ABSTRACT

BACKGROUND: GSK3368715, a first-in-class, reversible inhibitor of type I protein methyltransferases (PRMTs) demonstrated anticancer activity in preclinical studies. This Phase 1 study (NCT03666988) evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK3368715 in adults with advanced-stage solid tumors.

METHODS: In part 1, escalating doses of oral once-daily GSK3368715 (50, 100, and 200 mg) were evaluated. Enrollment was paused at 200 mg following a higher-than-expected incidence of thromboembolic events (TEEs) among the first 19 participants, resuming under a protocol amendment starting at 100 mg. Part 2 (to evaluate preliminary efficacy) was not initiated.

RESULTS: Dose-limiting toxicities were reported in 3/12 (25%) patients at 200 mg. Nine of 31 (29%) patients across dose groups experienced 12 TEEs (8 grade 3 events and 1 grade 5 pulmonary embolism). Best response achieved was stable disease, occurring in 9/31 (29%) patients. Following single and repeat dosing, GSK3368715 maximum plasma concentration was reached within 1 h post dosing. Target engagement was observed in the blood, but was modest and variable in tumor biopsies at 100 mg.

CONCLUSION: Based on higher-than-expected incidence of TEEs, limited target engagement at lower doses, and lack of observed clinical efficacy, a risk/benefit analysis led to early study termination.

TRIAL REGISTRATION NUMBER: NCT03666988.

PMID:37237172 | DOI:10.1038/s41416-023-02276-0

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PubMed articles on: Cancer & VTE/PE

The Role of EGFR Amplification in Deep Venous Thrombosis Occurrence in IDH Wild-Type Glioblastoma

Curr Oncol. 2023 May 12;30(5):4946-4956. doi: 10.3390/curroncol30050373.

ABSTRACT

Introduction:Glioblastoma (GBM) patients have a 20-30 incidence of venous thromboembolic events. EGFR is a widely used prognostic marker for many cancers. Recent lung cancer studies have described relationships between EGFR amplification and an increased incidence of thromboembolic complications. We aim to explore this relationship in glioblastoma patients. Methods: Two hundred ninety-three consecutive patients with IDH wild-type GBM were included in the analysis. The amplification status of EGFR was measured using fluorescence in situ hybridization (FISH). Centromere 7 (CEP7) expression was recorded to calculate the EGFR-to-CEP7 ratio. All data were collected retrospectively through chart review. Molecular data were obtained through the surgical pathology report at the time of biopsy. Results:There were 112 subjects who were EGFR-amplified (38.2%) and 181 who were non-amplified (61.8%). EGFR amplification status was not significantly correlated with VTE risk overall (p = 0.2001). There was no statistically significant association between VTE and EGFR status after controlling for Bevacizumab therapy (p = 0.1626). EGFR non-amplified status was associated with an increased VTE risk in subjects greater than 60 years of age (p = 0.048). Conclusions:There was no significant difference in occurrence of VTE in patients with glioblastoma, regardless of EGFR amplification status. Patients older than 60 years of age with EGFR amplification experienced a lower rate of VTE, contrary to some reports on non-small-cell lung cancer linking EGFR amplification to VTE risk.

PMID:37232831 | PMC:PMC10217574 | DOI:10.3390/curroncol30050373

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PubMed articles on: Cancer & VTE/PE

Preoperative Venous Thromboembolism Screening and Postoperative Selective Anticoagulant Therapy Effectively Prevents Postoperative Symptomatic Venous Thromboembolism in Gynecological Malignancies: A 15-Year, Single-Center Study

Clin Appl Thromb Hemost. 2023 Jan-Dec;29:10760296231178300. doi: 10.1177/10760296231178300.

ABSTRACT

The aim of this study was to determine which type of prophylaxis was effective for postoperative symptomatic venous thromboembolism (VTE) in patients with gynecological malignancies. A total of 1756 consecutive patients undergoing laparotomy as first-line treatment were included. In Period 1 (2004-2009), low-molecular weight heparin (LMWH) was not available for postoperative VTE prophylaxis, but available in after Period 2 (2009-2013). In Period 3 (2013-2020), patients with pretreatment VTE could switch from LMWH to direct oral anticoagulant (DOAC) as of 2015. Preoperative VTE was screened by measuring D-dimer, followed by venous ultrasound imaging, and computed tomography and/or perfusion lung scintigraphy. Postoperative symptomatic VTE occurred with an incidence of 2.8% by the measures without prophylactic LMWH administration in Period 1. The incidence of postoperative symptomatic VTE was 0.6% in Period 2 and 0.3% in Period 3, being significantly reduced compared with Period 1 (P < .01 and < .0001). The incidences were not significantly different between Periods 2 and 3, but no patient switching to DOAC in Period 3 (n = 79) developed symptomatic VTE. Our preoperative VTE screening and postoperative selective LMWH administration were significantly preventive against postoperative symptomatic VTE.

