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OBJECTIVES AND METHODS Intracranial hemorrhage (ICH) in acute myeloid leukemia (AML) patients is a major concern due to the increased risk of mortality. Few studies have examined ICH specifically in newly diagnosed AML patients receiving intensive induction chemotherapy (IC) and prophylactic platelet transfusions during thrombocytopenia

Treatment‐related complications contribute substantially to morbidity and mortality in acute myeloid leukemia (AML) patients undergoing induction chemotherapy. Although AML patients are susceptible to fluid overload (FO) (e.g., in the context of chemotherapy protocols, during sepsis treatment or to prevent tumor lysis syndrome), little attention has been paid to its role in AML patients undergoing induction chemotherapy. AML patients receiving induction chemotherapy between 2014 and 2019 were included in this study. FO was defined as ≥5% weight gain on day 7 of induction chemotherapy compared to baseline weight determined on the day of admission. We found FO in 23 (12%) of 187 AML patients undergoing induction chemotherapy. Application of >100 ml crystalloid fluids/kg body weight until day 7 of induction chemotherapy was identified as an independent risk factor for FO. AML patients with FO suffered from a significantly increased 90-day mortality rate and FO was demonstrated as an independent risk factor for 90-day mortality. Our data suggests an individualized, weight-adjusted calculation of crystalloid fluids in order to prevent FO-related morbidity and mortality in AML patients during induction chemotherapy. Prospective trials are required to determine the adequate fluid management in this patient population.

Acute kidney injury (AKI) complicates the clinical course of hospitalized patients by increasing need for intensive care treatment and mortality. There is only little data about its impact on AML patients undergoing intensive induction chemotherapy. In this study, we analyzed the incidence as well as risk factors for AKI development and its impact on the clinical course of AML patients undergoing induction chemotherapy. We retrospectively analyzed data from 401 AML patients undergoing induction chemotherapy between 2007 and 2019. AKI was defined and stratified according to KIDGO criteria by referring to a defined baseline serum creatinine measured on day 1 of induction chemotherapy. Seventy-two of 401 (18%) AML patients suffered from AKI during induction chemotherapy. AML patients with AKI had more days with fever (7 vs. 5, p = 0.028) and were more often treated on intensive care unit (45.8% vs. 10.6%, p < 0.001). AML patients with AKI had a significantly lower complete remission rate after induction chemotherapy and, with 402 days, a significantly shorter median overall survival (OS) (median OS for AML patients without AKI not reached). In this study, we demonstrate that the KIDGO classification allows mortality risk stratification for AML patients undergoing induction chemotherapy. Relatively mild AKI episodes have impact on the clinical course of these patients and can lead to chronic impairment of kidney function. Therefore, we recommend incorporating risk factors for AKI in decision-making considering nutrition, fluid management, as well as the choice of potentially nephrotoxic medication in order to decrease the incidence of AKI. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-021-04482-3.

Tyrosine kinase inhibitors (TKI) targeting the epidermal growth factor receptor (EGFR) like the third-generation TKI osimertinib have substantially improved the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring sensitizing EGFR mutations. However, there is a subset of patients that do not benefit from these therapies in terms of response rate or progression-free-survival (PFS). It has been shown that persistence of EGFR mutations in circulating tumor DNA (ctDNA) at weeks 3 and 6 after start of osimertinib predicts shorter PFS. These patients may benefit from additional chemotherapy. While combination therapies with older TKI have been demonstrated effective in improving outcome, they are associated with a significant increase in toxicity.PACE-LUNG is a multicenter, single-arm, investigator initiated, phase II trial conducted with the German national Network Genomic Medicine (nNGM). Patients with stage IIIB or IV NSCLC and exon 19 deletion or p.L858R EGFR mutation not amenable to curative treatment with persisting ctDNA after 3 to 4 weeks of first-line osimertinib monotherapy will receive additional chemotherapy (4 cycles of either cisplatin/pemetrexed or carboplatin/pemetrexed). Afterwards, osimertinib will be continued as standard of care until disease progression or intolerable toxicity. The primary endpoint is PFS. Secondary endpoints include overall survival, response rate, safety, and quality of life. Concomitant translational research will be performed to identify patterns of mutational evolution in ctDNA upon disease progression or ctDNA persistence. Enrollment started in December 2021.The PACE-LUNG trial is designed to evaluate the efficacy and safety of a biomarker-driven strategy for therapy escalation in patients at high risk for early treatment failure. This approach aims not only to improve treatment outcomes, but also to limit the anticipated additional toxicity to high-risk patients.2019-004757-88 (EudraCT).

PurposeTo investigate the work situation of lung cancer survivors and to identify the factors associated with their returning to work.MethodsDescriptive analysis and logistic regression were used to evaluate study population characteristics and independent factors of subsequently returning to work. To analyze time to return to work, Cox regression was used.ResultsThe study sample included 232 lung cancer survivors of working age from 717 enrolled participants in the multi-center cross-sectional LARIS (Quality of Life and Psychosocial Rehabilitation in Lung Cancer Survivors) study. About 67% of the survivors were not employed during the survey. More than 51% of the survivors who were employed before their illness did not return to their work. The survivors who had returned to their careers were younger, associated with higher household income, lower fatigue score, and stable relationship and vocational training. Patients who received social service counseling showed a higher chance of regaining their career.ConclusionsLung cancer survivors were found to be associated with a high risk of unemployment and very low professional reintegration after interruption due to illness. More comprehensive studies are needed to support lung cancer survivors and targeting of patients in need of special attention in rehabilitation that would benefit from the findings in the present study.

