Zoledronic Acid Add-on Therapy for Standard-Risk Ewing Sarcoma Patients in the Ewing 2008R1 Trial.

PURPOSE: The phase III, open-label, prospective, multicenter, randomized Ewing 2008R1 trial (EudraCT2008-003658-13) was conducted in 12 countries to evaluate the effect of zoledronic acid (ZOL) maintenance therapy compared with no add-on regarding event-free survival (EFS, primary endpoint) and overall survival (OS) in standard-risk Ewing sarcoma (EWS). PATIENTS AND METHODS: Eligible patients had localized EWS with either good histologic response to induction chemotherapy and/or small tumors (<200 mL). Patients received six cycles of VIDE induction and eight cycles of VAI (male) or eight cycles of VAC (female) consolidation. ZOL treatment started parallel to the sixth consolidation cycle. Randomization was stratified by tumor site (pelvis/other). The two-sided adaptive inverse-normal four-stage design (planned sample size 448 patients, significance level 5%, power 80%) was changed after the first interim analysis using the Müller-Schäfer method. RESULTS: Between April 2010 and November 2018, 284 patients were randomized (142 ZOL/142 no add-on). With a median follow-up of 3.9 years, EFS was not significantly different between ZOL and no add-on group in the adaptive design (HR, 0.74; 95% CI, 0.43-1.28, P = 0.27, intention-to-treat). Three-year EFS rates were 84.0% (95% CI, 77.7%-90.8%) for ZOL vs. 81.7% (95% CI, 75.2%-88.8%) for no add-on. Results were similar in the per-protocol collective. OS was not different between groups. The 3-year OS was 92.8% (95% CI, 88.4%-97.5%) for ZOL and 94.6% (95% CI, 90.9%-98.6%) for no add-on. Noticeable more renal, neurologic, and gastrointestinal toxicities were observed for ZOL (P < 0.05). Severe renal toxicities occurred more often in the ZOL arm (P = 0.003). CONCLUSIONS: In patients with standard-risk localized EWS, there is no additional benefit from maintenance treatment with ZOL.

Primary osteosarcoma of the ribs: A report from the Cooperative Osteosarcoma Study Group.

PURPOSE: Primary rib osteosarcoma has not been investigated extensively, and clinical characteristics and optimal therapeutic strategies have not been defined. The authors used the database of the Cooperative Osteosarcoma Study Group (COSS) to analyze this tumor-site in depth. METHODS: The COSS database was searched for treatment-naive, high-grade osteosarcomas of the rib. Affected patients were analyzed for demographic and tumor-related factors, treatments, and outcomes. RESULTS: A total of 44 patients (23 males, 21 females; median age, 23 years [range, 6-59]) were identified. Primary metastases were detected in six of 44 (14%) patients. Surgery was performed in 40 of 44 (91%) patients and rendered 35 of 44 (80%) patients macroscopically disease-free. Chemotherapy was known to have been administered in 43 of 44 (98%) patients and radiotherapy in seven of 42 (17%) (no data for two patients). A good response to chemotherapy was only noted in five (33%) of those 15 evaluable patients who had received any preoperative chemotherapy. After a median follow-up of 2.49 (0.22-40.35) years for all patients and 6.61 (0.25-40.35) years for 26 survivors (21 of these in first complete remission), 5-year actuarial overall and event-free survival were 53.0% (8.5%) and 42.2% (8.1%), respectively. Incomplete tumor surgery was the most notable negative prognostic factor. Osteoblastic histology and a poor response to chemotherapy may have contributed. CONCLUSION: This large series provides evidence that patients with costal primaries are older than the average osteosarcoma patient, but appear to share the similar tumor biology and-if treated according to standard protocols-prognostic factors with tumors of other sites. Early, preoperative diagnosis and permanent, definitive local control remain major challenges and should contribute to improved outcomes.

Amsacrine-based induction therapy in AML patients with cardiac comorbidities: a retrospective single-center analysis.

