Efficacy and safety of high-dose chemotherapy as the first or subsequent salvage treatment line in patients with relapsed or refractory germ cell cancer: an international multicentric analysis.

BACKGROUND: In relapsed or refractory (RR) metastatic germ cell cancer (GCC), high-dose (HD) chemotherapy (CTX) plus autologous stem cell transplantation is considered the standard of care. Limited data exist regarding the efficacy of HD-CTX following conventionally dosed salvage regimens (CDRs). This analysis explores and contrasts the efficacy of HD-CTX as the first or subsequent salvage regimen. PATIENTS AND METHODS: Data were retrospectively collected to explore the efficacy of HD-CTX administered as the first (group A) or subsequent salvage CTX (group B) after a CDR. The primary endpoint was OS from the time of HD-CTX. Associations of survival, overall response rate (ORR), and toxicity with clinical characteristics were explored using stratified Kaplan-Meier and Cox regression models. RESULTS: Overall, 283 patients with GCC were included from 11 international centers, with 159 patients (56%) in group A and 124 patients (44%) in group B. The first salvage treatment was administered between 1998 and 2022, with a median follow-up of 27.0 [standard deviation (SD) 46.2] months for group A and 17.0 (SD 48.5) months for group B. The median OS from HD-CTX treatment initiation was not reached in group A, compared with 25 months in group B (P = 0.00027), associated with 2- and 5-year OS rates of 74% and 63% (group A) versus 53% and 37% (group B), respectively. When administered as the first salvage treatment, HD-CTX was associated with a higher ORR (79% versus 60%; P = 0.013) and lower nonhematologic grade ≥3 toxicity rate (78% versus 97%; P < 0.001). Concerning risk factor analysis for the total cohort, the International Prognostic Factors Study Group score was the only independent predictor of OS in multivariable analysis (P = 0.006). CONCLUSIONS: When administered as the initial salvage treatment or after CDR, HD-CTX exhibits curative potential for patients with RR GCC. The efficacy and safety outcomes were more favorable when HD-CTX was conducted as the first salvage treatment line.

Fluoropyrimidine type, patient age, tumour sidedness and mutation status as determinants of benefit in patients with metastatic colorectal cancer treated with EGFR monoclonal antibodies: individual patient data pooled analysis of randomised trials from the ARCAD database.

BACKGROUND: KRAS mutations in metastatic colorectal cancer (mCRC) are used as predictive biomarkers to select therapy with EGFR monoclonal antibodies (mAbs). Other factors may be significant determinants of benefit. METHODS: Individual patient data from randomised trials with a head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or best supportive care) in mCRC, across all lines of therapy, were pooled. Overall survival (OS) and progression-free survival (PFS) were compared between groups. Treatment effects within the predefined KRAS biomarker subsets were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). EGFR mAb efficacy was measured within the KRAS wild-type subgroup according to BRAF and NRAS mutation status. In both KRAS wild-type and mutant subgroups, additional factors that could impact EGFR mAb efficacy were explored including the type of chemotherapy, line of therapy, age, sex, tumour sidedness and site of metastasis. RESULTS: 5675 patients from 8 studies were included, all with known mCRC KRAS mutation status. OS (HRadj 0.90, 95% CI 0.84-0.98, p = 0.01) and PFS benefit (HRadj 0.73, 95% CI 0.68-0.79, p < 0.001) from EGFR mAbs was observed in the KRAS wild-type group. PFS benefit was seen in patients treated with fluorouracil (HRadj 0.75, 95% CI 0.68-0.82) but not with capecitabine-containing regimens (HRadj 1.04, 95% CI 0.86-1.26) (pinteraction = 0.002). Sidedness also interacted with EGFR mAb efficacy, with survival benefit restricted to left-sided disease (pinteraction = 0.038). PFS benefits differed according to age, with benefits greater in those under 70 (pinteraction = 0.001). The survival benefit was not demonstrated in those patients with mutations found in the KRAS, NRAS or BRAF genes. The presence of liver metastases interacted with EGFR mAb efficacy in patients with KRAS mutant mCRC (pinteraction = 0.004). CONCLUSION: The benefit provided by EGFR mAbs in KRAS WT mCRC is associated with left-sided primary tumour location, younger patient age and absence of NRAS or BRAF mutations. Survival benefit is observed with fluorouracil but not capecitabine. Exploratory results support further research in KRAS mutant mCRC without liver metastases.

