A 68 y–o woman, treated with propranolol for hypertension, amiodarone due to a previous atrial flutter and levothyroxine for previous thyroidectomy, developed bilateral pleural effusion (dx › sn) and recurrent pericardial effusion (max 5 cm) treated with pericardiocentesis. After complaining for uterine non–major bleedings complicated by anemia (Hg: 9.9 g/dl), she was diagnosed with M1c BRAF wild–type IV stage vulva melanoma with bladder, endometrial and soft tissues metastases. Admitted to our hospital, she started nivolumab and ipilimumab replaced by carboplatin and paclitaxel and, lastly, nemvaleukin. An ECG showed a negative T wave in V2–V4 (Fig.1). Despite asymptomatic, her HS–Troponin was high (T1: 183 pg/mL, T2: 195 pg/ml). Echocardiogram (Eco) showed a slight pericardial effusion without tamponade, a normal EF (59%) and severe septal hypertrophy (18 mm), without right heart enlargement or dysfunction. Moreover, a 1.7 x 2.1 cm hyperechogenic mass attached to the roof of the right atrium without tricuspid valve orifice involvement, suggestive of blood clot, was detected (Fig.2). Therefore, she started enoxaparin 0.5 mg/kgx2/die. However, the CT–scan revealed further intracardiac lesions not Eco highlighted suggestive for multiple intracardiac and pericardial metastases (Fig.3), together with subsegmental and segmental filling defects of the right pulmonary artery. Accordingly, enoxaparin dose was increased to 1 mg/kgx2/die (Hg: 10 g/dl); however, at discharge, heparin could not be replaced by direct oral anticoagulants (DOACs) due both to the uncertainty of drug–drug interactions (DDI) with nemvaleukin and anemia. At the 3–month follow up, she was asymptomatic, still on nemvaleukin without substantial enlargement of the heart metastases. In accordance with the pulmonary embolism (PE) regression and the patient’s preference for a more practical anticoagulant therapy, we halved enoxaparin dose (1 injection/die instead of 2). Thromboembolism is the second leading cause of death in malignancy after cancer progression. Cardiac metastases are a rare condition, mostly due to pleural mesothelioma, lung–renal–breast cancer, lymphoma and melanoma. In this challenging clinical case, the cancer journey of the patient with melanoma and cardiac metastases was further complicated by the occurrence of an incidental PE, whose injectable anticoagulant treatment could not be optimized into a more manageable DOAC option due to the lack of DDI data.Fig. 1 Fig. 2 Fig. 3

Abstract A 43 y–o woman, without cardiovascular risk factors, was diagnosed with BRAF+ IIIC melanoma of unknown origin with bilateral axillary lymph node metastases. She started a combined treatment with vemurafenib, cobimetinib (braf/mek inhibitors) and atezolizumab (PDL1 inhibitor) as neoadjuvant therapy, followed after 6 weeks by surgical treatment (that showed pathological complete response) and adjuvant immunotherapy with atezolizumab hitherto ongoing. A serial CT–scan revealed a 0.9x1.3 cm mass (Fig.1) close to the right jugular vein (RJV) with increased contrast enhancement susceptible of vessel ectasia by the radiologist who expressed uncertainty about its site (intra or extravascular?) and asked for further imaging assessment. Therefore, a duplex ultrasound (DU) was performed with the detection of a 0.6x1.2 cm endovascular mobile “blackberry shaped” mass in the RJV and the indication for a vascular surgery evaluation. The patient started enoxaparin 1 mg/Kgx2/die s.c. according to “ex iuvantibus therapy”. However, the vascular surgeon diagnosis confirmed the undetermined site of the mass. The patient decided for a second DU opinion and reached our Cancer Angiology Lab, where a novel DU detected a deep vein thrombosis (DVT) of the RJV (Fig.2–Fig.3). Enoxaparin was replaced with edoxaban 60 mg 1 cp/die since the patient preferred a more manageable root of administration for the requested long–term anticoagulant treatment. After 2 months a DU follow up showed no regression of the mass. Accordingly, the patient proceeded with edoxaban 60 mg/die without any side effects, whereas still in treatment with immunotherapy. Conclusions Thromboembolism is the second leading cause of death in malignancy. Overall, biomarkers and thrombotic risk factors related to patient, tumor and anticancer regimens favor the development of cancer associated thrombosis. Delay in DVT diagnosis and, mostly, in the initiation of a full and long–term anticoagulant treatment, like in this case, enables a chronic evolution of the clot which makes its timely regression more challenging.