Intensive chemotherapy is the backbone of induction treatment in patients with acute myeloid leukemia (AML). However, AML patients with concomitant cardiac disease may not be eligible for anthracycline-based therapies. In a small cohort of patients, we have previously shown that anthracycline-free, amsacrine-based chemotherapy TAA (thioguanine, cytarabine, amsacrine) may be as effective as cytarabine/daunorubicin for induction therapy in these patients. In this systematic retrospective single-center analysis, we documented the outcome of 31 patients with significant cardiac comorbidities including coronary heart disease or cardiomyopathy receiving TAA as induction chemotherapy. Median (range) ejection fraction (EF) was 48% (30-67%) in this cohort. Patients with EF below 30% were considered unfit for intensive induction therapy. Event-free survival (EFS), overall survival (OS), and relapse-free survival (RFS) were 1.61, 5.46, and 13.6 months respectively. Poor outcome was primarily related to a high early mortality rate within the first 30 days of therapy, mainly caused by infectious complications. TAA cannot be recommended as a substitute of standard induction for AML patients with significant concomitant cardiac disease. In the era of novel agents, alternative strategies (e.g., hypomethylating agents plus venetoclax) should be considered when anthracycline-based regimens are not suitable.

High-Dose Treosulfan and Melphalan as Consolidation Therapy Versus Standard Therapy for High-Risk (Metastatic) Ewing Sarcoma.

PURPOSE: Ewing 2008R3 was conducted in 12 countries and evaluated the effect of treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous hematopoietic stem cells on event-free survival (EFS) and overall survival in high-risk Ewing sarcoma (EWS). METHODS: Phase III, open-label, prospective, multicenter, randomized controlled clinical trial. Eligible patients had disseminated EWS with metastases to bone and/or other sites, excluding patients with only pulmonary metastases. Patients received six cycles of vincristine, ifosfamide, doxorubicin, and etoposide induction and eight cycles of vincristine, actinomycin D, and cyclophosphamide consolidation therapy. Patients were randomly assigned to receive additional TreoMel-HDT or no further treatment (control). The random assignment was stratified by number of bone metastases (1, 2-5, and > 5). The one-sided adaptive-inverse-normal-4-stage-design was changed after the first interim analysis via Müller-Schäfer method. RESULTS: Between 2009 and 2018, 109 patients were randomly assigned, and 55 received TreoMel-HDT. With a median follow-up of 3.3 years, there was no significant difference in EFS between TreoMel-HDT and control in the adaptive design (hazard ratio [HR] 0.85; 95% CI, 0.55 to 1.32, intention-to-treat). Three-year EFS was 20.9% (95% CI, 11.5 to 37.9) in TreoMel-HDT and 19.2% (95% CI, 10.8 to 34.4) in control patients. The results were similar in the per-protocol collective. Males treated with TreoMel-HDT had better EFS compared with controls: median 1.0 years (95% CI, 0.8 to 2.2) versus 0.6 years (95% CI, 0.5 to 0.9); P = .035; HR 0.52 (0.28 to 0.97). Patients age < 14 years benefited from TreoMel-HDT with a 3-years EFS of 39.3% (95% CI, 20.4 to 75.8%) versus 9% (95% CI, 2.4 to 34); P = .016; HR 0.40 (0.19 to 0.87). These effects were similar in the per-protocol collective. This observation is supported by comparable results from the nonrandomized trial EE99R3. CONCLUSION: In patients with very high-risk EWS, additional TreoMel-HDT was of no benefit for the entire cohort of patients. TreoMel-HDT may be of benefit for children age < 14 years.

Using stroma-anchoring cytokines to augment ADCC: a phase 1 trial of F16IL2 and BI 836858 for posttransplant AML relapse.

