 0.0001)., Conclusions: Prognosis of patients after developing BMs varies significantly according to the subtype. The outcome in this cohort is similarly poor in triple-negative and HR-positive/HER2-negative patients. Our results underline the high medical need for improvement of treatment and prevention strategies for BMs in breast cancer patients., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Late blight disease caused by the plant pathogenic oomycete pathogen Phytophthora infestans is one of the most limiting factors in potato production. P. infestans is able to overcome introgressed late blight resistance by adaptation of effector genes. AVR1 is an RXLR effector that triggers immune responses when recognized by the potato resistance protein R1. P. infestans isolates avirulent on R1 plants were found to have AVR1 variants that are recognized by R1. Virulent isolates though, lack AVR1 but do contain a close homologue of AVR1, named A-L, of which all variants escape recognition by R1. Co-expression of AVR1 and R1 in Nicotiana benthamiana results in a hypersensitive response (HR). In contrast, HR is not activated when A-L is co-expressed with R1 . AVR1 and A-L are highly similar in structure. They share two W motifs and one Y motif in the C-terminal part but differ in the T-region, a 38 amino acid extension at the carboxyl-terminal tail of AVR1 lacking in A-L. To pinpoint what determines R1-mediated recognition of AVR1 we tested elicitor activity of AVR1 and A-L chimeric and deletion constructs by co-expression with R1. The T-region is important as it enables R1-mediated recognition of A-L, not only when fused to A-L but also via trans-complementation. Yet, AVR1 lacking the T-region is still active as an elicitor of HR, but this activity is lost when certain motifs are swapped with A-L. These data show that A-L circumvents R1 recognition not only because it lacks the T-region, but also because of differences in the conserved C-terminal effector motifs.

This phase III, open-label, randomized, controlled study aimed to evaluate the benefit of adding continuous low-dose oral cyclophosphamide to bortezomib-dexamethasone in patients with primary relapsed/refractory multiple myeloma. Patients were randomized 1:1 to receive up to eight 3-week cycles of bortezomib (1.3 mg/m 2 ) and dexamethasone (20 mg; VD; n = 48) or bortezomib-dexamethasone plus oral cyclophosphamide (50 mg; VCD; n = 48). Median time to progression (primary endpoint) was slightly longer in the VD versus VCD group (12.6 vs 9.9 months, P = 0.192), and the hazard ratio for disease progression was in favor of VD (hazard ratio = 0.71, 95% confidence interval = 0.43-1.19, P = 0.196). The overall response rate was 74% with VD and 70% with VCD. Most adverse events were similar in frequency between arms; however, grade ≥ 3 peripheral neuropathy was more frequent in the VCD versus VD arm (15 vs 4%). Infection rate was higher in the VCD arm (64 vs 52%); however, grade ≥3 infection rates were comparable (19 vs 17%). Further trials are needed to determine whether addition of cyclophosphamide to VD at a different dose/schedule confers clinical benefit. This study was terminated prematurely, with insufficient sample size to adequately compare the arms; the results should, therefore, be considered descriptive. This trial is registered: EudraCT Number 2008-003213-27; ClinicalTrials.gov NCT00813150.

Background: Randomized clinical trials do not reflect the day-to-day reality of patient care; hence, the treatment of patients with advanced pancreatic cancer in oncology group practices was evaluated., Patients and Methods: All consecutive patients with advanced pancreatic cancer who were treated between 01/2012 and 12/2015 in 4 oncology group practices were analyzed retrospectively using SPSS software., Results: 324 patients with a median age of 70 years (range 32-94 years) were analyzed. The majority were male (56%) and had distant metastases (74%). Chemotherapy was the major modality of treatment (86%) with a median overall survival (OS) of 33.3 weeks (range 1.7-245.4 weeks). Chemotherapy significantly (p < 0.001) improved OS in comparison to best supportive care only (37.6 vs. 13.9 weeks). Patients with locally advanced disease had a better prognosis compared to patients with metastases (median OS 49.6 vs. 30.4 weeks; p < 0.001). An age-adjusted Charlson comorbidity score of ≥ 9 was found to influence the OS significantly (p = 0.004)., Conclusion: Chemotherapy remains the main modality of treatment for patients with advanced pancreatic cancer with an OS comparable to prospective randomized trials. The OS of this patient cohort has remained the same over the last 20 years despite advances in treatment modalities., (© 2017 S. Karger GmbH, Freiburg.)