Background and objectives Red blood cell (RBC) transfusions are needed by almost every acute myeloid leukaemia (AML) patient undergoing induction chemotherapy and constitute a cornerstone in supportive measures for cancer patients in general. Randomized controlled trials have shown non-inferiority or even superiority of restrictive transfusion guidelines over liberal transfusion guidelines in specific clinical situations outside of medical oncology. In this study, we analysed whether more restrictive RBC transfusion reduces blood use without affecting hard outcomes. Materials and methods A total of 352 AML patients diagnosed between 2007 and 2018 and undergoing intensive induction chemotherapy were included in this retrospective analysis. In the less restrictive transfusion group, patients received RBC transfusion for haemoglobin levels below 8 g/dl (2007-2014). In the restrictive transfusion group, patients received RBC transfusion for haemoglobin levels below 7 g/dl (2016-2018). Liberal transfusion triggers were never endorsed. Results A total of 268 (76·1%) and 84 (23·9%) AML patients fell into the less restrictive and restrictive transfusion groups, respectively. The less restrictive transfusion group had 1 g/dl higher mean haemoglobin levels, received their first RBC transfusions earlier and needed 1·5 more units of RBC during the hospital stay of induction chemotherapy. Febrile episodes, C-reactive protein levels, admission to the intensive care unit, length of hospital stay as well as response and survival rates did not differ between the two cohorts. Conclusion From our retrospective analysis, we conclude that a more restrictive transfusion trigger does not affect important outcomes of AML patients. The opportunity to test possible effects of the more severe anaemia in the restrictive transfusion group on quality of life was missed.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy caused by severely reduced activity of the von-Willebrand factor-cleaving protease ADAMTS13, mainly caused by anti-ADAMTS-13 antibodies. Although several test systems for ADAMTS13 measurement exist, long turn-around times hamper the usability in daily practice. We performed a method comparison study for two commercially available ADAMTS13 assays and evaluated the agreement between the fully-automated rapid turn-over HemosIL AcuStar ADAMTS13 Activity assay and the manually performed TECHNOZYM ADAMTS-13 Activity assay. Twenty-four paired test samples derived from 10 consecutively recruited patients (n = 8, acquired TTP; n = 1, atypical hemolytic uremic syndrome; n = 1, control), of which nine test samples were collected in case of clinically apparent TTP and 13 samples were collected from TTP patients in clinical remission were included. Overall correlation between the TECHNOZYM and AcuStar assay was good with a Pearson R of 0.93 (p or

PURPOSE Third-generation epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes. METHODS Using the databases of two lung cancer networks and two lung cancer centers, we molecularly characterized 124 patients with EGFR p.T790M-positive AR to early-generation EGFR TKIs. In 56 patients, correlative analyses of third-generation EGFR TKI treatment outcomes and molecular characteristics were feasible. In addition, matched post-treatment biopsy samples were collected for 29 patients with progression to third-generation EGFR TKIs. RESULTS Co-occurring genetic aberrations were found in 74.4% of EGFR p.T790-positive samples (n = 124). Mutations in TP53 were the most frequent aberrations detected (44.5%; n = 53) and had no significant impact on third-generation EGFR TKI treatment. Mesenchymal-epithelial transition factor ( MET) amplifications were found in 5% of samples (n = 6) and reduced efficacy of third-generation EGFR TKIs significantly (eg, median progression-free survival, 1.0 months; 95% CI, 0.37 to 1.72 v 8.2 months; 95% CI, 1.69 to 14.77 months; P ≤ .001). Genetic changes in the 29 samples with AR to third-generation EGFR TKIs were found in EGFR (eg, p.T790M loss, acquisition of p.C797S or p.G724S) or in other genes (eg, MET amplification, KRAS mutations). CONCLUSION Additional genetic aberrations are frequent in EGFR-mutant lung cancer and may mediate innate and AR to third-generation EGFR TKIs. MET amplification was strongly associated with primary treatment failure and was a common mechanism of AR to third-generation EGFR TKIs. Thus, combining EGFR inhibitors with TKIs targeting common mechanisms of resistance may delay AR.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Due to often unspecific disease symptoms, locally advanced or metastatic disease is diagnosed in the majority of all cases. Palliative treatment options comprise of conventional cytotoxic agents, immunotherapy with checkpoint inhibitors and the use of specific small-molecule tyrosine kinase inhibitors (TKI). However, these TKIs are mainly restricted to a small proportion of patients with lung cancer that harbor activating driver mutations. Still, the effectiveness and favorable safety profile of these compounds have prompted a systematic search for specific driver mechanisms of tumorigenesis and moreover the development of corresponding kinase inhibitors. In recent years, the Polo-like kinase (PLK) family has emerged as a key regulator in mitotic regulation. Its role in cell proliferation and the frequently observed overexpression in various tumor entities have raised much interest in basic and clinical oncology aiming to attenuate tumor growth by targeting the PLK. In this review, we give a comprehensive summary on the (pre-) clinical development of the different types of PLK inhibitors in lung cancer and summarize their mechanisms of action, safety and efficacy data and give an overview on translational research aiming to identify predictive biomarkers for a rational use of PLK inhibitors.