Natural killer (NK) cells are key effectors in cancer immunosurveillance and posttransplant immunity, but deficiency of environmental signals and insufficient tumor recognition may limit their activity. We hypothesized that the antibody-mediated anchoring of interleukin-2 (IL-2) to a spliced isoform of the extracellular matrix (ECM) glycoprotein tenascin-C would potentiate NK-cell-mediated antibody-dependent cellular cytotoxicity against leukemic blasts. In this novel-novel combination, dose-escalation, phase 1 trial, we enrolled patients with posttransplant acute myeloid leukemia (AML) relapse to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of the antibody-cytokine fusion F16IL2 (10 × 106 to 20 × 106 IU IV; days 1, 8, 15, and 22 of each 28-day cycle) in combination with the anti-CD33 antibody BI 836858 (10-40 mg IV, 2 days after each F16IL2 infusion). Among the 15 patients (median [range] age, 50 [20-68] years) treated across 4 dose levels (DLs), 6 (40%) had received 2 or 3 prior transplantations. The most frequent adverse events were pyrexia, chills, and infusion-related reactions, which were manageable, transient and of grade ≤2. One dose-limiting toxicity occurred at each of DLs 3 (pulmonary edema) and 4 (graft-versus-host disease). Three objective responses were observed among 7 patients treated at the 2 higher DLs, whereas no responses occurred at the 2 starting DLs. Combination therapy stimulated the expansion and activation of NK cells, including those expressing the FcγRIIIA/CD16 receptor. ECM-targeted IL-2 combined with anti-CD33 immunotherapy represents an innovative approach associated with acceptable safety and encouraging biologic and clinical activity in posttransplant AML relapse. This trial was registered at EudraCT as 2015-004763-37.

Upstream open reading frames regulate translation of cancer-associated transcripts and encode HLA-presented immunogenic tumor antigens.

BACKGROUND: Upstream open reading frames (uORFs) represent translational control elements within eukaryotic transcript leader sequences. Recent data showed that uORFs can encode for biologically active proteins and human leukocyte antigen (HLA)-presented peptides in malignant and benign cells suggesting their potential role in cancer cell development and survival. However, the role of uORFs in translational regulation of cancer-associated transcripts as well as in cancer immune surveillance is still incompletely understood. METHODS: We examined the translational regulatory effect of 29 uORFs in 13 cancer-associated genes by dual-luciferase assays. Cellular expression and localization of uORF-encoded peptides (uPeptides) were investigated by immunoblotting and immunofluorescence-based microscopy. Furthermore, we utilized mass spectrometry-based immunopeptidome analyses in an extensive dataset of primary malignant and benign tissue samples for the identification of naturally presented uORF-derived HLA-presented peptides screening for more than 2000 uORFs. RESULTS: We provide experimental evidence for similarly effective translational regulation of cancer-associated transcripts through uORFs initiated by either canonical AUG codons or by alternative translation initiation sites (aTISs). We further demonstrate frequent cellular expression and reveal occasional specific cellular localization of uORF-derived peptides, suggesting uPeptide-specific biological implications. Immunopeptidome analyses delineated a set of 125 naturally presented uORF-derived HLA-presented peptides. Comparative immunopeptidome profiling of malignant and benign tissue-derived immunopeptidomes identified several tumor-associated uORF-derived HLA ligands capable to induce multifunctional T cell responses. CONCLUSION: Our data provide direct evidence for the frequent expression of uPeptides in benign and malignant human tissues, suggesting a potentially widespread function of uPeptides in cancer biology. These findings may inspire novel approaches in direct molecular as well as immunotherapeutic targeting of cancer-associated uORFs and uPeptides.

Characteristics and Outcome of Elderly Patients (>55 Years) with Acute Lymphoblastic Leukemia.

Prognosis of elderly ALL patients remains dismal. Here, we retrospectively analyzed the course of 93 patients > 55 years with B-precursor (n = 88) or T-ALL (n = 5), who received age-adapted, pediatric-inspired chemotherapy regimens at our center between May 2003 and October 2020. The median age at diagnosis was 65.7 years, and surviving patients had a median follow-up of 3.7 years. CR after induction therapy was documented in 76.5%, while the rate of treatment-related death within 100 days was 6.4%. The OS of the entire cohort at 1 and 3 year(s) was 75.2% (95% CI: 66.4-84.0%) and 47.3% (95% CI: 36.8-57.7%), respectively, while the EFS at 1 and 3 years(s) was 59.0% (95% CI: 48.9-69.0%) and 32.9% (95% CI: 23.0-42.8%), respectively. At 3 years, the cumulative incidence (CI) of relapse was 48.3% (95% CI: 38.9-59.9%), and the CI rate of death in CR was 17.3% (95% CI: 10.9-27.5%). Older age and an ECOG > 2 represented risk factors for inferior OS, while BCR::ABL1 status, immunophenotype, and intensity of chemotherapy did not significantly affect OS. We conclude that intensive treatment is feasible in selected elderly ALL patients, but high rates of relapse and death in CR underline the need for novel therapeutic strategies.