Introduction: Currently, about 360 000 breast cancer patients who could, after completion of their primary therapy, take advantage of follow-up options are living in Germany. Up to now very little is known about the extent to which the available options are used and as to how the follow-up reality is experienced and evaluated. Thus, an explorative examination among the patients and their physicians was undertaken. Patients and Methods: All patients who underwent surgery in a certified breast centre between 2007 and 2013 received a standardised questionnaire; at the same time the physicians responsible for the follow-up were invited to answer a standardised questionnaire. Results: 920 patients (response rate: 61 %) with a median age of 65 years (32-95) could be analysed. 99 % of the participants stated that they regularly attended follow-ups. The personal contact with the physician (mean value: 4.4) and the reassurance that the cancer disease had not recurred (mean value: 4.5) were described on a scale of 0 to 5 to be two of the most important factors of the follow-up. Deficits were expressed with regard to psychosocial care (70 %) and the perception and treatment of physical complaints (55 %). In addition, 105 physicians returned completed questionnaires (response rate: 12 %). For asymptomatic patients the physicians performed the following examinations most frequently: anamnesis (92 %), physical examination (87 %) as well as laboratory tests (63 %) and tumour marker determinations (40 %). Conclusion: On the whole it became clear that the vast majority of the patients took advantage of the follow-up options. From the patient's perspective the importance of the follow-up lies in contact to the physician and the comforting assurance that the breast cancer has not relapsed. Deficits are seen in the psychosocial care and the perception and treatment of physical impairments. Not recommended examinations were employed by a significant proportion of the surveyed physicians.

Due to the increase of oral agents nonadherence is an emerging challenge in cancer care. We evaluated how well different assessments match and how adherence could be measured in routine care. For this purpose patients suffering from metastatic solid tumors who were treated with oral anticancer drugs in an oncology group practice were surveyed. Attending oncologists answered a questionnaire, too, and a retrospective analysis of prescription data was conducted. Caregivers who were eligible for an interview were surveyed additionally. 128 patients (70 % female) with a median age of 69 years (36-88) took part, 95 % of all approached patients. 56 % suffered from metastatic breast cancer, 44 % from other metastatic solid tumors. 65 caregivers (60 % female) with a median age of 62 years (21-82) were interviewed as well. Patients were assessed in 84 % as very reliable in medication-taking by their oncologists. This high adherence rate was supported by patients, caregivers and prescription data. However, concordance between assessments of patients, caregivers and oncologists was not substantial. Our method of considering different perspectives to assess adherence has to be improved and validated but could help to evaluate adherence with oral cancer therapy in routine care.

Background: The aim of this study was to evaluate the treatment reality for outpatients with immune thrombocytopenia (ITP) managed by hematologists in routine care., Patients and Methods: All patients with ITP diagnosed between 06/1995 and 12/2014 in a community-based oncology group practice in Germany were retrospectively analyzed., Results: 422 patients with a median age of 55 years (range 7-91 years) were evaluated. 57% were female and 43% male. Only 198 (47%) patients needed therapy. First-line therapy (n = 198) consisted of steroids in 81%, intravenous immunoglobulins (IVIG) in 12%, and IVIG plus steroids in 6%. Patients received a median of 2 (range 1-10) lines of therapy. The most frequently used treatment modalities were steroids in 93%, IVIG in 55%, splenectomy in 21%, and other immunosuppressive agents (OISA) in 23% of patients. Rituximab and thrombopoietin receptor agonists (TRAs) were used in 10% and 6% only. 9 (2%) patients needed hospitalization due to bleeding complications. 72% of patients achieved a durable remission after their last line of therapy. 1 (0.2%) patient died due to bleeding complications., Conclusion: The treatment modalities most frequently used are steroids, immunoglobulins, splenectomy, and OISA. Rituximab and TRAs are only used infrequently. 72% of ITP patients achieve durable remissions. The rate of hospital admissions due to bleeding complications and the ITP-related mortality are low. The majority of ITP patients can be safely managed by hematologists on an outpatient basis., (© 2015 S. Karger GmbH, Freiburg.)