Increased incidence of immune thrombocytopenia (ITP) in 2021 correlating with the ongoing vaccination campaign against COVID-19 in a tertiary center - A monocentric analysis.

Immune thrombocytopenia (ITP) was reported as a rare complication of COVID-19 vaccines. We conducted a retrospective single-center analysis of all ITP cases detected in 2021 and compared the quantity with the pre-vaccination years, from 2018 to 2020. In 2021, a two-fold increase in ITP cases was identified compared to previous years; 11 of 40 cases (27.5%) were considered COVID-19-vaccine related. Our study highlights an increase in ITP cases at our institution, probably related to COVID-19 vaccinations. Further studies are needed to investigate this finding globally.

Symptom burden, psychosocial distress and palliative care needs in heart failure - A cross-sectional explorative pilot study.

BACKGROUND: Beyond guideline-directed treatments aimed at improving cardiac function and prognosis in heart failure (HF), patient-reported outcomes have gained attention. PURPOSE: Using a cross-sectional approach, we assessed symptom burden, psychosocial distress, and potential palliative care (PC) needs in patients with advanced stages of HF. METHODS: At a large tertiary care center, we enrolled HF patients in an exploratory pilot study. Symptom burden and psychosocial distress were assessed using the MIDOS (Minimal Documentation System for Patients in PC) questionnaire and the Distress Thermometer (DT), respectively. The 4-item Patient Health Questionnaire (PHQ-4) was used to screen for anxiety and depression. To assess PC needs, physicians used the "Palliative Care Screening Tool for HF Patients". RESULTS: We included 259 patients, of whom 137 (53%) were enrolled at the Heart Failure Unit (HFU), and 122 (47%) at the outpatient clinic (OC). Mean age was 63 years, 72% were male. New York Heart Association class III or IV symptoms were present in 56%. With a mean 5-year survival 64% (HFU) vs. 69% (OC) calculated by the Seattle Heart Failure Model, estimated prognosis was comparatively good. Symptom burden (MIDOS score 8.0 vs. 5.4, max. 30 points, p < 0.001) and level of distress (DT score 6.0 vs. 4.8, max. 10 points, p < 0.001) were higher in hospitalised patients. Clinically relevant distress was detected in the majority of patients (HFU 76% vs. OC 57%, p = 0.001), and more than one third exhibited at least mild symptoms of depression or anxiety. Screening for PC needs revealed 82% of in- and 52% of outpatients fulfil criteria for specialized palliative support. CONCLUSION: Despite a good prognosis, we found multiple undetected and unaddressed needs in an advanced HF cohort. This study's tools and screening results may help to early explore these needs, to further improve integrated HF care.

Effects of a communication training for oncologists on early addressing palliative and end-of-life care in advanced cancer care (PALLI-COM): a randomized, controlled trial.

INTRODUCTION: In advanced cancer care, early communication about palliative care (PC) and end-of-life (EoL)-related issues is recommended, but is often impeded by physicians' communication insecurities. We investigated the effect of a newly developed compact communication skills training 'PALLI-COM' on oncologists' competencies to early address PC/EoL-related issues. MATERIALS AND METHODS: We conducted a randomized, controlled trial (RCT) with an intervention group (IG; 2 × 90 min training) and a wait list control group (CG) at five sites. At two assessment points, participating oncologists led videotaped medical consultations with simulated patients (SPs) via a privacy compliant video conference platform. SPs were represented by trained actors. The taped conversations were rated for primary outcome (communication skills assessed by adapted COM-ON-checklist and COM-ON-coaching rating scales) by raters blinded for study group. Secondary outcomes included oncologists' self-reported communication skills (Self-Efficacy in Palliative Care Scale, Thanatophobia-Scale, Communication about End of Life Survey, study-specific items) as well as external rating of the SPs. Univariate analyses of covariance with baseline adjustment were used to analyze intervention effects. RESULTS: A total of 141 oncologists [age: mean (standard deviation) = 32.7 (6.3) years, 60% female (nIG = 73, nCG = 68)] participated. Following intervention, the IG showed significantly more improvement in four out of five assessed communication skills: 'reacting to emotions and showing empathy', 'pointing out opportunities and giving hope', 'addressing the EoL' and 'explaining the concept of PC'. IG participants also improved more than CG participants in almost all secondary outcomes assessed by participants and SPs: oncologists' self-efficacy, attitudes towards caring for terminally ill patients, communication strategies and confidence in dealing with PC/EoL-related issues as well as communication quality from the SPs' perspective. CONCLUSION: Findings indicate that the compact communication skills training PALLI-COM increases oncologists' competencies in early addressing PC/EoL-related issues from different perspectives. Implementation in routine oncology residency might improve advanced cancer care by strengthening these communication skills.

Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM).

BACKGROUND: Atypical EGFR mutations occur in 10%-30% of non-small-cell lung cancer (NSCLC) patients with EGFR mutations and their sensitivity to classical epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) is highly heterogeneous. Patients harboring one group of uncommon, recurrent EGFR mutations (G719X, S768I, L861Q) respond to EGFR-TKI. Exon 20 insertions are mostly insensitive to EGFR-TKI but display sensitivity to exon 20 inhibitors. Clinical outcome data of patients with very rare point and compound mutations upon systemic treatments are still sparse to date. PATIENTS AND METHODS: In this retrospective, multicenter study of the national Network Genomic Medicine (nNGM) in Germany, 856 NSCLC cases with atypical EGFR mutations including co-occurring mutations were reported from 12 centers. Clinical follow-up data after treatment with different EGFR-TKIs, chemotherapy and immune checkpoint inhibitors were available from 260 patients. Response to treatment was analyzed in three major groups: (i) uncommon mutations (G719X, S7681, L861Q and combinations), (ii) exon 20 insertions and (iii) very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions). RESULTS: Our study comprises the largest thus far reported real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments. We validated higher efficacy of EGFR-TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR-TKI responsive. In addition, we found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Notably, treatment responses in group 3 (very rare) were highly heterogeneous. Co-occurring TP53 mutations exerted a non-significant trend for a detrimental effect on outcome in EGFR-TKI-treated patients in groups 2 and 3 but not in group 1. CONCLUSIONS: Based on our findings, we propose a novel nNGM classification of atypical EGFR mutations.

Increased frequency of TIGIT+CD73-CD8+ T cells with a TOX+ TCF-1low profile in patients with newly diagnosed and relapsed AML.

The inhibitory receptor TIGIT, as well as theectonucleotidases CD39 and CD73 constitute potential exhaustion markers for T cells. Detailed analysis of these markers can shed light into dysregulation of the T-cell response in acute myeloid leukemia (AML) and will help to identify potential therapeutic targets.  The phenotype and expression of transcription factors was assessed on different T-cell populations derived from peripheral blood (PB, n = 38) and bone marrow (BM, n = 43). PB and BM from patients with AML diagnosis, in remission and at relapse were compared with PB from healthy volunteers (HD) (n = 12) using multiparameter flow cytometry. An increased frequency of terminally differentiated (CD45R-CCR7-)CD8+ T cells was detected in PB and BM regardless of the disease state. Moreover, we detected an increased frequency of two distinct T-cell populations characterized by the co-expression of PD-1 or CD39 on TIGIT+CD73-CD8+ T cells in newly diagnosed and relapsed AML in comparison to HDs. In contrast to the PD-1+TIGIT+CD73-CD8+ T-cell population, the frequency of CD39+TIGIT+CD73-CD8+ T cells was normalized in remission. PD-1+- and CD39+TIGIT+CD73-CD8+ T cells exhibited additional features of exhaustion by decreased expression of CD127 and TCF-1 and increased intracellular expression of the transcription factor TOX. CD8+ T cells in AML exhibit a key signature of two subpopulations, PD-1+TOX+TIGIT+CD73-CD8+- and CD39+TOX+TIGIT+CD73-CD8+ T cells that were increased at different stages of the disease. These results provide a rationale to analyze TIGIT blockade in combination with inhibition of the purinergic signaling and depletion of TOX to improve T-cell mediated cytotoxicity in AML. Abbreviations: AML: Acute myeloid leukemia; pAML: newly diagnosed AML; rAML: relapse AML; lrAML: AML in remission; HD: healthy donor; PB: peripheral blood; BM: bone marrow; TIGIT: T-cell immunoreceptor with Ig and ITIM domains; PD-1: Programmed cell death protein 1; CD73: ecto-5'-nucleotidase; CD39: ectonucleoside triphosphate diphosphohydrolase 1; ATP: adenosine triphosphate; ADO: adenosine; CD127: interleukin-7 receptor; CAR-T cell: chimeric antigen receptor T cell; TCF-1: transcription factor T-cell factor 1; TOX: Thymocyte selection-associated high mobility group box protein; NFAT: nuclear factor of activated T cells; NA: Naïve; CM: Central Memory; EM Effector Memory; EMRA: Terminal Effector Memory cells; FMO: Fluorescence minus one; PVR: poliovirus receptor; PVRL2: poliovirus receptor-related 2; IFN-γ: Interferon-γ; IL-2: interleukin-2; MCF: multiparametric flow cytometry; TNFα: Tumornekrosefaktor α; RT: room temperature.