Abstract Herein, we present the case of a 58 y–o Caucasian man with unremarkable cardiovascular history and a strong family history for cancer. He was diagnosed with lung adenocarcinoma IVb (pleura, pleural effusion, lymph nodes), PDL1: 2% TPS and absence of actionable driver mutations on DNA and RNA NGS (only ERBB2 mutation). Started first–line chemotherapy with cisplatin–pemetrexed regimen and immunotherapy with pembrolizumab. He developed common/superficial femoral and popliteal deep vein thrombosis (DVT) and pulmonary embolism (PE). The patient started low–molecular–weight heparin (LMWH) namely enoxaparin 1 mg/kg x 2/d (weight: 65 Kg). After 1 mo, CT showed PE resolution. Due to DVT persistence and patient’s preference for oral administration, LMWH was replaced with direct oral anticoagulant (DOAC) namely edoxaban 60 mg 1 cp/d. After 2 mo, resolution of common femoral and popliteal vein thrombosis with partial recanalization of superficial femoral DVT were detected. However, he developed brain metastases treated with WB radiotherapy. We decided for edoxaban full dose long–term anticoagulant treatment with monthly cardioncological surveillance. After 6 mo since cancer diagnosis, the patient was still adherent to DOAC therapy, although in a maintenance combined regimen pemetrexed–pembrolizumab based, without both drug–drug interactions and brain bleeding. Conclusions Thromboembolism is the second leading cause of death in malignancy. In this clinical case, a man with advanced lung cancer developed extended cancer–associated thrombosis (CAT). However, the appearance of brain metastases has posed a clinical dilemma: to continue or to withdraw the anticoagulant therapy and, also, which drug to choose between LMWH and DOAC. Literature is limited on the use of DOACs in cancer patients with brain metastases. Besides, current guidelines neither advocate contraindication to DOAC, nor suggest caution as requested for gastrointestinal and genitourinary sites of cancer. We decided to proceed with edoxaban therapy, despite chemotherapy combined to immunotherapy were still ongoing and the concurrent appearance of brain metastases, with good results in efficacy, patient’s adherence and, mostly, safety. In conclusion, in regard to our clinical experience, we point out DOAC as a reliable and manageable therapeutical choice in CAT, also in active cancer patients with brain metastases receiving chemo–immunotherapy.

Cancer-associated thrombosis (CAT) is a devastating complication of cancer that can significantly impact a patient’s health and life. The incidence of CAT is approximately 20%, and 1 in 5 cancer patients will develop CAT annually. Indeed, CAT can promote pulmonary embolism and deep vein thrombosis, leading to increased morbidity and mortality that dramatically impact survival. CAT can also provoke delay or discontinuation of anticancer treatment, which may result in a lack of treatment efficacy and high costs for patients, institutions, and society. Current guidelines advocate direct oral anticoagulants (DOACs) as the first-line anticoagulant option in CAT. Compared to low-molecular-weight-heparins (LMWHs), DOACs are advantageous in that they typically have an oral route of administration, do not require laboratory monitoring, and have a more predictable anticoagulant effect. However, in patients with thrombocytopenia, renal failure, or those receiving anticancer regimens with potential for drug-drug interactions, LMWH is still the mainstay of care. The main limitation of current anticoagulant agents is related to bleeding risk (BR), both for DOACs and LMWHs. Specifically, DOACs have been associated with high BR in gastrointestinal and genitourinary cancers. In this challenging scenario, abelacimab, an anti-factor XI agent, could represent a viable option in the management of CAT due to its “hemostasis sparing” effect. The safe profile of abelacimab could be useful in patients with active malignancy and CAT, as long-term anticoagulant therapy is often required. Two ongoing international phase III trials (Aster and Magnolia) compare abelacimab with the standard of care (i.e., apixaban in patients with CAT and dalteparin in those with CAT and high BR, respectively). Abelacimab is a new and attractive anticoagulant for the management of CAT, especially in the insidious and critical scenario of active cancer patients with venous thromboembolism and high BR. The aim of this narrative review is to discuss the updated evidence on the performance of DOACs and LMWHs in the treatment of CAT and to focus on the potential role of abelacimab in CAT and its promising associated clinical trials.

BACKGROUND:The incidental detection of a right atrial mass during routine cardioncological workup is a rare condition. The correct differential diagnosis between cancer and thrombi is challenging. A biopsy may not be feasible while diagnostic techniques and tools may not be available.CASE SUMMARY:We report the case of a 59-year-old female patient with a history of breast cancer and current secondary metastatic pancreatic cancer. She developed deep vein thrombosis and pulmonary embolism and was admitted to the Outpatient Clinic of our Cardio-Oncology Unit for follow-up. Transthoracic echocardiogram incidentally found a right atrial mass. Clinical management was difficult due to the abrupt worsening of the patient's clinical condition and the progressive severe thrombocytopenia. We suspected a thrombus, according to its echocardiographic appearance, the patient's cancer history and recent venous thromboembolism. The patient was unable to adhere to low molecular weight heparin treatment. Due to worsening prognosis, palliative care was recommended. We also highlighted the distinguishing features between thrombi and tumors. We proposed a diagnostic flowchart to aid diagnostic decision making in the case of an incidental atrial mass.CONCLUSION:This case report highlights the importance of cardioncological surveillance during anticancer treatments to detect cardiac masses.

