Abdominal venous thromboses: detection of the JAK2 p.V617F mutation by next-generation ultradeep sequencing-A prevalence study of patients in Mecklenburg-West Pomerania (2017-2021).

Background: Abdominal venous thromboses are rare thrombotic events with heterogeneous etiologies. They are related to myeloproliferative neoplasms (MPNs) in some patients and can occur as first signs of the disease. MPNs are characterized by mutations in the genes of Janus kinase 2 (JAK2), myeloproliferative leukemia virus oncogene (MPL), and calreticulin (CALR). Methods: Within the prospective trial "Prevalence of JAK2 mutations in patients with abdominal venous thromboses" (JAK2 MV study; German Clinical Trials Register: DRKS00026943), the peripheral blood of patients with abdominal venous thromboses in Mecklenburg-West Pomerania, a federal state located in north-east Germany, was analyzed by next-generation ultradeep sequencing for MPN-associated mutations. Clinical characteristics and blood cell counts were also of interest. The primary endpoint was the detection of the mutation JAK2 p.V617F. Secondary endpoints were the detection of other acquired variants of JAK2, as well as MPL and CALR. Results: A total of 68 patients with abdominal venous thromboses were included from February 2017 to January 2021, with splanchnic veins affected in 65 patients. The mutation JAK2 p.V617F was present in 13 patients (19%), with four patients showing low variant allele frequencies (VAF 0.1% to 1.9%). The time interval from the thrombotic event to analysis was longer for patients with the mutation. The mutation MPL p.W515R was detected in three cases, all of them with low VAF. One patient among them had a concurrent mutation of JAK2 p.V617F. The mutations CALR type I or type II were not found. Discussion: By analyzing peripheral blood for the mutation JAK2 p.V617F, an important cause of these rare thrombotic events can be identified. The development of a diagnostic workup with next-generation ultradeep sequencing for the analysis of the JAK2 p.V617F mutation and further mutations has the potential to better understand the etiology of abdominal venous thromboses in individual patients in regional clinical care, as abdominal venous thromboses are diagnosed by various medical disciplines.

AFM13 in patients with relapsed or refractory classical Hodgkin lymphoma: final results of an open-label, randomized, multicenter phase II trial.

In patients with relapse of classical Hodgkin lymphoma (cHL) after autologous stem cell transplant, brentuximab vedotin and anti-PD1 treatment, the outcome is poor. To assess the efficacy of the bispecific anti-CD30/CD16A, NK-cell engaging antibody AFM13 and to select the optimal treatment schedule (arm A-C), we initiated a randomized two-stage phase II trial (NCT02321592). Due to slow recruitment, the trial was terminated after treatment of 25 patients. Treatment with AFM13 was well tolerated: only two treatment-associated serious adverse events (SAEs) were reported; all SAEs resolved completely. With an objective response rate (ORR) of 16.7% (1/5 in arm A, 1/11 in arm B, and 2/8 in arm C) and a 12-month progression-free survival (PFS) of 12.6% (95% CI 3.2-28.9), treatment efficacy of AFM13 monotherapy in all evaluable patients was modest. The continuous application schedule (arm C) might be more effective, but the visit schedule should be better aligned with patients' daily life.

Preclinical Head and Neck Squamous Cell Carcinoma Models for Combined Targeted Therapy Approaches.