The 2016 revised World Health Organization (WHO) classification of lymphoid neoplasms included the category of high-grade B cell lymphomas (HGBLs) with combined MYC and BCL2 and/or BCL6 rearrangements (double-hit, DH). However, the clinical features of B cell precursor leukemia (BCP-ALL) that harbor DH genetics remain widely unknown. We performed a retrospective analysis of the German Multicenter Study Group for Adult ALL registry and a literature search for de novo DH-BCP-ALLs. We identified 6 patients in the GMALL registry and 11 patients published in the literature between 1983 and June 2018. Patients of all ages (range, 15-86 years) are affected. There is a high incidence of meningeal disease and other extramedullary disease manifestations. Current treatment approaches are mainly ALL-based and are sufficient to induce first complete remissions, but progression-free survival is only 4.0 months (95% CI, 1.5-6.5 months) and all patients succumb to their disease, once relapsed, with a median survival of 5.0 months (95% CI, 3.1-6.9 months), despite intensive salvage and targeted therapy approaches. Of all patients, only two that attained an initial complete remission were alive at data cutoff. In all cases, the BCL2 gene was rearranged to be in proximity to the IGH locus, whereas MYC had various translocation partners juxtaposed. There was no significant survival difference between IG and non-IG translocation partners (HR, 1.03; 95% CI, 0.33-3.2; p = 0.89). In conclusion, de novo DH-BCP-ALL is an aggressive B cell malignancy with deleterious outcome. Physicians have to be aware of this rare disease subset due to the atypical clinical behavior and especially because latest classification systems do not cover this sub-entity.

Background: Autologous stem cell transplantation is considered a standard of care treatment in eligible patients with multiple myeloma, but puts the patient at high risk for infections and bleeding complications. Acquired von-Willebrand's disease (AVWD) and acquired platelet dysfunction are rare bleeding disorders that are associated with lymphoproliferative disorders such as multiple myeloma. Patients with acquired bleeding disorders who are planned for ASCT to treat the underlying condition are considered at highest risk for bleeding complications, and optimal treatment strategies are not known. Materials and Methods: We summarized the diagnostic and therapeutic approach to a patient affected by AVWD and acquired platelet disorder related to multiple myeloma. The patient who was planned for ASCT presented with moderate to severe bleeding symptoms. Results: Acute bleeding episodes were successfully controlled and prevented during induction and consolidation therapy with immunoglobulins, whereas replacement of plasma-derived VW factor showed no clinical improvement. High-dose melphalan-based consolidation therapy supported with autologous stem-cell transplantation led to an immediate and sustainable rise of von-Willebrand antigen and activity and a subsequent normalization of platelet aggregation activity. After a follow-up of 40 weeks, the patient maintained normalized VW levels and platelet aggregation capacity. There were no further signs or symptoms of bleeding. Conclusion: This case report highlights the necessity for combined supportive and causal treatment in patients with AVWD and paraproteinemic PD. High-dose melphalan with autologous stem cell support may function as a treatment option in patients with myeloma-related AVWD.

Introduction MDRO-colonization has been shown to impair survival in patients with hematological malignancies and solid tumors as well as in patients with liver disease. Despite the increasing spread of multidrug-resistant organisms (MDRO), its impact on patients with hepatocellular carcinoma (HCC) has not been studied. We conducted this retrospective study to analyze the impact of MDRO-colonization on overall prognosis in HCC patients. Materials and methods All patients with confirmed HCC diagnosed between January 2008 and December 2017 at the University Hospital Frankfurt were included in this study. HCC patients with a positive MDRO screening before or within the first 90 days after diagnosis of HCC were defined as colonized HCC patients, HCC patients with a negative MDRO screening were defined as noncolonized HCC patients. Results 59 (6%) colonized and 895 (94%) noncolonized HCC patients were included. Enterobacterales with extended-spectrum β-lactamase-like phenotype with or without resistance to fluoroquinolones (ESBL/ ± FQ) were the most frequently found MDRO with 59%, followed by vancomycin-resistant Enterococcus faecium with 37%. Colonized HCC patients had more severe cirrhosis and more advanced HCC stage compared to noncolonized HCC patients. Colonized HCC patients showed an impaired survival with a median OS of 189 days (6.3 months) compared to a median OS of 1001 days (33.4 months) in noncolonized HCC patients. MDRO-colonization was identified as an independent risk factor associated with survival in multivariate analysis. Conclusion MDRO-colonization is an independent risk factor for survival in patients with HCC highlighting the importance of regular MDRO screening, isolation measures as well as interdisciplinary antibiotic steward-ship programs to guide responsible use of antibiotic agents.

Introduction In contrast to other driver mutations, no targeted therapies have yet been approved in ERBB2-mutated NSCLC (HER2mu NSCLC). Nevertheless, several compounds have revealed promising early efficacy data, which need to be evaluated in the context of current standard approaches. Although data on the efficacy of immune checkpoint inhibitors (ICIs) in second or subsequent lines of treatment remain limited and conflicting, there are virtually no data on patient outcome under ICI/platinum-doublet combinations in the first-line setting. Methods We retrospectively evaluated outcomes of patients with HER2mu NSCLC treated with ICI alone or in combination with chemotherapy within the German National Network Genomic Medicine Lung Cancer consortium by means of overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results ICI either in combination with chemotherapy or as monotherapy was applied as first-line treatment in 27 patients, whereas 34 received single-agent ICI in second or subsequent lines. Patient characteristics were in line with previously published data. In treatment-naive patients receiving ICI in combination with chemotherapy, the ORR, median PFS, and OS rate at 1 year were 52%, 6 months, and 88%, respectively. In second or subsequent lines, ICI monotherapy was associated with an ORR of 16%, a median PFS of 4 months, and a median OS of 10 months. Conclusions ICIs are effective as monotherapy and in combination with platinum-doublet chemotherapy. Therefore, ICI-based treatments may be found as the current standard of care and benchmark for targeted therapies in HER2mu NSCLC.