The role of autologous stem cell transplantation (ASCT) in aggressive B-cell lymphomas: real-world data from a retrospective single-center analysis.

Patients with high-risk or relapsed aggressive B-cell lymphomas are characterized by poor prognosis. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) can induce durable remissions in these patients and is potentially curative. Two hundred forty-seven patients with aggressive B-cell lymphomas treated with high-dose chemotherapy and ASCT, either as consolidation after first-line therapy or after salvage therapy for relapsed disease, between 2002 and 2019 at the University Hospital Muenster, were analyzed. The median follow-up of surviving patients was 36 months (range 0-163). Progression-free survival (PFS) and overall survival (OS) after 3 years was 63% and 68%, respectively. After ASCT, 28% of all patients experienced a relapse. The cumulative incidence of non-relapse mortality at day 100 after ASCT was 4%. Multivariate analysis identified remission status at ASCT, age at ASCT, and the numbers of infused CD34+ cells as independent prognostic factors for both PFS and OS. Patients with mantle cell lymphoma (MCL) or primary CNS lymphoma (PCNSL) treated with ASCT in first-line had a superior OS and PFS when compared to patients treated with ASCT in relapsed disease. For patients with diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), early relapse (< 12 months) after first-line therapy showed a trend towards an inferior PFS and OS. Deaths after ASCT were predominantly caused by lymphoma relapse and/or progression (64%) or due to infections (23%). In conclusion, high-dose chemotherapy followed by ASCT in the era of novel targeted agents remains a feasible and effective approach for patients with high-risk or relapsed aggressive B-cell lymphomas. Remission status and age at ASCT, and the number of infused stem cells were of prognostic relevance.

Targeting Tissue Factor to Tumor Vasculature to Induce Tumor Infarction.

Besides its central functional role in coagulation, TF has been described as being operational in the development of malignancies and is currently being studied as a possible therapeutic tool against cancer. One of the avenues being explored is retargeting TF or its truncated extracellular part (tTF) to the tumor vasculature to induce tumor vessel occlusion and tumor infarction. To this end, multiple structures on tumor vascular wall cells have been studied at which tTF has been aimed via antibodies, derivatives, or as bifunctional fusion protein through targeting peptides. Among these targets were vascular adhesion molecules, oncofetal variants of fibronectin, prostate-specific membrane antigens, vascular endothelial growth factor receptors and co-receptors, integrins, fibroblast activation proteins, NG2 proteoglycan, microthrombus-associated fibrin-fibronectin, and aminopeptidase N. Targeting was also attempted toward cellular membranes within an acidic milieu or toward necrotic tumor areas. tTF-NGR, targeting tTF primarily at aminopeptidase N on angiogenic endothelial cells, was the first drug candidate from this emerging class of coaguligands translated to clinical studies in cancer patients. Upon completion of a phase I study, tTF-NGR entered randomized studies in oncology to test the therapeutic impact of this novel therapeutic modality.

Outcome in dedifferentiated chondrosarcoma for patients treated with multimodal therapy: Results from the EUROpean Bone Over 40 Sarcoma Study.