This study aimed to refine combined targeted approaches on well-characterized, low-passage tumor models. Upon in vivo xenografting in immunodeficient mice, three cell lines from locally advanced or metastatic HNSCC were established. Following quality control and basic characterization, drug response was examined after therapy with 5-FU, Cisplatin, and cyclin-dependent kinase inhibitors (abemaciclib, THZ1). Our cell lines showed different in vitro growth kinetics, morphology, invasive potential, and radiosensitivity. All cell lines were sensitive to 5-FU, Cisplatin, and THZ1. One cell line (HNSCC48 P0 M1) was sensitive to abemaciclib. Here, Cyto-FISH revealed a partial CDKN2a deletion, which resulted from a R58* mutation. Moreover, this cell line demonstrated chromosome 12 polysomy, accompanied by an increase in CDK4-specific copy numbers. In HNSCC16 P1 M1, we likewise identified polysomy-associated CDK4-gains. Although not sensitive to abemaciclib per se, the cell line showed a G1-arrest, an increased number of acidic organelles, and a swollen structure. Notably, intrinsic resistance was conquered by Cisplatin because of cMYC and IDO-1 downregulation. Additionally, this Cisplatin-CDKI combination induced HLA-ABC and PD-L1 upregulation, which may enhance immunogenicity. Performing functional and molecular analysis on patient-individual HNSCC-models, we identified CDK4-gains as a biomarker for abemaciclib response prediction and describe an approach to conquer intrinsic CDKI resistance.

Quality of Life of Patients with Head and Neck Cancer Receiving Cetuximab, Fluorouracil, Cisplatin Comparing to Cetuximab, Fluorouracil, Cisplatin, and Docetaxel within the CEFCID Trial.

INTRODUCTION: CeFCiD was a multicenter phase II study comparing the efficacy of cetuximab (C), 5-flourouracil, and cisplatin with the same regimen adding docetaxel (D) in recurrent/metastatic head and neck cancer. The primary analysis trial did not demonstrate survival benefit from therapy intensification in first-line recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). The current analysis of the trial assessed the impact of treatment on quality of life (QoL). METHODS: The European Organization for Research and Treatment of Cancer Quality of life Questionnaire QLQ-C30 and the tumor-specific module for head and neck cancer (QLQ-H&N35) were used to assess QoL at baseline (visit 1), after 2 (visit 3), 4 (visit 5), and 6 (visit 7) cycles of chemotherapy. RESULTS: Of 180 patients included in this study, 86 patients (47.8%) completed the questionnaires at baseline. Considering selected scores over treatment time, there was no difference in global QoL, dyspnea, swallowing, and speech between the treatment arms in the course. For fatigue, a significant increase from baseline to visit 3 (p = 0.02), visit 5 (p = 0.002), and to visit 7 (p = 0.003) was observed for patients receiving D, cisplatin or carboplatin (P), 5-fluorouracil (F), and C. At the end of chemotherapy, the manifestation of fatigue was similar compared in the 2 treatment arms. DISCUSSION/CONCLUSION: Therapy intensification not adversely affects selected scores of QoL of patients with recurrent and/or metastatic SCCHN. Nevertheless, fatigue seems to be pronounced in patients treated with D.

Long-term survivor of metastatic squamous-cell head and neck carcinoma with occult primary after cetuximab-based chemotherapy: A case report.

BACKGROUND: Cancer of unknown primary (CUP) is a histological proven malignant tumor whose origin cannot be detected despite careful examination. Most cervical lymph node metastases in CUP (80%) will originate from head and neck sites, and 15% show infiltration of squamous carcinoma cells. The survival rates of CUP are poor: The 5-year-survival rate ranges from 10% to 15%. First-line treatment recommendation for advanced, inoperable squamous cell carcinoma of head/neck (HNSCC) was cetuximab plus platinum-fluorouracil chemotherapy until recently, when checkpoint inhibitors proved clinically beneficial therapies. CASE SUMMARY: Here, we report a case of a 42-year-old female patient with cervical and abdominal lymph node and distant bone metastases of an occult primary of the head and neck (squamous cell carcinoma, human papillomavirus positive). The cancer was diagnosed during pregnancy 10 years ago, and after giving birth, the patient was treated with cetuximab plus platinum-fluorouracil chemotherapy achieving complete remission (CR). CR lasted 26 mo when new metastases (abdominal lymph node, lumbar vertebral body) emerged. Both manifestations were irradiated. From then on, the patient has not received any further treatment, and her disease has remained controlled. Ten years after the initial cancer diagnosis, the patient is still alive and in good health, representing an exceptional case of HNSCC. CONCLUSION: This case illustrates the exceptional clinical course and benefits of combined therapy approaches in advanced metastatic HNSCC with occult primary.