PURPOSE: To investigate whether minimum intensity projection (MinIP) reconstructions enable more accurate depiction of pulmonary ground-glass opacity (GGO) compared to standard transverse sections and multiplanar reformat (MPR) series in patients with suspected coronavirus disease 2019 (COVID-19). METHOD: In this multinational study, chest CT scans of 185 patients were retrospectively analyzed. Diagnostic accuracy, diagnostic confidence, image quality regarding the assessment of GGO, as well as subjective time-efficiency of MinIP and standard MPR series were analyzed based on the assessment of six radiologists. In addition, the suitability for COVID-19 evaluation, image quality regarding GGO and subjective time-efficiency in clinical routine was assessed by five clinicians. RESULTS: The reference standard revealed a total of 149 CT scans with pulmonary GGO. MinIP reconstructions yielded significantly higher sensitivity (99.9 % vs 95.6 %), specificity (95.8 % vs 86.1 %) and accuracy (99.1 % vs 93.8 %) for assessing of GGO compared with standard MPR series. MinIP reconstructions achieved significantly higher ratings by radiologists concerning diagnostic confidence (medians, 5.00 vs 4.00), image quality (medians, 4.00 vs 4.00), contrast between GGO and unaffected lung parenchyma (medians, 5.00 vs 4.00) as well as subjective time-efficiency (medians, 5.00 vs 4.00) compared with MPR-series (all P < .001). Clinicians preferred MinIP reconstructions for COVID-19 assessment (medians, 5.00 vs 3.00), image quality regarding GGO (medians, 5.00 vs 3.00) and subjective time-efficiency in clinical routine (medians, 5.00 vs 3.00). CONCLUSIONS: MinIP reconstructions improve the assessment of COVID-19 in chest CT compared to standard images and may be suitable for routine application.

91st Annual Meeting of the International Association of Applied Mathematics and Mechanics, GAMM 2020, ; Proceedings in applied mathematics and mechanics : PAMM 20(1), e202000318 (2021). doi:10.1002/pamm.202000318 special issue: "Special Issue: 91st Annual Meeting of the International Association of Applied Mathematics and Mechanics (GAMM) / Issue Edited by: D. Kuhl, A. Meister, A. Ricoeur, O. Wünsch", Published by Wiley-VCH, Weinheim [u.a.]

Introduction: We report on the results of the German early access program (EAP) with the third-generation ALK- and ROS1-inhibitor lorlatinib. Patients and Methods: Patients with documented treatment failure of all approved ALK/ROS1-specific therapies or with resistance mutations not covered by approved inhibitors or leptomeningeal carcinomatosis were enrolled and analyzed. Results: In total, 52 patients were included [median age 57 years (range 32–81), 54% female, 62% never smokers, 98% adenocarcinoma]; 71% and 29% were ALK- and ROS1-positive, respectively. G1202R and G2032R resistance mutations prior to treatment with lorlatinib were observed in 10 of 26 evaluable patients (39%), 11 of 39 patients showed TP53 mutations (28%). Thirty-six patients (69%) had active brain metastases (BM) and nine (17%) leptomeningeal carcinomatosis when entering the EAP. Median number of prior specific TKIs was 3 (range 1–4). Median duration of treatment, progression-free survival (PFS), response rate and time to treatment failure were 10.4 months, 8.0 months, 54% and 13.0 months. Calculated 12-, 18- and 24-months survival rates were 65, 54 and 47%, overall survival since primary diagnosis (OS2) reached 79.6 months. TP53 mutations were associated with a substantially reduced PFS (3.7 versus 10.8 month, HR 3.3, p = 0.003) and were also identified as a strong prognostic biomarker (HR for OS2 3.0 p = 0.02). Neither prior treatments with second-generation TKIs nor BM had a significant influence on PFS and OS. Conclusions: Our data from real-life practice demonstrate the efficacy of lorlatinib in mostly heavily pretreated patients, providing a clinically meaningful option for patients with resistance mutations not covered by other targeted therapies and those with BM or leptomeningeal carcinomatosis.

Background: Demographic development and continuing improvements in supportive and antineoplastic therapies are reasonable predictors of increasing travel activities carried out by patients with malignant diseases in the near future. There is a lack of data on travel habits of patients with end-stage oncological diseases. Methods: We performed a multi-phased cross-sectional study to gain insights into the intersection of travel medicine and oncology and report the process development and results of a first-in-class comprehensive questionnaire of travel habits in this particular subset of patients. Results: A total of 82 patients with 21 different cancer entities at a median age of 63 years (range, 28-84 years) completed the final questionnaire. 90.2% of all participants rated travelling as an important or very important aspect in their lives, of whom 73.2% had participated in a short- or holiday trip after the cancer diagnosis. All but one (98.8%) participant were about to plan a short- or holiday trip in the near future. Germany (home country) was the most important travel destination, ‘Relaxing’ and ‘enjoying nature’ were the most important travel motives. Fatigue and overall (medical) insecurities were major obstacles to carry out travel plans. Pre-travel advice by a healthcare provider was considered by less than 50% of all participants. Conclusions: In conclusion, a high proportion of patients enjoy national and international travelling. Physicians and patients are encouraged to openly discuss holiday-taking in accordance with available guidelines. More research is needed to fully understand needs and obstacles at the crossroads of travel medicine and oncology.