INTRODUCTION: The role of chemotherapy for patients with dedifferentiated chondrosarcoma (DDCS) is still under discussion. Here, we present the outcome in patients with DDCS treated with intensive chemotherapy from the EUROpean Bone Over 40 Sarcoma Study. MATERIALS AND METHODS: The chemotherapy regimen included doxorubicin, ifosfamide and cisplatin. Postoperative methotrexate was added in case of poor histological response. Toxicity was graded based on the National Cancer Institute expanded common toxicity criteria, version 2.0, and survival was analysed using Kaplan-Meier curves, log-rank tests and univariate Cox regression models. RESULTS: Fifty-seven patients with DDCS (localised, 34 [60%]; metastatic, 23 [40%]) aged 42-65 years were included. Surgical complete remission (SCR) was achieved in 36 (63%) patients. The median overall survival (OS) was 24 months (95% confidence interval, 22-25), and the 5-year OS was 39%. Patients with extremity localisation had a 5-year OS of 49% compared with 29% in patients with a central tumour (P = 0.08). Patients with localised disease had a 5-year OS of 46%, whereas patients with metastatic disease had a 5-year OS of 29% (P = 0.12). Patients in SCR had a 5-year OS of 49%, whereas patients not in SCR had a 5-year OS of 23% (P = 0.004). Chemotherapy toxicity was considerable but manageable. There was no treatment-related death, and 39 (70%) patients received ≥6 cycles of the planned nine chemotherapy cycles. CONCLUSIONS: Adding intensive chemotherapy to surgery for treatment of DDCS is feasible and shows favourable survival data compared with previous reports. With the limitations of data from a non-controlled trial, we conclude that chemotherapy could be considered in the management of patients aged >40 years.

Dose escalation and expansion phase I studies with the tumour-targeting antibody-tumour necrosis factor fusion protein L19TNF plus doxorubicin in patients with advanced tumours, including sarcomas.

BACKGROUND: L19TNF is a recombinant fusion protein composed of a human antibody fragment and human tumour necrosis factor. L19TNF targets the EDB domain of oncofetal fibronectin highly expressed in tumour vasculature and induces tumour remission in mouse tumours. We summarise two phase I trials testing a combination of L19TNF with doxorubicin in patients with solid tumours, particularly soft tissue sarcomas (STS). PATIENTS AND METHODS: The first study, an open-label, dose-escalation and expansion phase I study of L19TNF plus doxorubicin, enrolled 27 patients. Three cohorts (10.4-17 µg/kg L19TNF) of patients received L19TNF intravenously at days 1, 3, and 5 and doxorubicin (75 mg/m2, then 60 mg/m2) on day 1 every 3 weeks. The expansion cohort enrolled patients with STS. The second study tried to re-escalate the doxorubicin dose to 75 mg/m2 with 13 µg/kg L19TNF. Among primary objectives was the establishment of a recommended dose (RD). RESULTS: The combination was safely applicable. Dose-limiting toxicity occurred either at 17 µg/kg L19TNF or at 75 mg/m2 doxorubicin. RD is 13 µg/kg L19TNF plus 60 mg/m2 doxorubicin. In 15 STS patients of the extension cohort evaluable for efficacy, antitumour activity was observed with complete remission in 1, partial remission in 1 and minor tumour shrinkage in 7 patients. The median overall survival for this heavily pretreated cohort was 14.9 months. CONCLUSION: L19TNF can be safely applied in combination with doxorubicin and induces encouraging tumour remissions in patients with soft tissue sarcomas.

Allogeneic hematopoietic stem cell transplantation for therapy-related myeloid neoplasms following treatment of a lymphoid malignancy.

Advances in lymphoma treatment lead to increasing numbers of long-term survivors. Thus, secondary therapy-related myeloid neoplasms (t-MN) gain clinical relevance. We analyzed 38 t-MN patients receiving an allogeneic stem cell transplantation (SCT) after successful cytotoxic treatment of Hodgkin lymphoma (n = 9), non-Hodgkin lymphoma (n = 24), and multiple myeloma (n = 5), who had developed t-AML (n = 20) or t-MDS (n = 18). Overall survival (OS) and relapse-free survival at 3 years after allogeneic SCT were 43% and 39%. The cumulative incidences of relapse and non-relapse mortality (NRM) at 3 years were 19% and 42%. More than one therapy line for the lymphoid malignancy resulted in a significantly higher NRM rate and inferior 3-year-OS. Our data indicate that allogeneic SCT for patients with t-MN after treatment of a lymphoid malignancy leads to OS rates comparable to patients transplanted for de novo MN. Multiple lines of lymphoma therapy increase NRM and lead to inferior survival after allogeneic SCT.