Establishment and characterization of patient-derived head and neck cancer models from surgical specimens and endoscopic biopsies.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is heterogeneous in etiology, phenotype and biology. Patient-derived xenografts (PDX) maintain morphology and molecular profiling of the original tumors and have become a standard "Avatar" model for human cancer research. However, restricted availability of tumor samples hindered the widespread use of PDX. Most PDX-projects include only surgical specimens because reliable engraftment from biopsies is missing. Therefore, sample collection is limited and excludes recurrent and metastatic, non-resectable cancer from preclinical models as well as future personalized medicine. METHODS: This study compares the PDX-take rate, -growth, histopathology, and molecular characteristics of endoscopic specimens with surgical specimens. HNSCC samples (n = 55) were collected ad hoc, fresh frozen and implanted into NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice. RESULTS: Engraftment was successful in both sample types. However, engraftment rate was lower (21 vs. 52%) and growth delayed (11.2 vs. 6.7 weeks) for endoscopic biopsies. Following engraftment, growth kinetic was similar. Comparisons of primary tumors and corresponding PDX models confirmed preservation of histomorphology (HE histology) and molecular profile (Illumina Cancer Hotspot Panel) of the patients' tumors. Accompanying flow cytometry on primary tumor specimens revealed a heterogeneous tumor microenvironment among individual cases and identified M2-like macrophages as positive predictors for engraftment. Vice versa, a high PD-L1 expression (combined positive score on tumor/immune cells) predicted PDX rejection. CONCLUSION: Including biopsy samples from locally advanced or metastatic lesions from patients with non-surgical treatment strategies, increases the availability of PDX for basic and translational research. This facilitates (pre-) clinical studies for individual response prediction based on immunological biomarkers.

A Prospective Real-World Multi-Center Study to Evaluate Progression-Free and Overall Survival of Radiotherapy with Cetuximab and Platinum-Based Chemotherapy with Cetuximab in Locally Recurrent Head and Neck Cancer.

Treatment options of locoregional recurrent head and neck squamous cell cancer (HNSCC) include both local strategies as surgery or re-radiotherapy and systemic therapy. In this prospective, multi-center, non-interventional study, patients were treated either with platinum-based chemotherapy and cetuximab (CT + Cet) or re-radiotherapy and cetuximab (RT + Cet). In the current analysis, progression-free survival (PFS) and overall survival (OS) were compared in patients with locoregional recurrence. Four hundred seventy patients were registered in 97 German centers. After exclusion of patients with distant metastases, a cohort of 192 patients was analyzed (129 CT + Cet, 63 RT + Cet). Radiotherapy was delivered as re-irradiation to 70% of the patients. The mean radiation dose was 51.8 Gy, whereas a radiation dose of ≥60 Gy was delivered in 33% of the patients. Chemotherapy mainly consisted of cisplatin/5-flurouracil (40%) or carboplatin/5-flurouracil (29%). The median PFS was 9.2 months in the RT + Cet group versus 5.1 months in the CT + Cet group (hazard ratio for disease progression or death, 0.40, 95% CI, 0.27-0.57, p < 0.0001). Median OS was 12.8 months in the RT + Cet group versus 7.9 months in the CT + Cet group (hazard ratio for death, 0.50, 95% CI, 0.33-0.75, p = 0.0008). In conclusion, radiotherapy combined with cetuximab improved survival compared to chemotherapy combined with cetuximab in locally recurrent HNSCC.

The Individual Effects of Cyclin-Dependent Kinase Inhibitors on Head and Neck Cancer Cells-A Systematic Analysis.