We report the case of a 50-year-old female patient with breast cancer who, during preoperative workup, presented repeated wide QRS complex tachycardias, recorded by Holter ECG. She was immediately referred to a hub center for electrophysiological study where she was diagnosed with right ventricular outflow tract ventricular tachycardia and underwent catheter ablation. The chemotherapy with paclitaxel that the patient was receiving combined with psychological stress may have triggered the arrhythmias.

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Cancer-associated thrombosis (CAT) is the second main cause of cancer death with high related mortality and morbidity, leading to anticancer agent delays and interruptions. The recommended therapy, low-molecular-weight heparin (LMWH), however, is burdensome for patients and costly for society, as treatment should last until cancer is no longer active, even indefinitely. Tinzaparin is a manageable, efficient, safe, and cost-effective option. Compared to the other LMWHs, advantages are single-daily dose and safety in the elderly and those with renal impairment (RI). The purpose of this review is to critically discuss recent data on its efficacy and safety in CAT.

Abstract Introduction TEV is the second highest cause of death in malignancy with 20% incidence. Platelets is a leading mediator of thrombosis as well as of tumor development. Indeed, thrombocytosis is a predictive biomarker of thrombosis risk and contributes to CAT burden. However, the management of thrombocytopenia in patients with CAT is well investigated, whereas evidence is poor on the management of patients with concomitant occurrence of thrombocytosis and CAT. Case report A 67 y-o woman, in primary thromboprophylaxis with 100 mg/die aspirin for myeloproliferative syndrome (PC: 771 x103/µl), was treated with left mastectomy for infiltrating ductal carcinoma (G3 pT1cN1a Mx Ki67:25%) and adjuvant chemotherapy with anthracyclines and anastrozole. Due to bone metastases, zoledronic acid, fulvestrant and palbociclib were administrated. For liver metastases, she was treated with exemestane, paclitaxel and bevacizumab and for disease progression, started capecitabine and cyclophosphamide, still ongoing. She experienced left jugular vein thrombosis (Fig 1-2) treated with edoxaban 60 mg/die with an almost total DVT regression after 2 months. The multidisciplinary team (oncologist, cardiologist, hematologist) decided to interrupt aspirin, proceeding antithrombotic therapy with edoxaban full dose. Concomitant cytoreductive therapy with hydroxyurea was started concomitantly with edoxaban. PC was reduced (522 x103/µl). After 1-month follow-up duplex ultrasound still documented mild persistence of the DVT (Fig 3-4), the patient was compliant and the anticancer regimens (addressed to both the solid cancer and the hematologic disease) were still administrated without any adverse effects. Conclusions CAT is a frequent and major complication of malignancy, worsening mortality, morbidity and decision-making. Platelets play a central role in promoting the hypercoagulable melieu of cancer as well as the metastases growth. Notably, thrombocytosis occurrence further increases the thrombogenic burden in malignancy; nevertheless, its concomitant development together with CAT is understudied. In the reported case, a solid tumor, together with hematologic cancer and DVT, concurred to a difficult management of a patient admitted to our multidisciplinary team. The use of a DOAC, edoxaban, at full dose, without concomitant therapy with aspirin, was an effective, safe and manageable antithrombotic treatment option, allowing the continuation of anticancer agents with no interruptions or delays. The knowledge of tumor-specific pathways may help to personalize strategies for CAT prevention. Fig 1-2 Fig 3-4

RATIONALE:Venous thromboembolism is a feared frequent complication of cancer with a 2-way relationship. Low molecular weight heparin is the mainstay of treatment. The use of direct oral anticoagulants is supported by established evidence for the treatment of deep vein thrombosis also in active cancer and they are prioritized over low molecular weight heparin for cancer-associated thrombosis according to current guidelines. However, upper limb deep vein thrombosis is poorly studied with scant data on the use of direct oral anticoagulants in noncatheter-related deep vein thrombosis. We report the case of a patient with noncatheter-related deep vein thrombosis and a rare tumor site effectively and safely treated with a direct oral anticoagulant, edoxaban, after lack of efficacy with low molecular weight heparin.PATIENT CONCERNS:A 35-year-old man with primitive mediastinal seminoma presented at our Cardio-Oncology Unit for prechemotherapy assessment.DIAGNOSIS:Persistent brachiocephalic deep vein thrombosis, despite full-dose enoxaparin, was detected at ultrasonography.INTERVENTION:We decided to switch the anticoagulant treatment from enoxaparin to edoxaban.OUTCOME:The 3-month ultrasonography showed almost total regression of the deep vein thrombosis without any adverse effects and a good patient compliance.LESSONS:We conducted a literature review on upper limb deep vein thrombosis, since its management is challenging due to inconsistency of evidence. This report highlights the benefits of direct oral anticoagulants compared to low molecular weight heparins in cancer-associated thrombosis therapy in terms of efficacy, safety and ease of use.