Low-density lipoprotein receptor (LDLR) is an independent adverse prognostic factor in acute myeloid leukaemia.

The low-density lipoprotein receptor (LDLR) is a membrane receptor that mediates the endocytosis of low-density lipoprotein (LDL). Uptake of LDL has been proposed to contribute to chemotherapy resistance of acute myeloid leukaemia (AML) cell lines in vitro. In the present study, we analysed LDLR expression and survival using bone marrow biopsies from 187 intensively treated patients with AML. Here, increasing LDLR expression was associated with decreasing overall (58·4%, 44·2%, and 24·4%; P = 0·0018), as well as event-free survival (41·7%, 18·1%, and 14·3%; P = 0·0077), and an increasing cumulative incidence of relapse (33·9%, 55·1%, and 71·4%; P = 0·0011). Associations of LDLR expression with survival were confirmed in 557 intensively treated patients from two international validation cohorts. In the analytic and validation cohorts, LDLR expression remained associated with outcome in multivariable regression analyses including the European LeukemiaNet genetic risk classification. Thus, LDLR predicts outcome of patients with AML beyond existing risk factors. Furthermore, we found low expression levels of LDLR in most healthy tissues, suggesting it as a promising target for antibody-based pharmacodelivery approaches in AML.

Efficacy of Pazopanib With or Without Gemcitabine in Patients With Anthracycline- and/or Ifosfamide-Refractory Soft Tissue Sarcoma: Final Results of the PAPAGEMO Phase 2 Randomized Clinical Trial.

IMPORTANCE: Pazopanib and gemcitabine have shown good tolerability, albeit modest single-agent activity in pretreated soft tissue sarcoma. A combined regimen to improve outcomes is required. OBJECTIVE: To determine the efficacy of gemcitabine and pazopanib compared with pazopanib alone. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, randomized phase 2 clinical trial was conducted in Germany from September 2011 to July 2014 and included patients with an Eastern Cooperative Oncology Group performance status score of 0 to 2, adequate organ function, measurable lesion, and progression after at least 1 prior treatment with anthracyclines and/or ifosfamide. Data analysis was performed during 2019 and 2020. INTERVENTIONS: Patients were randomized to pazopanib with gemcitabine (A) or without gemcitabine (B). MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival rate (PFSR) at 12 weeks; secondary end points included toxicity, quality of life, overall survival, and response rates. RESULTS: A total of 90 patients were randomized, and 86 eligible patients (43 women [50%]) were evaluable, with a median age of 57 (range, 22-84) years and Eastern Cooperative Oncology Group performance status score of 0/1 in 77 participants (90%). The predominant histological subtypes were leiomyosarcoma (22 [26%]) and liposarcoma (16 [19%]). After a median follow-up of 12.4 (range, 1-48) months, the primary end point was met, with a PFSR at 12 weeks of 74% (A) vs 47% (B) (hazard ratio [HR], 1.60; 90% CI, 1.15-2.23; P = .01). In the combination arm, PFSR was significantly longer, with a median of 5.6 vs 2.0 months (HR, 0.58; 95% CI, 0.36-0.92; P = .02) compared with single-agent pazopanib, whereas overall survival was similar, with 13.1 vs 11.2 months (HR, 0.98; 95% CI, 0.60-1.58; P = .83). The objective response rate was overall low, with 11% (A) vs 5% (B) (P = .10). The toxicity of the combination of pazopanib and gemcitabine was increased, but it was manageable and mainly hematological. CONCLUSIONS AND RELEVANCE: This phase 2 randomized clinical trial of patients with soft tissue sarcoma found that the addition of gemcitabine to pazopanib was tolerable, and PFSR at 12 weeks was significantly higher compared with pazopanib alone. These results suggest clinical activity of the combination, but they should be confirmed in a phase 3 trial in a more homogeneous population (eg, leiomyosarcoma). TRIAL REGISTRATION: German Clinical Trials Identifier: DRKS00003139.

Quality of life and added value of a tailored palliative care intervention in patients with soft tissue sarcoma undergoing treatment with trabectedin: a multicentre, cluster-randomised trial within the German Interdisciplinary Sarcoma Group (GISG).