PMID:37231620 | DOI:10.1177/10760296231178300

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PubMed articles on: Cancer & VTE/PE

Cardiac Metastatic Tumors: Current Knowledge

Am J Clin Oncol. 2023 May 26. doi: 10.1097/COC.0000000000001013. Online ahead of print.

ABSTRACT

Cardiac tumors are a heterogeneous group of pathologic masses of the heart that contain primary tumors-benign or malignant, and secondary tumors. Metastases are significantly more frequent, mostly originating from lung, breast, gastrointestinal tract, or ovary carcinomas. Secondary cardiac tumors may be asymptomatic or may cause cardiovascular, systemic, or embolic symptoms. The study is a summary of the available knowledge on cancerous metastatic lesions of the heart. Pleural mesothelioma (48.4%), adenocarcinoma (19.5%), or squamous cell carcinoma (18.2%) of lung, breast carcinoma (15.5%), ovarian carcinoma (10.3%), and bronchoalveolar carcinomas (9.8%) are cited as the most common origin of secondary heart tumors. Masses can spread by direct tumor invasion, by lymphatic vessels, veins, or arteries. Patients with cancer and nonspecific cardiovascular symptoms should be particularly vigilant, and the possibility of metastasis in an unusual location such as the myocardium should be considered in the diagnosis. Diagnostic methods include echocardiography, cardiac magnetic resonance, computed tomography, positron emission tomography, and histologic evaluation. Treatment of choice is managing primary carcinoma, due to the poor outcomes of surgical methods.

PMID:37231541 | DOI:10.1097/COC.0000000000001013

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PubMed articles on: Cancer & VTE/PE

Venous thromboembolism secondary to hospitalization for COVID-19: patient management and long-term outcomes

Res Pract Thromb Haemost. 2023 May;7(4):100167. doi: 10.1016/j.rpth.2023.100167. Epub 2023 Apr 26.

ABSTRACT

BACKGROUND: Venous thromboembolism (VTE) is a complication of COVID-19 in hospitalized patients. Little information is available on long-term outcomes of VTE in this population.

OBJECTIVES: We aimed to compare the characteristics, management strategies, and long-term clinical outcomes between patients with COVID-19-associated VTE and patients with VTE provoked by hospitalization for other acute medical illnesses.

METHODS: This is an observational cohort study, with a prospective cohort of 278 patients with COVID-19-associated VTE enrolled between 2020 and 2021 and a comparison cohort of 300 patients without COVID-19 enrolled in the ongoing START2-Register between 2018 and 2020. Exclusion criteria included age <18<3

RESULTS: Patients with VTE secondary to COVID-19 had more frequent pulmonary embolism without deep vein thrombosis than controls (83.1% vs 46.2%, P<.001),P<.001),P<.001).P= 0.9) and the proportion of patients who discontinued anticoagulation (78.0% and 75.0%, P= 0.4) were similar between the 2 groups. Thrombotic event rates after discontinuation were 1.5 and 2.6 per 100 patient-years, respectively (P = 0.4).

CONCLUSION: The risk of recurrent thrombotic events in patients with COVID-19-associated VTE is low and similar to the risk observed in patients with VTE secondary to hospitalization for other medical diseases.

PMID:37229314 | PMC:PMC10131739 | DOI:10.1016/j.rpth.2023.100167

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PubMed articles on: Cancer & VTE/PE

Pulmonary embolism complicated by tamponade revealing metastatic lung cancer in a woman pregnant with twin: about a case report

Ann Med Surg (Lond). 2023 Apr 7;85(5):1966-1970. doi: 10.1097/MS9.0000000000000516. eCollection 2023 May.

ABSTRACT

Lung cancer can be revealed by thromboembolic complications. Its association with pregnancy is becoming more frequent due to the increasing number of smoking women. The care of a pregnant woman with cancer is quite delicate because it requires finding a balance between the treatment of the mother and the potential foetal risk.