Membrane-bound receptors play crucial roles as sentinels of plant immunity against a large variety of invading microbes. One class of receptors known to be involved in self/non-self-surveillance and plant resistance comprises the L-type lectin receptor kinases (LecRKs). Previously, we reported that several Arabidopsis LecRKs play a role in resistance to Phytophthora pathogens. In this study, we determined whether homologues of these LecRKs from the Solanaceous plants Nicotiana benthamiana and tomato (Solanum lycopersicum) play similar roles in defence against Phytophthora. In genome-wide screenings, a total of 38 (Nb)LecRKs were identified in N. benthamiana and 22 (Sl)LecRKs in tomato, each consisting of both a lectin and a kinase domain. Phylogenetic analysis revealed that, in contrast to Arabidopsis, which has a LecRK family comprising nine clades, Solanaceous species have just five of these nine clades (i.e. IV, VI, VII, VIII, and IX), plus four additional clades that lack Arabidopsis homologues. Several of the Solanaceous LecRKs were selected for functional analysis using virus-induced gene silencing. Infection assays with Phytophthora capsici and Phytophthora infestans on LecRK-silenced plants revealed that N. benthamiana and tomato homologues in clade IX play a role in Phytophthora resistance similar to the two Arabidopsis LecRKs in this clade, suggesting conserved functions of clade IX LecRKs across different plant families. This study provides a first insight into the diversity of Solanaceous LecRKs and their role in plant immunity, and shows the potential of LecRKs for Phytophthora resistance breeding., (© The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Background: Infections are major complications in chronic lymphoproliferative disorders, among them indolent non-Hodgkin's lymphoma (iNHL) including chronic lymphocytic leukemia, follicular lymphoma and multiple myeloma.We report on a retrospective cohort analysis of outpatients with indolent non-Hodgkin's lymphoma who were treated in an oncology / hematology group practice and received intravenous polyvalent immunoglobulin G (IVIG) as supportive care. The aim was to describe the treated iNHL population, the course of therapy and the effects of IVIG administrations on the levels of immunoglobulin G (IgG), the incidence of infections and the survival time., Patients and Method: 57 patients with secondary iNHL antibody deficiencies (n = 46) or IgG subclass deficiencies (n = 11) who received IVIG substitution were included. Patients received median 11 IVIG doses with a mean dose of 28 g over a period of median 9.5 months., Results: Mean IgG levels increased with IVIG substitution at about twice and then remained within the normal range. The incidence of infections decreased in 46 % of treated patients. Effects on survival could not be observed. Median overall survival was in the group of substituted patients 124 months (range 7-124), the control group had a median survival time of 96 months (range 3-129) (p = 0.537)., Conclusion: IgG levels should be reviewed during IVIG substitution on a regular basis and dosage and intervals should be adjusted individually., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: 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., Methods: 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., Results: 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 chemotherapy and at high risk (> 20%) of developing FN were treated with lipegfilgrastim during the first cycle, exposing disparity between real-world practices and current treatment guidelines. Lipegfilgrastim was well tolerated. The only grade 3/4 treatment-related adverse event was anemia in 1 patient., Conclusion: Lipegfilgrastim was effective and safe when administered for the prevention of chemotherapy-induced neutropenia under real-world conditions., (© 2015 S. Karger GmbH, Freiburg.)

18,000 women die due to metastatic breast cancer in Germany per year. Median survival is 20-28 months after diagnosis. The question we wanted to answer was whether survival has improved in routine care? For this purpose we conducted a retrospective analysis of all patients with metastatic breast cancer who were treated between 06/1995-06/2013 in a community-based oncology group practice in Germany. 716 patients were analyzed with a median age of 61 (31-93). Localizations of metastases were distributed as follows: 47% visceral, 36% bone, 9% lymphatic, 4% CNS, 4% others. 79% were hormone-receptor-positive, 20% Her2-positive, 9% triple-negative. Median overall survival was 34 months (95% Confidence Interval: 31-37), median disease-specific survival 36.8 months and disease-specific survival after 5 years 34%. Survival was significantly correlated with localizations of metastases, number of metastasized organs, disease free survival since initial diagnosis, hormone-receptor status and age. Patients with hormone-receptor-positive tumors had a median overall survival of 37 months, Her2-positive patients of 34 months and triple-negative patients of 13 months. 86% of hormone-receptor-positive patients received antihormonal therapy. 81% of Her2-positive patients received anti-Her2 therapy. In summary, longer survival is strongly restricted to hormone receptor- and Her2-positive tumors most likely due to targeted therapies directed against the estrogen-receptor and Her2.