OBJECTIVES: The choice of drug treatment in advanced soft tissue sarcoma (STS) continues to be a challenge regarding efficacy, quality of life (QoL) and toxicity. Unlike other cancer types, where integrating patient-reported outcomes (PRO) has proven to be beneficial for QoL, there is no such evidence in patients with STS as of now. The YonLife trial aimed to explore the effect of a tailored multistep intervention on QoL, symptoms and survival in patients with advanced STS undergoing treatment with trabectedin as well as identifying predictors of QoL. DESIGN: YonLife is a cluster-randomised, open-label, proof-of-concept study. The intervention incorporates electronic PRO assessment, a case vignette and expert-consented treatment recommendations. PARTICIPANTS: Six hospitals were randomised to the control arm (CA) or interventional arm (IA). Seventy-nine patients were included of whom 40 were analysed as per-protocol analysis set. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary end point was the change of Functional Assessment for Cancer Therapy (FACT-G) total score after 9 weeks. Secondary outcomes included QoL (FACT-G subscales), anorexia and cachexia (Functional Assessment of Anorexia/Cachexia Therapy (FAACT)), symptoms (MD Anderson Symptom Inventory (MDASI)), anxiety and depression (HADS), pain intensity and interference (Brief Pain Inventory (BPI)) and survival assessment. RESULTS: After 9 weeks of treatment, QoL declined less in the IA (ΔFACT-G total score: -2.4, 95% CI: -9.2 to 4.5) as compared with CA (ΔFACT-G total score: -3.9; 95% CI:-11.3 to 3.5; p=0.765). In almost all FACT-G subscales, average declines were lower in IA, but without reaching statistical significance. Smaller adverse trends between arms were observed for MDASI, FAACT, HADS and BPI scales. These trends failed to reach statistical significance. Overall mean survival was longer in IA (648 days) than in CA (389 days, p=0.110). QoL was predicted by symptom severity, symptom interference, depression and anxiety. CONCLUSION: Our data suggest a potentially favourable effect of an electronic patient-reported outcomes based intervention on QoL that needs to be reappraised in confirmatory studies. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier (NCT02204111).

Aneurysmal bone cyst inadvertently treated with chemotherapy-A series of three cases.

Aneurysmal bone cyst (ABC) is a benign locally aggressive tumor that occurs in childhood and early adulthood. Most relevant differential diagnoses are the telangiectatic osteosarcoma and the giant cell tumor. In the present case series chemotherapy following the EURAMOS or the Euro-Ewing 99 protocol was externally applied in three patients with the misdiagnosis of ABC as malignant bone tumor. In all three cases, a significant reduction of the volume of the ABC was achieved. This is the first report about the use of neoadjuvant chemotherapy in ABC. Chemotherapy reduces the size of an ABC and leads to progressive sclerosis.

First-In-Class CD13-Targeted Tissue Factor tTF-NGR in Patients with Recurrent or Refractory Malignant Tumors: Results of a Phase I Dose-Escalation Study.

BACKGROUND: Aminopeptidase N (CD13) is present on tumor vasculature cells and some tumor cells. Truncated tissue factor (tTF) with a C-terminal NGR-peptide (tTF-NGR) binds to CD13 and causes tumor vascular thrombosis with infarction. METHODS: We treated 17 patients with advanced cancer beyond standard therapies in a phase I study with tTF-NGR (1-h infusion, central venous access, 5 consecutive days, and rest periods of 2 weeks). The study allowed intraindividual dose escalations between cycles and established Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicity (DLT) by verification cohorts. RESULTS: MTD was 3 mg/m2 tTF-NGR/day × 5, q day 22. DLT was an isolated and reversible elevation of high sensitivity (hs) Troponin T hs without clinical sequelae. Three thromboembolic events (grade 2), tTF-NGR-related besides other relevant risk factors, were reversible upon anticoagulation. Imaging by contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) showed major tumor-specific reduction of blood flow in all measurable lesions as proof of principle for the mode of action of tTF-NGR. There were no responses as defined by Response Evaluation Criteria in Solid Tumors (RECIST), although some lesions showed intratumoral hemorrhage and necrosis after tTF-NGR application. Pharmacokinetic analysis showed a t1/2(terminal) of 8 to 9 h without accumulation in daily administrations. CONCLUSION: tTF-NGR is safely applicable with this regimen. Imaging showed selective reduction of tumor blood flow and intratumoral hemorrhage and necrosis.