Cyclin-dependent kinase inhibitors (CDKi´s) display cytotoxic activity against different malignancies, including head and neck squamous cell carcinomas (HNSCC). By coordinating the DNA damage response, these substances may be combined with cytostatics to enhance cytotoxicity. Here, we investigated the influence of different CDKi´s (palbociclib, dinaciclib, THZ1) on two HNSCC cell lines in monotherapy and combination therapy with clinically-approved drugs (5-FU, Cisplatin, cetuximab). Apoptosis/necrosis, cell cycle, invasiveness, senescence, radiation-induced γ-H2AX DNA double-strand breaks, and effects on the actin filament were studied. Furthermore, the potential to increase tumor immunogenicity was assessed by analyzing Calreticulin translocation and immune relevant surface markers. Finally, an in vivo mouse model was used to analyze the effect of dinaciclib and Cisplatin combination therapy. Dinaciclib, palbociclib, and THZ1 displayed anti-neoplastic activity after low-dose treatment, while the two latter substances slightly enhanced radiosensitivity. Dinaciclib decelerated wound healing, decreased invasiveness, and induced MHC-I, accompanied by high amounts of surface-bound Calreticulin. Numbers of early and late apoptotic cells increased initially (24 h), while necrosis dominated afterward. Antitumoral effects of the selective CDKi palbociclib were weaker, but combinations with 5-FU potentiated effects of the monotherapy. Additionally, CDKi and CDKi/chemotherapy combinations induced MHC I, indicative of enhanced immunogenicity. The in vivo studies revealed a cell line-specific response with best tumor growth control in the combination approach. Global acting CDKi's should be further investigated as targeting agents for HNSCC, either individually or in combination with selected drugs. The ability of dinaciclib to increase the immunogenicity of tumor cells renders this substance a particularly interesting candidate for immune-based oncological treatment regimens.

Longitudinal observation of anxiety and depression among palliative care cancer patients.

BACKGROUND: Anxiety and depressive symptoms are commonly reported to have a high prevalence in advanced cancer patients. However, whether the severity of the symptoms change during a stay in a palliative care unit (PCU) and after discharge home has not been studied thus far. This prospective, longitudinal, single-center study screened for anxiety and depression as measured on the German version of Hospital Anxiety and Depression Scale (HADS-D) in a palliative care (PC) cancer cohort at three different time points. METHODS: Consecutive patients (N=206) admitted to a PCU were evaluated of whom N=102 could be enrolled. Patients were screened for anxiety and depression using the HADS-D questionnaire: 24 h after admittance (P1), within 24 h before discharge (P2) and 2 weeks after discharge (P3). Longitudinal changes and influencing factors were determined. RESULTS: Nearly 80% of all patients had at least at one time point a HADS score ≥8 indicating a clinically meaningful symptom burden. The P1 mean scores were 7.1±3.3 (anxiety) and 8.9±4.6 (depression). Depression was associated with underlying cancer type (P<0.05). Anxiety and depression stabilized during hospitalization (P2). However, a significant deterioration after discharge (P3) was observed (anxiety P=0.046; depression P=0.003), in particular in older patients (>65 years) and higher ECOG status (≥3). Patients with a short time since first diagnosis (<1 year) had significantly higher symptom burden compared to patients with a longer disease course. Participation was 50% emphasizing the difficulty to study PC patients. Most patients had advanced cancers (99%). Underlying cancer types consisted of a broad variety of solid tumors including 15% hematological cases. Median survival was 1.1 months. CONCLUSIONS: The high prevalence of anxiety and depressive symptoms points to the need for psychological support. All PC patients should be screened for psychological distress to identify those in need of further assessment and treatment. The deterioration at home suggests the need for improved outpatient management, including home-based psychological support. Caregivers should be aware of the psychological vulnerability of newly diagnosed cancer patients, patients with lower functional status and higher age.

Cyclin-dependent kinase inhibitors in head and neck cancer and glioblastoma-backbone or add-on in immune-oncology?

Cyclin-dependent kinases (CDK) control the cell cycle and play a crucial role in oncogenesis. Pharmacologic inhibition of CDK has contributed to the recent clinical approval of dual CDK4/6 inhibitors for the treatment of breast and small cell lung cancer. While the anticancer cell effects of CDK inhibitors are well-established, preclinical and early clinical studies describe additional mechanisms of action such as chemo- and radiosensitization or immune stimulation. The latter offers great potential to incorporate CDK inhibitors in immune-based treatments. However, dosing schedules and accurate timing of each combination partner need to be respected to prevent immune escape and resistance. In this review, we provide a detailed summary of CDK inhibitors in the two solid cancer types head and neck cancer and glioblastoma multiforme; it describes the molecular mechanisms of response vs. resistance and covers strategies to avoid resistance by the combination of immunotherapy or targeted therapy.