Background: Many women have symptoms of various kinds after being treated for breast cancer. It is unclear how frequently these different side effects of treatment arise., Method: All women who underwent surgery for breast cancer and subsequently received adjuvant systemic treatment in a single certified breast-cancer center from 2006 to 2010 were asked to fill out a standardized questionnaire. Medical data were retrieved from their charts and statistically analyzed together with the questionnaire responses. The questionnaire was also given to an age-adjusted control group., Results: 734 questionnaires were filled out and returned (response rate, 70%). The mean interval from the diagnosis of breast cancer to the time of response to the questionnaire was 38 months. The median age at time of response to the questionnaire was 65 years (range, 30 to 91 years). The distribution of UICC stages at the time of initial diagnosis was as follows: I 46%, II 42%, III 12%. 78% of the patients underwent breat conserving surgery, 85% had radio - therapy, 85% had antihormonal treatment, and 49% had chemotherapy. 91% were satisfied or very satisfied with the outcome of surgery. 34% reported operation site pain; 35% reported limitations of shoulder or arm function. Younger patients suffered from emotional sequelae more than older ones did. 25% reported a change in their relationship with their spouse. Before being diagnosed with breast cancer, 9% had consulted a psychiatrist or psychotherapist; after the diagnosis, 19% did. 14% had taken psychoactive medication before the diagnosis, and 26% did afterward., Conclusion: Treatment for breast cancer has negative physical, emotional, and social effects on many patients. They suffer these effects to varying degrees depending on age, type of surgery, and systemic treatment.

Late blight caused by the plant pathogenic oomycete Phytophthora infestans is known as one of the most destructive potato diseases. Plant breeders tend to employ NB-LRR-based resistance for introducing genetically controlled late blight resistance in their breeding lines. However, P. infestans is able to rapidly escape this type of resistance, and hence, NB-LRR-based resistance in potato cultivars is often not durable. Previously, we identified a novel type of Phytophthora resistance in Arabidopsis. This resistance is mediated by the cell surface receptor LecRK-I.9, which belongs to the family of L-type lectin receptor kinases. In this study, we report that expression of the Arabidopsis LecRK-I.9 gene in potato and Nicotiana benthamiana results in significantly enhanced late blight resistance. Transcriptional profiling showed strong reduction in salicylic acid (SA)-mediated defence gene expression in LecRK-I.9 transgenic potato lines (TPLs). In contrast, transcripts of two protease inhibitor genes accumulated to extreme high levels, suggesting that LecRK-I.9-mediated late blight resistance is relying on a defence response that includes activation of protease inhibitors. These results demonstrate that the functionality of LecRK-I.9 in Phytophthora resistance is maintained after interfamily transfer to potato and N. benthamiana and suggest that this novel type of LecRK-based resistance can be exploited in breeding strategies to improve durable late blight resistance in Solanaceous crops., (© 2013 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.)

Background: In a single-center retrospective donor versus no-donor comparison, we investigated if allogeneic stem cell transplantation (alloSCT) can improve the dismal course of poor-risk chronic lymphocytic leukemia (CLL)., Patients and Methods: All patients with CLL who were referred for evaluation of alloSCT within a 7-year time frame and had a donor search indication according to the EBMT criteria or because of Richter's transformation were included. Patients for whom a matched donor could be found within 3 months (matches) were compared with patients without such a donor (controls). Primary end point was overall survival measured from the 3-month landmark after search initiation., Results: Of 105 patients with donor search, 97 (matches 83; controls 14) were assessable at the 3-month landmark. Matches and controls were comparable for age, gender, time from diagnosis, number of previous regimens, and remission status. Disregarding if alloSCT was actually carried out or not, survival from the 3-month landmark was significantly better in matches versus controls [hazard ratio 0.38, 95% confidence interval (CI) 0.17-0.85; P = 0.014]. The survival benefit of matches remained significant on multivariate analysis., Conclusion: This study provides first comparative evidence that alloSCT may have the potential to improve the natural course of poor-risk CLL as defined by the EBMT criteria.