Patients with acute myeloid leukemia (AML) are often exposed to broad-spectrum antibiotics and thus at high risk of Clostridioides difficile infections (CDI). As bacterial infections are a common cause for treatment-related mortality in these patients, we conducted a retrospective study to analyze the incidence of CDI and to evaluate risk factors for CDI in a large uniformly treated AML cohort. A total of 415 AML patients undergoing intensive induction chemotherapy between 2007 and 2019 were included in this retrospective analysis. Patients presenting with diarrhea and positive stool testing for toxin-producing Clostridioides difficile were defined to have CDI. CDI was diagnosed in 37 (8.9%) of 415 AML patients with decreasing CDI rates between 2013 and 2019 versus 2007 to 2012. Days with fever, exposition to carbapenems, and glycopeptides were significantly associated with CDI in AML patients. Clinical endpoints such as length of hospital stay, admission to ICU, response rates, and survival were not adversely affected. We identified febrile episodes and exposition to carbapenems and glycopeptides as risk factors for CDI in AML patients undergoing induction chemotherapy, thereby highlighting the importance of interdisciplinary antibiotic stewardship programs guiding treatment strategies in AML patients with infectious complications to carefully balance risks and benefits of anti-infective agents.

Introduction Cancer patients tend to prefer oral instead of parenteral chemotherapy. To date, there is little evidence on the medication adherence in cancer patients. We investigated medication adherence to tyrosine kinase inhibitors in patients suffering from non-small cell lung cancer. Methods Tyrosine kinase inhibitor adherence was measured electronically by MEMS® (medication event monitoring system) over at least six months. Adherence rates were calculated in terms of Dosing Compliance, Timing Compliance, Taking Compliance, and Drug Holidays. Patients were dichotomized as adherent when Dosing Compliance and Timing Compliance were ≥80%, Taking Compliance ranged between 90 and 110%, and Results Out of 32 patients enrolled, data from 23 patients were evaluable. Median Dosing Compliance, Taking Compliance, and Timing Compliance adherence rates of tyrosine kinase inhibitor intake amounted to 100%, 98%, and 99%, respectively; Drug Holidays were observed in three patients. Four patients were dichotomized as non-adherent. Three of them had a twice-daily tyrosine kinase inhibitor regimen. Median quality of life scores amounted to 67 (max. 100) and remained unchanged over the study period. Fatigue and rash were the most frequently reported adverse drug events. Conclusion Medication adherence of non-small cell lung cancer patients treated with tyrosine kinase inhibitors was extraordinarily high and is likely to support the effectiveness of tyrosine kinase inhibitor treatment and a good quality of life over a long period of time. Adherence facilitating information and education is especially relevant for patients taking tyrosine kinase inhibitors in a twice-daily regimen.

Osimertinib, a third-generation irreversible mutant-selective inhibitor of EGFR kinase activity was clinically evaluated in the AURA trials, where it showed high clinical efficacy and a favorable toxicity profile in patients with acquired exon 20-EGFR pT790M mutation. We provide the clinical data of the German expanded access program that further characterizes the efficacy and safety of osimertinib in a heterogeneous patient population outside clinical trials. We performed a retrospective data analysis on patients who were included into the German osimertinib EAP. Of 81 patients enrolled, 51 patients (62.9%) with sufficient case report form data were available for efficacy and safety analysis. Unconfirmed overall response rate was 80.0% with 2 patients (3.9%) achieving a complete remission and 37 patients (72.5%) having a partial remission. Disease control rate was 95.9% and only two patients showed refractory disease. Disease control rate did not correlate with clinical characteristics and was independent of number as well as type of the previous therapy line(s). Estimated progression-free survival was 10.1 months (95% CI 9.2–11.0 months). Osimertinib showed a favorable toxicity profile with no dose reductions in our observation period, even in patients with low performance status. Median survival from first diagnosis to data cut-off was 47.3 months (95% CI 43.3–51.9 months). Repeated tissue/liquid biopsy of three patients in our cohort who showed disease progression revealed an amplification of MET. We confirm safety and efficacy of osimertinib with high response rates among all subgroups, including patients with poor performance status and multiple prior therapy lines. Amplification of MET might mediate acquired resistance to osimertinib.

Hintergrund Das aggressive biologische Verhalten des kleinzelligen Lungenkarzinoms (SCLC) im Sinne einer kurzen Tumorverdopplungszeit und fruhen Metastasierungstendenz begrundet, dass 70 % der Betroffenen bereits bei Erstdiagnose an einem fortgeschrittenen metastasierten Krankheitsstadium leiden. Die genetische Komplexitat und Instabilitat des SCLC sowie die fruhe Selektion therapieresistenter Zelllinien bedingt eine ausgepragte Neigung zu Rezidiven, liefert jedoch Ansatzpunkte fur zielgerichtete Therapien. Insgesamt ist die Chemotherapie ein wesentliches Standbein der multimodalen und interdisziplinaren Behandlung.