Ultradeep targeted sequencing reveals low allele frequencies of somatic JAK2 and MPL variants in patients with abdominal vein thromboses: results of an ongoing prospective prevalence study in Mecklenburg-West Pomerania.

Myeloproliferative neoplasms are characterized by mutations in JAK2, MPL and CALR genes. Commonly in diagnostics and previous studies mainly sequencing and common PCR techniques under conventional detection limits are used.Splanchnic vein thromboses are rare, but often appear associated with myeloproliferative neoplasms and represent serious complications.Herein, blood from patients with abdominal vein thromboses in Mecklenburg-West Pomerania (federal district of northern Germany), included in an ongoing prospective prevalence study, was analyzed by next generation sequencing representing the complete protein coding regions of JAK2, MPL and CALR genes with a coverage of > 2000 reads, therefore an ultradeep targeting approach.JAK2 V617F mutations were detected in 11/44 patients. In four of these cases allele frequencies ranged below the conventional cut off of 2%. MPL W515R was detected in 3/44 cases in low frequencies.Very low allele frequencies of JAK2 and MPL variants in patients with abdominal vein thromboses may indicate early manifestations of myeloproliferative neoplasms.

Treatment response lowers tumor symptom burden in recurrent and/or metastatic head and neck cancer.

BACKGROUND: Head and neck squamous cell cancer (HNSCC) frequently causes severe symptoms that may be reduced, when the tumor is successfully treated. The SOCCER trial studied the association of treatment response with patient reported tumor symptom burden in first line treatment of recurrent and/or metastatic HNSCC. METHODS: In this prospective, multi-center, non-interventional trial patients were treated either with platinum-based chemotherapy and cetuximab or radiotherapy and cetuximab. Tumor symptom burden was assessed every four weeks with a questionnaire containing ten visual analogue scales (VAS, range 0-100), which were summarized to the overall VAS score. RESULTS: Fourhundred seventy patients were registered in 97 German centers. A total of 315 patients with at least the baseline and one subsequent questionnaire were available for analysis. Changes in the VAS score were rated as absolute differences from baseline. Negative values indicate improvement of symptoms. The overall VAS score improved significantly at the first post-baseline assessment in responders (- 2.13 vs. non-responders + 1.15, p = 0.048), and even more for the best post-baseline assessment (- 7.82 vs. non-responders - 1.97, p = 0.0005). The VAS for pain (- 16.37 vs. non-responders - 8.89, p = 0.001) and swallowing of solid food (- 16.67 vs. non-responders - 5.06, p = 0.002) improved significantly more in responders (best post-baseline assessment). In the multivariable Cox regression analysis, worse overall VAS scores were associated with worse overall survival (hazard ratio for death 1.12 per 10 points increment on the overall VAS scale, 95% CI 1.05-1.20, p = 0.0009). CONCLUSION: In unselected patients beyond randomized controlled trials, treatment response lowers tumor symptom burden in recurrent and/or metastatic HNSCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00122460 . Registered 22 Juli 2005.

Motivation and preferences of cancer patients to perform physical training.

OBJECTIVE: The aims of this cross-sectional study were to investigate the knowledge about and experience with exercise as well as the motivation and preferences (e.g. availability) of cancer patients to participate in training groups. METHODS: From 11/2017-06/2018, 181 cancer patients undergoing or completing treatment responded to a compiled questionnaire. The stage of motivation (transtheoretical model of behavioural change), exercise-related knowledge, experience and preferences were evaluated. RESULTS: Knowledge about the positive effects of exercise was not associated with higher motivation stages. Higher motivation stages showed significant correlations with age (p = 0.044), exercise experience before cancer disease onset (p = 0.022) and exercise experience during cancer therapy (p = 0.013). For 59% of patients, group offers were an attractive option. Physically inactive patients preferred specialised cancer exercise groups (p = 0.002), whereas physically active patients preferred cross-disease rehabilitation exercise groups (p = 0.034) and exercise groups with healthy people (p = 0.018). CONCLUSIONS: Results indicate that motivation of cancer patients for exercise depends on their experiences with physical training before and during disease treatment. Motivation could be increased by integrating exercise programmes during cancer therapy. These programmes should focus on patients inexperienced in physical training.