Bendamustine and bendamustine/rituximab combinations have shown high efficacy in relapsed/refractory chronic lymphocytic leukemia (CLL) and indolent B-cell malignancies (non-Hodgkin lymphoma, NHL). No data exist about bendamustine retreatment after relapse, concerning efficacy and toxicity in this patient population. Eighty-eight outpatients (57 patients with CLL, 31 patients with NHL) who had previously been treated with bendamustine were retreated with a bendamustine regimen. Treatment consisted of bendamustine (B) or bendamustine + mitoxantrone (BM) or bendamustine + rituximab (BR) or bendamustine + mitoxantrone + rituximab (BMR). Median age was 72 years (50-88). A reversible grade 3 or 4 leukocytopenia or thrombocytopenia was observed in 24% and 13%, respectively. The overall response rate (ORR) was 76% (7% complete remission [CR], 69% partial remission [PR]) with 77% (6% CR, 71% PR) in CLL and 71% (8% CR, 63% PR) in NHL. ORR according to regimen was as follows: B: 57% (14% CR, 43% PR), BM: 70% (4% CR, 66% PR), BR: 55% (10% CR, 45% PR), BMR: 84% (7% CR, 78% PR). Bendamustine retreatment is feasible and achieves high response rates and some long lasting remissions.

The actin cytoskeleton is conserved in all eukaryotes, but its functions vary among different organisms. In oomycetes, the function of the actin cytoskeleton has received relatively little attention. We have performed a bioinformatics study and show that oomycete actin genes fall within a distinct clade that is divergent from plant, fungal and vertebrate actin genes. To obtain a better understanding of the functions of the actin cytoskeleton in hyphal growth of oomycetes, we studied the actin organization in Phytophthora infestans hyphae and the consequences of treatment with the actin depolymerising drug latrunculin B (latB). This revealed that latB treatment causes a concentration dependent inhibition of colony expansion and aberrant hyphal growth. The most obvious aberrations observed upon treatment with 0.1 μM latB were increased hyphal branching and irregular tube diameters whereas at higher concentrations latB (0.5 and 1 μM) tips of expanding hyphae changed into balloon-like shapes. This aberrant growth correlated with changes in the organization of the actin cytoskeleton. In untreated hyphae, staining with fluorescently tagged phalloidin revealed two populations of actin filaments: long, axially oriented actin filament cables and cortical actin filament plaques. Two hyphal subtypes were recognized, one containing only plaques and the other containing both cables and plaques. In the latter, some hyphae had an apical zone without actin filament plaques. Upon latB treatment, the proportion of hyphae without actin filament cables increased and there were more hyphae with a short apical zone without actin filament plaques. In general, actin filament plaques were more resilient against actin depolymerisation than actin filament cables. Besides disturbing hyphal growth and actin organization, actin depolymerisation also affected the positioning of nuclei. In the presence of latB, the distance between nuclei and the hyphal tip decreased, suggesting that the actin cytoskeleton plays a role in preventing the movement of nuclei towards the hyphal tip., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The efficacy of bendamustine (50 mg/m², days 1-3) plus mitoxantrone (10 mg/m², day 1), every 28 days for up to four courses, was evaluated in a Phase II multicentre trial enrolling 59 patients with relapsed or refractory B-cell chronic lymphocytic leukaemia (CLL). Major toxicities were grade 3/4 leucopenia, thrombocytopenia and infections in 42%, 12% and 12% of patients, respectively. Complete and partial response was achieved in 5/59 and 25/29 patients, respectively (overall response rate, 51%). Median time to progression was 22 months (range 1-49 + ) and median survival 27 months (range 0-49 + ). The combination of bendamustine and mitoxantrone is an active regime in relapsed or refractory CLL., (© 2012 Blackwell Publishing Ltd.)

Myelodysplastic syndromes (MDS) with del(5q) are considered to have a benign course of the disease. In order to address the issue of the propensity of those patients to progress to acute myeloid leukemia (AML), data on 381 untreated patients with MDS and del(5q) characterized by low or intermediate I International Prognostic Scoring System (IPSS) risk score were collected from nine centers and registries. Median survival of the entire group was 74 months. Transfusion-dependent patients had a median survival of 44 months vs 97 months for transfusion-independent patients (P<0.0001). Transfusion need at diagnosis was the most important patient characteristic for survival. Of the 381 patients, 48 (12.6%) progressed to AML. The cumulative progression rate calculated using the Kaplan-Meier method was 4.9% at 2 years and 17.6% at 5 years. Factors associated with the risk of AML transformation were high-risk World Health Organization adapted Prognostic Scoring System (WPSS) score, marrow blast count >5% and red-cell transfusion dependency at diagnosis. In conclusion, patients with MDS and del(5q) are facing a considerable risk of AML transformation. More detailed cytogenetic and molecular studies may help to identify the patients at risk of progression.