[Diagnosis and treatment of rare testicular tumors using the example of malignant mesothelioma of the tunica vaginalis testis and Sertoli cell tumors]. / Diagnose und Therapie seltener Hodentumoren am Beispiel des malignen Mesothelioms der Tunica vaginalis testis und Sertoli-Zell-Tumoren.

BACKGROUND: Rare tumors of the testis not originating from germinal epithelium are a diagnostic and therapeutic challenge. OBJECTIVES: To present current approaches in rare tumors of the testis using the examples of Sertoli cell tumor (SCT) and malignant mesothelioma of the tunica vaginal testis (MMTVT). METHODS: A literature search in PubMed and the abstract databases of ASCO and ESMO was performed. Articles and book chapters were selected based on relevance to everyday treatment. RESULTS: The low incidence of testicular tumors not originating from the germinal epithelium makes a standardized approach difficult. Diagnosis and treatment depend on the underlying diagnosis. While most SCT are benign, malignant subtypes require extensive resection including metastatic surgery if complete resection is possible. In MMTVT, multimodality treatment concepts are followed, according to the malignant mesotheliomas of the pleura. CONCLUSION: Systematic registration of rare testicular tumors and comprehensive molecular pathological analysis are urgently needed to improve the understanding of tumor biology and to develop new therapeutic strategies.

Supportive care in patients with cancer during the COVID-19 pandemic.

Cancer care has been profoundly impacted by the global pandemic of severe acute respiratory syndrome coronavirus 2 disease (coronavirus disease 2019, COVID-19), resulting in unprecedented challenges. Supportive care is an essential component of cancer treatment, seeking to prevent and manage chemotherapy complications such as febrile neutropenia, anaemia, thrombocytopenia/bleeding, thromboembolic events and nausea/vomiting, all of which are common causes of hospitalisation. These adverse events are an essential consideration under routine patient management, but particularly so during a pandemic, a setting in which clinicians aim to minimise patients' risk of infection and need for hospital visits. Professional medical oncology societies have been providing updated guidelines to support health care professionals with the management, treatment and supportive care needs of their patients with cancer under the threat of COVID-19. This paper aims to review the recommendations made by the most prominent medical oncology societies for devising and modifying supportive care strategies during the pandemic.

[Tumor vaccines-therapeutic vaccination against cancer]. / Tumorvakzinierung ­ therapeutische Vakzinierung gegen Krebs.

Tumor cells always exhibit differences to normal cells. These differences can be recognized by the immune system, enabling the destruction of tumor cells by T cells, as was impressively demonstrated by the success of immune checkpoint inhibition, e.g., in malignant melanoma. Many cancers, however, do not respond to this kind of therapy. In these cases, vaccination against tumor antigens could be very helpful. Nevertheless, all of the efforts made in this respect during the past 30 years have been virtually futile. With current knowledge and technology there is new hope.

Correction: Role of growth arrest-specific gene 6-mer axis in multiple myeloma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Comprehensive assessments and related interventions to enhance the long-term outcomes of child, adolescent and young adult cancer survivors - presentation of the CARE for CAYA-Program study protocol and associated literature review.