Feasibility and Effects of a Supervised Exercise Program Suitable for Independent Training at Home on Physical Function and Quality of Life in Head and Neck Cancer Patients: A Pilot Study.

Introduction: Head and neck cancer patients often suffer from physical and cognitive impairments after cancer treatment. During rehabilitation, exercise therapy can improve physical function and quality of life (QoL). Surveys demonstrated patients' preference for home training with low- to moderate-intensity. This study was conducted in order to develope a suitable home-based training program. Therefore, the feasibility and effects of a low- to moderate-intensity exercise intervention on physical functions and QoL were evaluated. Methods: Training was conducted as supervised group training and consisted of mobilization, coordination, resistance, stretching, and relaxation exercises. The intervention lasted 12 weeks with 2 training sessions per week. Feasibility, attendance rate, physical function (eg, range of motion, 6-minute walk test [6MWT]), and QoL (eg, EORTC QLQ-30) were analyzed. Results: Ten out of 12 participants completed the intervention (83%) with an average attendance rate of 83%. Participants showed significant improvements in selected physical functions. For example, head rotation increased by 11.2° (P = .042), walking distance in the 6MWT increased by an average of 43.3 m (P = .010), and the global QoL scale improved by 8.2 points (P = .059). Additionally, there were positive changes in the physical function scale (P = .008), cognitive function scale (P = .015), and social function scale (P = .031) of the EORTC QLQ-30. Conclusion: Data indicate that the exercise program was feasible and had positive effects on physical function and QoL. Future research will analyze the effects of a home-based exercise program on physical function and QoL in a large-scale study.

Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial.

BACKGROUND: Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. METHODS: We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18-70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts <5% in bone marrow) or myelodysplastic syndrome (blast counts <20% in bone marrow), Karnofsky index of 60% or higher, and were indicated for allogeneic HSCT but considered at an increased risk for standard myeloablative preparative regimens based on age (≥50 years), an HSCT-specific comorbidity index of more than 2, or both. Patients were randomly assigned (1:1) to receive either intravenous 10 g/m2 treosulfan daily applied as a 2-h infusion for 3 days (days -4 to -2) or 0·8 mg/kg busulfan applied as a 2-h infusion at 6-h intervals on days -4 and -3. Both groups received 30 mg/m2 intravenous fludarabine daily for 5 days (days -6 to -2). The primary outcome was event-free survival 2 years after HSCT. The non-inferiority margin was a hazard ratio (HR) of 1·3. Efficacy was assessed in all patients who received treatment and completed transplantation, and safety in all patients who received treatment. The study is registered with EudraCT (2008-002356-18) and ClinicalTrials.gov (NCT00822393). FINDINGS: Between June 13, 2013, and May 3, 2016, 476 patients were enrolled (240 in the busulfan group received treatment and transplantation, and in the treosulfan group 221 received treatment and 220 transplanation). At the second preplanned interim analysis (Nov 9, 2016), the primary endpoint was met and trial was stopped. Here we present the final confirmatory analysis (data cutoff May 31, 2017). Median follow-up was 15·4 months (IQR 8·8-23·6) for patients treated with treosulfan and 17·4 months (6·3-23·4) for those treated with busulfan. 2-year event-free survival was 64·0% (95% CI 56·0-70·9) in the treosulfan group and 50·4% (42·8-57·5) in the busulfan group (HR 0·65 [95% CI 0·47-0·90]; p<0·0001 for non-inferiority, p=0·0051 for superiority). The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (33 [15%] of 221 patients in the treosulfan group vs 35 [15%] of 240 patients in the busulfan group) and gastrointestinal disorders (24 [11%] patients vs 39 [16%] patients). Serious adverse events were reported for 18 (8%) patients in the treosulfan group and 17 (7%) patients in the busulfan group. Causes of deaths were generally transplantation-related. INTERPRETATION: Treosulfan was non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for allogeneic HSCT for older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. The improved outcomes in patients treated with the treosulfan-fludarabine regimen suggest its potential to become a standard preparative regimen in this population. FUNDING: medac GmbH.