Background: Systematic evaluation of psychosocial distress in oncology outpatients is an important issue. We assessed feasibility and benefit of standardized routine screening using the Distress Thermometer (DT) and Problem List (PL) in all patients of our community-based hematooncology group practice., Patients and Methods: One thousand four hundred forty-six patients were screened between July 2008 and September 2008. Five hundred randomly selected patients were sent a feedback form., Results: The average distress level was 4.7, with 37% indicating a distress level >5. Patients with nonmalignant diseases (81% autoimmune diseases or hereditary hemochromatosis) showed the highest distress level of 5.2. Most distressed were patients who just learned about relapse or metastases (6.4), patients receiving best supportive care (5.4) and patients receiving adjuvant antihormonal therapy (5.4). Ninety-seven percent of patients appreciated to speak to their doctor about their distress. Fifty-six percent felt better than usual after this consultation., Conclusion: DT and PL are feasible instruments to measure distress in hematooncology outpatients receiving routine care. DT and PL are able to improve doctor-patient communication and thus should be implemented in routine patient care. The study shows that distress is distributed differently between individuals, disease groups and treatment phases., (© The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

In plants, an active defense against biotrophic pathogens is dependent on a functional continuum between the cell wall (CW) and the plasma membrane (PM). It is thus anticipated that proteins maintaining this continuum also function in defense. The legume-like lectin receptor kinase LecRK-I.9 is a putative mediator of CW-PM adhesions in Arabidopsis and is known to bind in vitro to the Phytophthora infestans RXLR-dEER effector IPI-O via a RGD cell attachment motif present in IPI-O. Here we show that LecRK-I.9 is associated with the plasma membrane, and that two T-DNA insertions lines deficient in LecRK-I.9 (lecrk-I.9) have a 'gain-of-susceptibility' phenotype specifically towards the oomycete Phytophthora brassicae. Accordingly, overexpression of LecRK-I.9 leads to enhanced resistance to P. brassicae. A similar 'gain-of-susceptibility' phenotype was observed in transgenic Arabidopsis lines expressing ipiO (35S-ipiO1). This phenocopy behavior was also observed with respect to other defense-related functions; lecrk-I.9 and 35S-ipiO1 were both disturbed in pathogen- and MAMP-triggered callose deposition. By site-directed mutagenesis, we demonstrated that the RGD cell attachment motif in IPI-O is not only essential for disrupting the CW-PM adhesions, but also for disease suppression. These results suggest that destabilizing the CW-PM continuum is one of the tactics used by Phytophthora to promote infection. As countermeasure the host may want to strengthen CW-PM adhesions and the novel Phytophthora resistance component LecRK-I.9 seems to function in this process.

Due to necessary selection criteria, the results obtained in clinical trials may not reflect the actual impact of current treatment options for unselected general populations. We analysed the treatment modalities and the outcome in 206 consecutive patients with advanced colorectal cancer who started treatment between 1/1999 and 11/2004. The median age of this cohort was 66 years (range 30-87) and 39 patients (19%) were ≥ 75 years old. First-line treatment consisted of low-dose bolus 5-fluorouracil and folinic acid regimens in 68 patients (33%), weekly 24-h 5-fluorouracil infusion and folinic acid in 36 patients (17%), weekly 24-h 5-fluorouracil infusion plus oxaliplatin or irinotecan in 60 patients (29%), capecitabine regimens in 22 patients (11%), monotherapy with oxaliplatin or irinotecan in six patients (3%) and other regimens in 14 patients (7%). A total of 166 patients (81%) received a second-line treatment and third-line chemotherapy was given to 122/206 patients (59%). With a minimum follow-up of 18 months, the median survival of the cohort is 21 months (range 1-85) and 17 months (range 3-57) for patients ≥ 75 years. We conclude that the increased survival seen in prospective studies can be transferred to routine care for unselected patients with advanced colorectal cancer., (© 2009 The Authors. European Journal of Cancer Care © 2009 Blackwell Publishing Ltd.)