BACKGROUND: Improved, multimodal treatment strategies have been shown to increase cure rates in cancer patients. Those who survive cancer as a child, adolescent or young adult (CAYA), are at a higher risk for therapy-, or disease-related, late or long-term effects. The CARE for CAYA-Program has been developed to comprehensively assess any potential future problems, to offer need-based preventative interventions and thus to improve long-term outcomes in this particularly vulnerable population. METHODS: The trial is designed as an adaptive trial with an annual comprehensive assessment followed by needs stratified, modular interventions, currently including physical activity, nutrition and psycho-oncology, all aimed at improving the lifestyle and/or the psychosocial situation of the patients. Patients, aged 15-39 years old, with a prior cancer diagnosis, who have completed tumour therapy and are in follow-up care, and who are tumour free, will be included. At baseline (and subsequently on an annual basis) the current medical and psychosocial situation and lifestyle of the participants will be assessed using a survey compiled of various validated questionnaires (e.g. EORTC QLQ C30, NCCN distress thermometer, PHQ-4, BSA, nutrition protocol) and objective parameters (e.g. BMI, WHR, co-morbidities like hyperlipidaemia, hypertension, diabetes), followed by basic care (psychological and lifestyle consultation). Depending on their needs, CAYAs will be allocated to preventative interventions in the above-mentioned modules over a 12-month period. After 1 year, the assessment will be repeated, and further interventions may be applied as needed. During the initial trial phase, the efficacy of this approach will be compared to standard care (waiting list with intervention in the following year) in a randomized study. During this phase, 530 CAYAs will be included and 320 eligible CAYAs who are willing to participate in the interventions will be randomly allocated to an intervention. Overall, 1500 CAYAs will be included and assessed. The programme is financed by the innovation fund of the German Federal Joint Committee and will be conducted at 14 German sites. Recruitment began in January 2018. DISCUSSION: CAYAs are at high risk for long-term sequelae. Providing structured interventions to improve lifestyle and psychological situation may counteract against these risk factors. The programme serves to establish uniform regular comprehensive assessments and need-based interventions to improve long-term outcome in CAYA survivors. TRIAL REGISTRATION: Registered at the German Clinical Trial Register (ID: DRKS00012504, registration date: 19th January 2018).

Epigenetic treatment combinations to effectively target cisplatin-resistant germ cell tumors: past, present, and future considerations.

BACKGROUND: Type II germ cell tumors represent the most common solid malignancy in men aged 15-45 years. Despite high cure rates of >90% over all stages, 10-15% of advanced patients develop treatment resistance and potentially succumb to their disease. Treatment of refractory germ cell tumors remains unsatisfactory, and new approaches are needed to further improve outcomes. OBJECTIVES: With this narrative review, we highlight epigenetic mechanisms related to resistance to standard systemic treatment, which may act as promising targets for novel combined epigenetic treatment approaches. MATERIALS AND METHODS: A comprehensive literature search of PubMed and MEDLINE was conducted to identify original and review articles on resistance mechanisms and/or epigenetic treatment of germ cell tumors in vitro and in vivo. Review articles were hand-searched to identify additional articles. RESULTS: Distinct epigenetic phenomena have been linked to chemotherapy resistance in germ cell tumors, among which DNA hypermethylation, histone acetylation, and bromodomain proteins appear as promising targets for therapeutic exploitation. Inhibitors of key regulators, for example DNA methyltransferases (e.g. decitabine, guadecitabine), histone deacetylases (e.g. romidepsin), and bromodomain proteins (e.g. JQ1) decreased cell viability, triggered apoptosis, and growth arrest. Additionally, these epigenetic drugs induced differentiation and led to loss of pluripotency and re-sensitization towards cisplatin in cell lines and animal models. DISCUSSION: Epigenetic treatments hold promise to (i) reduce the treatment burden of and (ii) overcome resistance to standard cisplatin-based chemotherapy. Combined approaches may enhance activity, while the ideal target and treatment combination of epigenetic drugs, either with another epigenetic agent or conventional cytotoxic agents need to be defined. CONCLUSION: Epigenetic (combination) treatment for germ cell tumors should be further explored in pre-clinical and clinical research for its potential to further improve germ cell tumor treatment.

[Positron emission tomography in germ cell tumors in men : Possibilities and limitations]. / Positronenemissionstomographie bei Keimzelltumoren des Mannes : Einsatzmöglichkeiten und Grenzen.