Genetic Mutations in a Patient with Chronic Myeloid Leukemia Showing Blast Crisis 10 Years After Presentation.

Since the introduction of tyrosine kinase inhibitors (TKI), the prospects for patients with chronic myeloid leukemia (CML) have improved significantly. Herein we present the case of a patient with CML who experienced blast crisis and development of acute myeloid leukemia (AML) 10 years after presentation. The CML was characterized by the gene fusion of breakpoint cluster region BCR and tyrosine-protein kinase ABL1. During treatment different therapeutic protocols including imatinib, nilotinib, dasatinib and ponatinib were applied due to development of resistance or non-response. Fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) were used to describe cytogenetic and molecular aberrations elucidating the development into AML: A loss of chromosome 7, as well as an arising frequency of variants in the gene met proto-oncogene MET (p.T110I) and tyrosine-protein phosphatase non-receptor type 11 PTPN11 (p.Q510L) was observed. This report describes the comprehensive characterization of a clinical case showing multiple therapeutic resistances correlated with genetic aberrations.

Questionnaires measuring quality of life and satisfaction of patients and their relatives in a palliative care setting-German translation of FAMCARE-2 and the palliative care subscale of FACIT-Pal.

BACKGROUND: The evaluation of quality of life (QoL) and satisfaction with care in palliative care patients and their relatives is an important aspect of palliative care research, likewise important to get a direct feedback for the success of treatment. Here, questionnaires are important tools for measuring outcomes of care in medicine. Several validated, predominantly English, questionnaires already exist. These have been translated in different languages but German. The Functional Assessment of Chronic Illness Therapy (FACIT) is an established tool for the evaluation of QoL in cancer patients. The FACIT-Pal, a 46-itemquestionnaire of this group of questionnaires, measures the QoL in palliative care patients. It includes a new palliative care subscale which is not yet available in German. The FAMCARE-2, a 17-item-questionnaire, evaluates the relatives' satisfaction with the care and support they received from palliative care team. METHODS: The translation process followed a protocol including multiple independent translators as well as a forth and back translation. RESULTS: A German version of FAMCARE-2 and FACIT-Pal was translated based on the original questionnaire. Relevant differences between the English original versions and the back translations weren't revealed by the original scale developers. CONCLUSIONS: The final versions of the German translations have been authorized by the scale developers. The FAMCARE-2 and the FACIT-Pal are now available in German and can be used for research and quality control purposes.

Perforation of the superior vena cava - a rare complication of central venous catheters.

BACKGROUND: Central venous catheters (CVC) guarantee a reliable venous access and are an indispensable part of the therapy in patients with hematologic malignancies. On the other hand, they contribute significantly to the therapy-related morbidity in this group of patients. The most common complications are catheter-associated infections or thromboses. Here we report on the rare, but potentially life-threatening case of a vessel wall perforation by a CVC. CASE REPORT: A 29-year-old female with newly diagnosed acute lymphoblastic leukemia had a CVC inserted via the left subclavian vein. After two weeks she complained about acute chest pain. Radiology revealed right-sided pleural effusion which was due to a vena cava superior vessel wall perforation by the CVC. Chemotherapy extravasation was excluded by pleural fluid analyses. CONCLUSION: A vessel wall perforation by a CVC is a rare and often late CVC complication with usually unspecific symptoms. Especially patients with leftsided, large-bore catheters are at risk. Awareness of this complication and immediate therapy are essential. We discuss the possible mechanisms and treatment options of this rare CVC complication.