Uber die psychische Verfassung und psychosoziale Versorgungssituation von Uberlebenden mit kleinzelligem Lungenkrebs (SCLC) ist wenig bekannt. Vom Februar 2015 bis September 2016 befragten die Autoren SCLC-Patienten in Behandlung und in Nachsorge, welche nach der Diagnose mindestens 1 Jahr uberlebt hatten, mittels des Gesundheitsfragebogens fur Patienten (PHQ-4) nach ihrer psychischen Belastung. Die Inanspruchnahme von psychosozialen Versorgungsangeboten wurde mit Hilfe selbst entwickelter Fragen erhoben. Von 86 angeschriebenen Personen nahmen 60 an der Befragung teil (Teilnahmequote 70 %). Bei 26 % bestand der Verdacht auf eine depressive Storung, bei 26 % der Verdacht auf eine Angststorung. Insgesamt bestand bei 36 % der Verdacht auf eine behandlungsbedurftige psychische Belastung. Den psychoonkologischen Dienst im Krankenhaus hatten 17 % genutzt. 80 % derjenigen, welchen in der Rehabilitationsklinik Einzelgesprache angeboten worden waren, hatten diese genutzt. Ambulante Angebote hatten 35 % in Anspruch genommen. Insgesamt hatten 63 % der Befragten psychosoziale Angebote genutzt. Die psychische Belastung von SCLC-Uberlebenden ist hoch. Die Mehrheit der Befragten hat psychosoziale Angebote in Anspruch genommen.

BACKGROUND: Approximately 10% of patients with small cell lung cancer (SCLC) develop a paraneoplastic syndrome (PNS). Neurologic PNS are thought to improve prognosis, which we hypothesized is related to increased tumor infiltrating lymphocytes and immune recognition. METHODS: We queried 2,512,042 medical records from a single institution to identify SCLC patients with and without PNS and performed manual, retrospective chart review. We then performed multiplexed fluorescence immunohistochemistry and automated quantitative analysis (AQUA® Technology) on tumors to assess CD3, CD4, and CD8 T cell infiltrates and PD-1/PD-L1 interactions. T cell infiltrates and PD-1/PD-L1 interaction scores were compared among patients with neurologic PNS, endocrinologic PNS, and a control group without PNS. Clinical outcomes were analyzed using the Kaplan-Meier method and Cox proportional-hazards models. RESULTS: We evaluated 145 SCLC patients: 55 with PNS (25 neurologic and 30 endocrinologic) and 90 controls. Patients with neurologic PNS experienced improved overall survival (OS) compared to patients with endocrinologic PNS and controls (median OS 24mo vs. 12mo vs. 13mo, respectively). Of the 145 patients, we identified tumor tissue from 34 patients that was adequate for AQUA analysis. Among 37 specimens from these 34 patients, patients with neurologic PNS had increased T cell infiltrates (p=0.033) and PD-1/PD-L1 interaction (p=0.014) compared to tumors from patients with endocrinologic PNS or controls. CONCLUSION: Tumor tissue from patients with SCLC with neurologic PNS demonstrated increased tumor infiltrating lymphocytes and PD-1/PD-L1 interaction consistent with an inflamed tumor microenvironment.

Little is known about the use of psychosocial services in lung cancer survivors and patients who have survived the diagnosis for at least one year. We investigated the frequency of use, stratified by radiation therapy received, its associated factors, and the reasons for non-use of those services. We performed a multicenter (n = 6 hospitals) cross-sectional study using data from medical records, patient reported questionnaires, and computer-assisted telephone interviews. Odds ratios (OR) for factors potentially associated with the use of any type of psychosocial services were calculated using multivariable logistic regression. We included 604 lung cancer patients/survivors. Of them, 60% (69% of those who had received radiotherapy) had used some kind of psychological and/or social service in the past (47% psychological, 42% social); 39% had used inpatient care, 24% outpatient care (cancer counselling center, general counselling center, psychological counselling by family doctor, psychotherapy, patient support group, pastoral work). Of those who visited a rehabilitation clinic, 66% received psychosocial care there. Factors associated with using psychosocial services in general were female gender (OR 1.96, 95% CI 1.32–2.93), poor emotional functioning (per unit decrease: OR 0.99, 95% CI 0.98–0.996), and younger age (per year decrease: OR 0.95, 95% CI 0.93–0.97). The high proportion of psychosocial care users among lung cancer survivors in Germany indicates that patients are interested in using it and that an unmet need exists. The creation of a broad spectrum of easily accessible services with high quality is important to enable and facilitate use.