BACKGROUND: Conventional radiographic imaging may fail to safely distinguish clinical stage I from stage IIA germ cell cancer, to localize isolated tumor marker relapses, and to equivocally identify the viability of postchemotherapy residual masses. OBJECTIVES: To provide an overview of the diagnostic value and limitations of functional imaging by positron emission tomography with 2­deoxy-2-[fluorine-18]fluoro-D-glucose with computed tomography (18F-FDG-PET-CT) in male germ cell cancer. MATERIALS AND METHODS: A narrative review based on a literature search of PubMed/MEDLINE for original articles published from 1990-2018 and conference proceedings of ASCO (American Society of Clinical Oncology) and EAU (European Association of Urology) annual meetings 2014-2017 is presented. RESULTS: 18F-FDG-PET-CT does not improve diagnostic accuracy compared to conventional CT imaging clinical stage (CS) I disease. Particularly PET-negativity of postchemotherapy residual masses of seminomas >3 cm in size guide decision-making against further additional treatment. Even PET-positive residues must not result in relapse. For nonseminoma, the value of PET imaging is reduced by potential mature teratoma components, which are commonly PET negative. CONCLUSIONS: Current guidelines recommend 18F-FDG-PET-CT 6-8 weeks postchemotherapy for viability assessment of seminoma residues >3 cm in size. Exceptional circumstances, in which 18F-FDG-PET-CT may be helpful, include: (1) detection of active disease in CS IS, (2) viability assessment of residual masses >1 cm where complete secondary resection is impossible, (3) staging at marker relapse with unconspicuous conventional CT scan, (4) early response assessment during chemotherapy.

ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up.

The European Society for Medical Oncology (ESMO) consensus conference on testicular cancer was held on 3-5 November 2016 in Paris, France. The conference included a multidisciplinary panel of 36 leading experts in the diagnosis and treatment of testicular cancer (34 panel members attended the conference; an additional two panel members [CB and K-PD] participated in all preparatory work and subsequent manuscript development). The aim of the conference was to develop detailed recommendations on topics relating to testicular cancer that are not covered in detail in the current ESMO Clinical Practice Guidelines (CPGs) and where the available level of evidence is insufficient. The main topics identified for discussion related to: (1) diagnostic work-up and patient assessment; (2) stage I disease; (3) stage II-III disease; (4) post-chemotherapy surgery, salvage chemotherapy, salvage and desperation surgery and special topics; and (5) survivorship and follow-up schemes. The experts addressed questions relating to one of the five topics within five working groups. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel. A consensus vote was obtained following whole-panel discussions, and the consensus recommendations were then further developed in post-meeting discussions in written form. This manuscript presents the results of the expert panel discussions, including the consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

Mast cells decrease efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme B.

Resistance towards VEGF-centered anti-angiogenic therapy still represents a substantial clinical challenge. We report here that mast cells alter the proliferative and organizational state of endothelial cells which reduces the efficacy of anti-angiogenic therapy. Consequently, absence of mast cells sensitizes tumor vessels for anti-angiogenic therapy in different tumor models. Mechanistically, anti-angiogenic therapy only initially reduces tumor vessel proliferation, however, this treatment effect was abrogated over time as a result of mast cell-mediated restimulation of angiogenesis. We show that mast cells secrete increased amounts of granzyme b upon therapy, which mobilizes pro-angiogenic laminin- and vitronectin-bound FGF-1 and GM-CSF from the tumor matrix. In addition, mast cells also diminish efficacy of anti-angiogenic therapy by secretion of FGF-2. These pro-angiogenic factors act beside the targeted VEGFA-VEGFR2-axis and reinduce endothelial cell proliferation and angiogenesis despite the presence of anti-angiogenic therapy. Importantly, inhibition of mast cell degranulation with cromolyn is able to improve efficacy of anti-angiogenic therapy. Thus, concomitant mast cell-targeting might lead to improved efficacy of anti-angiogenic therapy.Resistance towards VEGF-centered anti-angiogenic therapy is an important clinical challenge. Here, the authors show that mast cells mediate resistance to anti-angiogenetic inhibitors by altering the proliferative and organizational state of endothelial cells through mobilization of FGF-1 and GM-CSF from the tumor matrix and secretion of FGF-2.