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l tromboembolismo venoso rappresenta una causa di elevata mortalità e morbilità nei pazienti oncologici; gli anticoagulanti iniettivi ed il warfarin presentano alcuni limiti, difficilmente superabili nella pratica clinica. I recenti trial sugli anticoagulanti orali diretti, in prevenzione primaria, secondaria e nel trattamento del tromboembolismo venoso nel paziente con cancro attivo hanno dimostrato che i DOACs sono una scelta terapeutica non solo sicura ed efficace, ma anche maneggevole. In un ambito clinico “challenging” a causa di concomitanti terapie antitumorali, cateteri venosi centrali, trombocitopenia, disfunzione epatica e renale, fragilità tissutale e frequenti procedure invasive che complessivamente concorrono a rendere i pazienti particolarmente suscettibili al tromboembolismo venoso, i DOACs aprono un nuovo scenario terapeutico molto promettente.

BackgroundCancer-associated thrombosis is a worrisome complication for patients receiving chemotherapy. Management of anticoagulant therapy is complex in cancer patients because of comorbidities such as thrombocytopenia, renal impairment and a hypercoagulability due to the cancer itself. Therefore, tailoring anticoagulant treatment is challenging. Case presentationWe describe the case of a 35-year-old male patient with primitive mediastinal seminoma undergoing treatment with Bleomycin, Etoposide and Cisplatin (BEP protocol) who presented with marked upper-extremity vein thrombosis unresponsive to low molecular weight heparin. After unsuccessful therapy with heparin, therapy was switched to edoxaban, a direct oral anticoagulant, which was able to dissolve the huge thrombus, suggesting that direct oral anticoagulants (DOACs) may be a reliable option especially in long-term anticoagulant treatments like in this case.A short review of the literature on cancer-related thrombosis and the use of direct oral anticoagulants in malignancies is also presented. ConclusionsOur case suggests that in severe and extended cancer-associated thrombosis, instituting treatment with direct oral anticoagulants instead of low molecular weight heparin can be an effective, safe and practical option. This choice is preferred by most patients as shown by their proper adherence to treatment.

Abstract Aims TEV is a common cancer complication with 20% incidence. LMWH is the standard therapy for efficacy, safety and ease of use. However, some scenarios are deeply challenging for intercurrent prothrombotic anticancer drugs. Methods A 35-year-old man reported dysphagia, EGDS: oesophagus ulcers, thyroid echography: thoracic mass compressing proximal borders. Vascular ultrasound: thrombosis of left internal giugular, subclavian, axillary and brachial veins; he began enoxaparin 6000 IU ×2/die (65 kg). CT-scan: solid anterior–superior mediastinum vascularized mass (16 × 13 cm) incorporating great thoracic vessels with 20 cm cranio-caudal longitudinal extension with trachea dislocation. PET-CT: massive superior-anterior mediastinum pathological 18F-FDG accumulation suggestive for malignancy. Lung perfusion scan: absence of left lung perfusion. Angio-CT: showed compression of pulmonary artery trunk and of branches. He presented marked asthenia, sweating and presyncope. D-dimer: 6026 µg/L, NT-proBNP: 1417 pg/mL. Mediastinum biopsy exhibited seminoma (ki67+: 65%), he started BEP Protocol (etoposide, cisplatin, bleomycin). TTE: periaortic cuff from mediastinum mass which ab extrinseco compressed pulmonary artery trunk and branches with occlusion of left one, right chambers dilatation, sovra-epatic veins and inferior vena cava (21 mm) ectasia, decreased inspiratory collapse, pulmonary hypertension (SPAP: 52 mmHg), EF: 55%. After 2 months of enoxaparin, vein ultrasound: persistent DVT and positive CUS. So, we replaced enoxaparin with edoxaban 60 mg/die. After 2 months of edoxaban, overall regression of vein thrombosis with minimal residual thrombosis of left internal giugular vein; D-dimer: 1554 µg/L. Results After 2 months of BEP Protocol, CT-scan: decrease mediastinum mass (6 × 12 cm) dimensions. Conclusions Cancer associated thrombosis is a frequent complication, worsening mortality, morbidity and decision-making. Cancer stage and drugs favour development of severe thrombosis, not solvable with LMWH, the cornerstone of anticoagulant therapy in cancer-related thrombosis. DOACs appear as a new and successful therapeutical option, especially in the most challenging cases of highly thrombotic profile after ‘heparin failure’.