9036 Background: The nNGM centralizes molecular diagnostics, treatment recommendations and follow-up reporting in NSCLC in Germany. Uncommon EGFR mutations pose a clinical challenge because they comprise a heterogenous group and analyses of treatment outcome are still scarce. Here, we analyzed follow-up data of patients with rare EGFR mutations and performed functional characterization of recurrent mutations with unknown function. Methods: This multicenter, retrospective analysis of uncommon EGFR mutations (excluding L858R-, T790M mutations and exon 19 deletions) includes stage IV patients with NSCLC from 12 nNGM centers. We categorized EGFR-mutations into 3 groups: uncommon EGFR mutations with known driver function, for instance E709X, G719X, S768I and L861Q (group 1), exon 20 insertions (group 2) and all other very rare mutations (group 3). Functional characterization of unknown mutations was performed by insertion mutagenesis in Ba/F3 cells and monitoring of growth factor-independent proliferation. Results: In total, 834 cases with uncommon EGFR mutations were reported. Follow-up data after EGFR-TKI (Erlotinib, Gefitinib, Afatinib and Osimertinib), chemotherapy and/or mono-PD(L)1 blockade was available for 252 patients. Mean progression free survival (mPFS) on EGFR-TKIs vs. chemotherapy was 6.6 months vs. 5.0 months (HR 0.54, 95%CI 0.35 to 0.81, P =.003) in group 1 (n = 84), and 6.7 months vs. 3.4 months (HR 0.66, 95%CI 0.47 to 0.92, P =.015) in group 3 (n = 104). Mono-anti-PD(L1) blockade was not superior to chemotherapy (group 1, mPFS 3.0 months, HR 1.32, 95% 0.55 – 3.15, P =.535 and group3, mPFS 4.3 months, HR 1.02, 95% CI 0.64 – 1.62, P = 0.951). Exon 20 insertions (group 2, n = 63) did not benefit from EGFR-TKIs or anti-PD(L1) blockade vs. chemotherapy. Overall survival (OS) analysis (n = 218) following chemotherapy (56%) or EGFR-TKI treatment (44%) showed median OS (mOS) of 18.0 months vs. 13.9 months in patients treated with EGFR-TKI and chemotherapy, respectively in group 1 (HR 0.97, 95%CI 0.54 to 1.75, P =.929). In group 3 patients treated with EGFR-TKI and chemotherapy had a mOS of 35.4 months vs. 12.0 months, respectively (HR 0.59, 95%CI 0.35 to 1.01, P =.056). In the Ba/F3 system we could identify 8 recurrent driver and 12 non-driver mutations with a clinically applicable assay turnaround time of 4 weeks to inform clinical decision-making in the future. Conclusions: This real-world dataset confirms that patients with group 1(uncommon) EGFR mutations benefit from EGFR-TKIs and indicates that mono-anti PD(L)1 blockade is not superior to chemotherapy. Furthermore, patients with very rare EGFR mutations (group 3) also experienced a PFS benefit from EGFR-TKI compared to chemotherapy while immune therapy was not beneficial.

From a series of molecular dynamics simulations, we show how the mechanical behaviour of amorphous carbon monolayers can be altered as a function of the underlying network topology. We control both the ring size as well as the ring neighbourhood distribution based on a Monte Carlo dual bond-switching algorithm. This leads to non-planar carbon monolayers whose out-of-plane displacements depend on the level of amorphousness. Subsequent tensile deformation reveals that increasing the network heterogeneity decreases both the tensile strength as well as the stiffness in the elastic range. Furthermore, we investigate the statistics of the elementary plastic events in the amorphous carbon monolayers and report on the power-law distribution of the stress-drops associated with the plastic deformation. The results of this study provide insights into the role of structural disorder of a carbon monolayer and can be used to modify its physical properties.

The objective was to assess quality of life (QoL) in lung cancer survivors, compare it to the general population, and identify factors associated with global QoL, physical functioning, emotional functioning, fatigue, pain, and dyspnea.Data from NSCLC patients who had survived 1 year or longer after diagnosis were collected cross-sectionally in a multicenter study. QoL was assessed with the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and the lung cancer module QLQ-LC13 across different clinical subgroups and compared to age- and sex-standardized general population reference values. Multivariable linear regression analyses were performed to test the associations of patient-, tumor-, and treatment-related factors with the six primary QoL scales.Six hundred fifty-seven NSCLC patients participated in the study with a median time since diagnosis of 3.7 years (range, 1.0-21.2 years). Compared to the age- and sex-standardized general population, clinically meaningful differences in the QoL detriment were found on almost all domains: lung cancer survivors had clinically relevant poorer global QoL (10 points, p0.001). Whereas in 12 months or longer treatment-free patients this detriment was small (8.3), it was higher in patients currently in treatment (16.0). Regarding functioning and symptom scales, respective detriments were largest for dyspnea (41 points), role function (33 points), fatigue (27 points), social function (27 points), physical function (24 points), and insomnia (21 points) observed across all subgroups. The main factor associated with poorer QoL in all primary QoL scales was mental distress (β |19-31|, all p0.001). Detriments in QoL across multiple primary QoL scales were also observed with current treatment (β |8-12|, p0.01), respiratory comorbidity (β |4-5|, p0.01), and living on a disability pension (β |10-11|, p0.01). The main factor associated with better QoL in almost all primary QoL scales was higher physical activity (β |10-20|, p0.001). Better QoL was also observed in patients with high income (β |10-14|, p0.01).Lung cancer survivors experience both functional restrictions and symptoms that persist long term after active treatment ends. This substantiates the importance of providing long-term supportive care.

Relapsed or refractory (R/R) disease remains challenging in acute myeloid leukemia (AML), especially in elderly patients not considered eligible for intensive treatment options. We retrospectively evaluated the safety and efficacy of low-dose melphalan (LD-Mel) in a multicenter analysis in patients over 65 years with R/R AML, who previously had received ≥1 non-curative treatment line. The study included 31 patients (median age 77 years) with 1-4 previous treatment lines. Three patients (9.7%) achieved a complete remission. Two patients (6.5%) achieved a partial remission, nine patients (29.0%) had disease stabilization with reduction of peripheral or bone marrow blast burden, resulting in an overall response rate of 16.1% and 45.2% achieved clinical benefit. Responders showed a significantly longer median overall survival than non-responders (16.3 vs. 2.3 months, p 0.001). Multivariate analysis identified complex karyotype as the only risk factor associated with inferior survival (p 0.001), whereas prior treatment with hypomethylating agents (HMAs) in 25 of 31 patients was associated with superior OS, regardless of prior response to HMAs (p = 0.03). LD-Mel was well tolerated, with mild myelosuppressive side effects. Conclusively, LD-Mel is an effective treatment option in elderly patients with R/R AML, particularly after HMA therapy and in the absence of a complex karyotype.