Aims: This retrospective study investigated the rates of renal impairment in patients with multiple myeloma treated with zoledronic acid and ibandronate., Materials and Methods: We retrospectively reviewed medical records in a German oncology clinic, from May 2001 to December 2005. Creatinine measurements were analyzed from baseline (before zoledronic acid or ibandronate treatment) to last evaluation for each patient. A total of 84 patients were included., Results: Zoledronic acid increased the risk of renal impairment by approximately 3-fold compared with ibandronate (renal impairment rates: zoledronic acid 37.7% vs. ibandronate 10.5%, relative risk [RR]=3.6, P=0.0029 serum creatinine [SCr]; 62.3% vs. 23.7%, RR=2.6, P=0.0001 glomerular filtration rate [GFR]). Ibandronate-treated patients switched from zoledronic acid had a significantly higher risk of renal impairment than patients receiving ibandronate monotherapy (zoledronic acid over ibandronate 39.1% vs. ibandronate monotherapy 6.7%, RR= 5.9, P=0.028 [SCr]; 65.2% vs 26.7%, RR=2.4, P=0.022 [GFR]). Multivariate analysis found significantly higher hazard ratios for zoledronic acid over ibandronate (SCr: Cox = 4.38, P=0.01; Andersen-Gill=8.22, P < 0.01; GFR: Cox = 4.31, P < 0.01; Andersen-Gill = 3.71, P < 0.01)., Conclusions: Overall, this retrospective study suggests that multiple myeloma patients are more likely to experience renal impairment with zoledronic acid than with ibandronate. The risk of renal impairment increased if patients had received prior therapy with zoledronic acid.

Phytophthora infestans is the most destructive pathogen of potato and a model organism for the oomycetes, a distinct lineage of fungus-like eukaryotes that are related to organisms such as brown algae and diatoms. As the agent of the Irish potato famine in the mid-nineteenth century, P. infestans has had a tremendous effect on human history, resulting in famine and population displacement. To this day, it affects world agriculture by causing the most destructive disease of potato, the fourth largest food crop and a critical alternative to the major cereal crops for feeding the world's population. Current annual worldwide potato crop losses due to late blight are conservatively estimated at $6.7 billion. Management of this devastating pathogen is challenged by its remarkable speed of adaptation to control strategies such as genetically resistant cultivars. Here we report the sequence of the P. infestans genome, which at approximately 240 megabases (Mb) is by far the largest and most complex genome sequenced so far in the chromalveolates. Its expansion results from a proliferation of repetitive DNA accounting for approximately 74% of the genome. Comparison with two other Phytophthora genomes showed rapid turnover and extensive expansion of specific families of secreted disease effector proteins, including many genes that are induced during infection or are predicted to have activities that alter host physiology. These fast-evolving effector genes are localized to highly dynamic and expanded regions of the P. infestans genome. This probably plays a crucial part in the rapid adaptability of the pathogen to host plants and underpins its evolutionary potential.

We have evaluated all outpatients with relapsed or refractory chronic lymphocytic leukemia (CLL) who were treated with bendamustine/mitoxantrone/rituximab (BMR) between May 1999 and December 2008. Treatment consisted of bendamustine 90 mg/m2 on day 1 + 2, Mitoxantrone 6 mg/m2 on day 1, and Rituximab 375 mg/m2 on day 8, 15, 22 + 29. Thirty-nine patients (19 males, 20 females) received BMR with a median age of 69 years (46–81). Nineteen patients (49%) were above 70 years and 13 patients (33%) were 75 years or above. Performance score ranged between 0 and 2. The median number of previous therapies was 2 (1–4). Therapy was tolerated well with two observed therapy-associated hospitalizations. A reversible grade 3 or 4 hematotoxicity was seen in 30 patients (77%). Other reversible grade 3 or 4 toxicities were seen in two patients (5%). The overall response rate was 92% (10% complete remission, 82% partial remission). Median time to next CLL-therapy was 13 months (0–69). We conclude that BMR is a short and effective outpatient chemoimmunotherapy for patients with relapsed or refractory CLL, which can be used safely in elderly patients.

Purpose: This retrospective study compared renal impairment rates in breast cancer, multiple myeloma, prostate cancer and non-small cell lung cancer patients treated with ibandronate or zoledronic acid., Study Design: Medical records in two German oncology clinics from May 2001 to March 2006 were retrospectively reviewed. Creatinine measurements were analyzed from baseline (before bisphosphonate treatment) to last available measurement for each patient. The Cox proportional hazards model and the Andersen-Gill extension of the Cox model for multiple events analysis were used for multivariate analysis, which controlled for age, clinic site, primary cancer type, baseline SCr or GFR value, prior bisphosphonate use, concomitant use of drugs associated with acute renal failure, and renal-related comorbidities., Results: Of 333 patients, 109 received ibandronate and 256 received zoledronic acid (32 patients had both drugs). Compared with ibandronate, the zoledronic acid group had a significantly better baseline renal function and fewer patients had a history of renal disease. Zoledronic acid treatment increased the relative risk (RR) and the incidence rate (IR) of renal impairment by approximately 1.5-fold in all assessed patients (all tumors) compared with ibandronate. Multivariate analysis found significantly higher hazards ratios for zoledronic acid over ibandronate (two to sixfold), after adjusting for differences in characteristics between the two treatment groups., Conclusions: In this retrospective review, patients were significantly more likely to experience renal impairment with zoledronic acid than with ibandronate.