Long-term survival and polyclonal immunoglobulin reconstitution after allogeneic stem cell transplantation in multiple myeloma.

Despite significant progress made in the treatment of patients with multiple myeloma (MM) in the last decade, for patients with early relapse or rapidly progressing high-risk disease, allogeneic hematopoietic stem cell transplantation (SCT) might be an option leading to long-term survival. Here, we retrospectively analyzed the outcomes of 90 MM patients who received allogeneic SCT in our center between 1999 and 2017. We specifically assessed the association of impaired humoral immune reconstitution, referred to as immunoparesis, and post-transplant survival. Sixty-four patients received allogeneic SCT in relapse following 2-7 lines of therapy; 26 patients received upfront tandem autologous-allogeneic SCT. With a median follow-up of 76 months, OS and PFS were 52.6% (95% CI 42.9-64.3) and 36.4% (95% CI 27.6-47.9) at 2 years and 38.6% (95% CI 29.2-51.1) and 25.3% (95% CI 17.5-36.4) at 5 years, respectively. Receiving more than two therapy lines prior to transplantation was an independent risk factor for OS (HR 3.68, 95% CI 2.02-6.70) and PFS (HR 3.69, 95% CI 2.09-6.50). In a landmark analysis at day 200, prolonged immunoparesis was associated with reduced OS (HR 3.22, 95% CI 1.14-9.11). Allogeneic stem cell transplantation offers an additional treatment element that may lead to long-term remission in selected patients with poor prognosis, probably exploiting graft-versus-myeloma effects. Immunoparesis could potentially serve as an indicator for impaired survival following allogeneic transplantation, an observation to be further studied prospectively.

Radiation synergizes with antitumor activity of CD13-targeted tissue factor in a HT1080 xenograft model of human soft tissue sarcoma.

BACKGROUND: Truncated tissue factor (tTF) retargeted by NGR-peptides to aminopeptidase N (CD13) in tumor vasculature is effective in experimental tumor therapy. tTF-NGR induces tumor growth inhibition in a variety of human tumor xenografts of different histology. To improve on the therapeutic efficacy we have combined tTF-NGR with radiotherapy. METHODS: Serum-stimulated human umbilical vein endothelial cells (HUVEC) and human HT1080 sarcoma cells were irradiated in vitro, and upregulated early-apoptotic phosphatidylserine (PS) on the cell surface was measured by standard flow cytometry. Increase of cellular procoagulant function in relation to irradiation and PS cell surface concentration was measured in a tTF-NGR-dependent Factor X activation assay. In vivo experiments with CD-1 athymic mice bearing human HT1080 sarcoma xenotransplants were performed to test the systemic therapeutic effects of tTF-NGR on tumor growth alone or in combination with regional tumor ionizing radiotherapy. RESULTS: As shown by flow cytometry with HUVEC and HT1080 sarcoma cells in vitro, irradiation with 4 and 6 Gy in the process of apoptosis induced upregulation of PS presence on the outer surface of both cell types. Proapoptotic HUVEC and HT1080 cells both showed significantly higher procoagulant efficacy on the basis of equimolar concentrations of tTF-NGR as measured by FX activation. This effect can be reverted by masking of PS with Annexin V. HT1080 human sarcoma xenografted tumors showed shrinkage induced by combined regional radiotherapy and systemic tTF-NGR as compared to growth inhibition achieved by either of the treatment modalities alone. CONCLUSIONS: Irradiation renders tumor and tumor vascular cells procoagulant by PS upregulation on their outer surface and radiotherapy can significantly improve the therapeutic antitumor efficacy of tTF-NGR in the xenograft model used. This synergistic effect will influence design of future clinical combination studies.