Platelet function (PF) plays a pivotal role in both hemostasis and thrombosis, and manual light transmission aggregometry (LTA) is considered the standard of care for platelet function testing but is an error-prone and time-consuming procedure. We aimed to test the agreement regarding maximum aggregation (MA), velocity (VEL), and lag-phase (LagP) of platelet aggregation of the automated Sysmex CS-2100 i analyzer (Siemens, Germany) against the APACT 4004 (Elitech, France) in samples derived from healthy participants and patients with hemostaseologic disorders. In total, 123 patient-derived samples were investigated, including 42 patients with acetylsalicylic acid and/or clopidogrel intake and 20 patients with other hemostaseologic disorders. Both MA and VEL showed good or excellent intermethod correlation. Agreement between the testing methods was only partially achieved, and values were indicative for a systematic bias to lower measurements below a threshold of 50% MA with the CS-2100 i compared to the APACT 4004. All patients with impaired PF in the APACT 4004 were successfully identified with the CS-2100 i, and reference values for automated LTA are provided. Conclusively, automated LTA with the CS-2100 i is a highly standardized and reliable PF testing method and represents a decisive step in the simplification of platelet function testing in clinical routine.

Background— Angiotensin II (ATII), a potent vasoconstrictor, causes hypertension, promotes infiltration of myelomonocytic cells into the vessel wall, and stimulates both vascular and inflammatory cell NADPH oxidases. The predominant source of reactive oxygen species, eg, vascular (endothelial, smooth muscle, adventitial) versus phagocytic NADPH oxidase, and the role of myelomonocytic cells in mediating arterial hypertension have not been defined yet. Methods and Results— Angiotensin II (1 mg · kg −1 · d −1 for 7 days) increased the number of both CD11b + Gr-1 low F4/80 + macrophages and CD11b + Gr-1 high F4/80 − neutrophils in mouse aorta (verified by flow cytometry). Selective ablation of lysozyme M-positive (LysM + ) myelomonocytic cells by low-dose diphtheria toxin in mice with inducible expression of the diphtheria toxin receptor (LysM iDTR mice) reduced the number of monocytes in the circulation and limited ATII-induced infiltration of these cells into the vascular wall, whereas the number of neutrophils was not reduced. Depletion of LysM + cells attenuated ATII-induced blood pressure increase (measured by radiotelemetry) and vascular endothelial and smooth muscle dysfunction (assessed by aortic ring relaxation studies) and reduced vascular superoxide formation (measured by chemiluminescence, cytochrome c assay, and oxidative fluorescence microtopography) and the expression of NADPH oxidase subunits gp91 phox and p67 phox (assessed by Western blot and mRNA reverse-transcription polymerase chain reaction). Adoptive transfer of wild-type CD11b + Gr-1 + monocytes into depleted LysM iDTR mice reestablished ATII-induced vascular dysfunction, oxidative stress, and arterial hypertension, whereas transfer of CD11b + Gr-1 + neutrophils or monocytes from gp91 phox or ATII receptor type 1 knockout mice did not. Conclusions— Infiltrating monocytes with a proinflammatory phenotype and macrophages rather than neutrophils appear to be essential for ATII-induced vascular dysfunction and arterial hypertension.

9041 Background: Resistance to early generation epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKI) inevitably develops in EGFR-mutant lung cancer. The secondary EGFR p.T790M mutation is the driving factor in 60% of cases and 3rd generation EGFR TKIs have been developed to overcome T790M-mediated resistance. However, besides T790M other genetic aberrations such as amplifications of MET may contribute to resistance to EGFR inhibition in the same patient. We here report on the systematic analysis of co-occurring genetic aberrations that may influence response to 3rd generation EGFR TKIs. Methods: Thirty-six patients were treated with 3rd generation EGFR TKIs in the setting of acquired resistance to EGFR inhibition in cancer centers in Germany and Switzerland. Pre-treatment samples were analyzed for co-occurring genetic aberrations in a subset of resistance-related genes including MET, HER2, RAS-gene family, PIK3CA, CTNNB1 and PTEN using next-generation sequencing and fluorescence in-situ hybridization assays. We investigated the association between clinical, epidemiological and molecular data and response to treatment (RECIST 1.1). Results: Co-occurring genetic aberrations were found in 68% of the pre-treatment samples where both, analyses by sequencing and FISH were feasible (N = 25). Efficacy of 3rd generation EGFR TKIs significantly dropped in the presence of high-level MET amplification as compared to wild-type MET (ORR, 0.0%; 95% CI, 0.0-60.4 vs. 70.0%; 95% CI, 45.7-87.2; p = 0.02; median PFS, 1.0 month; 95% CI, 0.37-1.72 months vs. 8.2 months; 95% CI, 1.69-14.77 months; p ≤ 0.001). No statistically significant association was found between treatment efficacy and the molecular status of the genes analyzed or the number of prior EGFR TKIs. Conclusions: Prevalence of additional genetic aberrations is frequent in the setting of acquired resistance to early generation EGFR TKIs and may not necessarily mediate resistance to 3rd generation EGFR TKIs. However, in our analysis high-level amplification of MET was associated with primary treatment failure and might be the main factor underlying resistance in this setting.