Treatment outcome data generated in prospective trials are intrinsically biased due to necessary selection criteria. Therefore the results obtained may not reflect the actual impact of current treatment options for an unselected general population. We analysed the treatment modalities and the outcome in 212 consecutive patients with non small cell lung cancer stages IIIB and IV who were seen in a community based oncology group practice between 6/1995 and 6/2006. 93 presented with stage IIIB and 119 with stage IV. Chemotherapy was given to 194/212 patients (92%), 114 patients (54%) received palliative radiation at one point during treatment. Treatment consisted of chemotherapy only in 86 patients (40%) and radiation only in 6 patients. 12 patients received best supportive care only. Patients with stage IIIB have survival rates at 12, 24 and 36 months of 64%, 27% and 21% respectively and for patients with stage IV the survival rates at 12, 24 and 36 months are 40%, 19% and 11% respectively. The median survival for stages IIIB and IV is 16 and 11 months respectively. In a multivariate analysis incorporating the factors stage (IIIB vs. IV), age (<70 vs. >/=70 years) and performance status (WHO 0/1 vs. 2/3) only stage and performance status were independent factors for survival. These retrospective data concerning analysis of survival, response rates and toxicity in a community setting confirm published results of phase II-III studies and indicate that results generated in prospective trials can be transferred into routine care.

Background: Inpatient CT-guided core needle biopsies are an integral diagnostic method to obtain a histology from lesions of unknown dignity in oncology. The purpose of this study was to evaluate feasibility, sensitivity, specificity, and complication rate of diagnostic CT-guided percutaneous core needle biopsies in oncology outpatients., Patients and Methods: We retrospectively analyzed data of all oncology outpatients who received CT-guided core needle biopsies between August 2001 and March 2005., Results: 432 outpatients received 465 CT-guided core needle biopsies using a 14-, 16-, or 18-gauge coaxial cutting needle. 174 patients (37%) were biopsied for intra-abdominal lesions, 130 (28%) for intrathoracic lesions, 55 (12%) for bone lesions, 40 (9%) for peripheral tumors, 36 (8%) for peripheral lymph nodes, and 30 (7%) for central lymph nodes. 249 (53%) biopsies were performed in local anesthesia, 216 (47%) in general anesthesia. Sensitivity was 94%, specificity 92%, and effective accuracy 92%. Complications occurred after 23 biopsies (4.9%). A pneumothorax occurred after 17 thorax biopsies (13%). 7 patients (1.5%) had to be hospitalized after the biopsy. No patient died due to the procedure., Conclusion: CT-guided core needle biopsies are feasible and safe in oncology outpatients. The technique shows a high diagnostic sensitivity and specificity with a low complication rate in routine care., (Copyright (c) 2009 S. Karger AG, Basel.)

Background: Little is known about the treatment reality in metastatic breast cancer (MBC) outside clinical trials. We undertook this analysis to evaluate the actual treatment reality for unselected patients with MBC in routine care., Patients and Methods: All patients with MBC, who were treated in our community-based group practice between 1995 and 2005, were analyzed retrospectively concerning prognostic factors, treatment, and survival., Results: 403 consecutive patients were evaluated with a median age of 60 years (range 32-93). Aromatase inhibitor therapy was used in 87% of all patients. 83% received chemotherapy with the median number of lines being 3 (1-15). An anthracycline was given to 49%, a taxane was used in 55%, vinorelbine in 42%, capecitabine in 36%, gemcitabine in 28%, and a platinum compound in 9%. 94% of patients with bone metastasis received a bisphosphonate, and 63% of HER-2/neu-positive patients were treated with trastuzumab. Median survival since the start of palliative therapy was 30 months. Statistical analysis revealed as major prognostic factors hormone receptor status and prevalence of only bone metastasis., Conclusions: Treatment reality of MBC in routine care reveals a prolonged median survival of 30 months which is probably due to the sequential use of the most effective treatment modalities., (Copyright 2009 S. Karger AG, Basel.)