CASE PRESENTATION: The authors report the case of a 38-year-old patient, with a twin pregnancy of 16 weeks, complicated by proximal and distal peripheral venous thrombosis of the left lower limb under low molecular weight heparin therapy at a curative dose. A week later, the patient presented to the emergency room with respiratory distress associated with chest pain and low-abundance metrorrhagia. The obstetrical ultrasound performed confirmed the vitality of only one of the two foetuses. The transthoracic ultrasound objectified a very abundant pericardial effusion producing a tamponade, which was drained percutaneously and whose cytological study revealed a liquid rich in tumour cells. After the unfortunate death of the second twin and an endouterine evacuation, a chest computed tomography angiogram demonstrated a bilateral proximal pulmonary embolism associated with bilateral moderate pulmonary effusion as well as multiple thrombosis and secondary aspect liver lesions with a suspicious parenchymal lymph node of the upper lung lobe. A liver biopsy concluded to a secondary hepatic localization of a moderately differentiated adenocarcinoma whose immunohistochemical complement revealed a pulmonary origin. A multidisciplinary consultation meeting leaned towards treatment with neoadjuvant chemotherapy. The patient died 7 months later.

DISCUSSION: Venous thromboembolic disease is more common in pregnant women. Delayed diagnosis is common in these cases, resulting in a high rate of locally advanced or metastatic disease. Since the treatment of pregnancy-associated cancer does not rely on a standardized approach, the decision on how to proceed must be made by a multidisciplinary team.

CONCLUSION: The cornerstone of management remains to find the balance between treating the mother as well as possible while preventing the foetus from the possible harm of cytotoxic drugs frequently used to treat lung cancer. Because of the delayed diagnosis, the maternal prognosis often remains poor.

PMID:37228933 | PMC:PMC10205297 | DOI:10.1097/MS9.0000000000000516

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PubMed articles on: Cancer & VTE/PE

A new anticoagulant strategy: the factor XI inhibitors

G Ital Cardiol (Rome). 2023 Jun;24(6):0-454. doi: 10.1714/4041.40204.

ABSTRACT

In the last 10 years the introduction of the direct oral anticoagulants (DOACs) has revolutionized the anticoagulant treatment, one of the cornerstones of the therapy for cardiovascular diseases. Thanks to their efficacy at least not inferior compared to vitamin K antagonists and their better safety profile, particularly with regard to intracranial bleeding, DOACs are now the first choice for the prevention of cardioembolism in patients with non-valvular atrial fibrillation and for the treatment of venous thromboembolism (VTE). Other areas of clinical use for DOACs include the prevention of VTE in orthopedic and oncology surgery and in outpatient cancer patients treated with anticancer therapy, or the use of low-dose in association with aspirin in patients with coronary or peripheral artery disease.An increased risk of gastrointestinal bleeding has been reported for some DOACs. In addition, DOACs have also experienced some failures including stroke prevention in patients with mechanical prosthetic valves or rheumatic diseases and VTE therapy in patients with antiphospholipid antibody syndrome. Also, no data are available on DOACs in some particular areas, including severe renal impairment and thrombocytopenia.In recent years, the clinical use of factor XI and factor XII inhibitors has been proposed. Currently, factor XI inhibitors have more clinical data than factor XII inhibitors. This article will report the rationale for the clinical use and the main evidences currently available on factor XI inhibitors.

PMID:37227204 | DOI:10.1714/4041.40204

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PubMed articles on: Cancer & VTE/PE

Ovarian Vein Thrombosis: An Unusual Cause of Abdominal Pain in Breast Cancer

Cureus. 2023 Apr 10;15(4):e37363. doi: 10.7759/cureus.37363. eCollection 2023 Apr.

ABSTRACT

Ovarian vein thrombosis (OVT) is a rare but potentially life-threatening complication that is usually seen in the intrapartum or postpartum period but can also be seen in patients with risk factors for venous thromboembolism. When symptomatic, it usually presents with abdominal pain and other vague constitutional symptoms, hence it is important for healthcare professionals to be aware of this condition when evaluating patients with risk factors. We present a rare case of OVT in a patient with breast cancer. Due to a lack of clear guidelines regarding the treatment and duration of treatment in non-pregnancy-related OVT, we followed the guidelines for the treatment of venous thromboembolism and started the patient on rivaroxaban for a three-month duration with close outpatient follow-up.

PMID:37181988 | PMC:PMC10170570 | DOI:10.7759/cureus.37363

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PubMed articles on: Cancer & VTE/PE

Thrombosis of Chiari's network in the setting of non-bacterial thrombotic endocarditis occurring under non-vitamin K antagonist oral anticoagulation: a case report

Eur Heart J Case Rep. 2023 May 3;7(5):ytad227. doi: 10.1093/ehjcr/ytad227. eCollection 2023 May.

ABSTRACT

BACKGROUND: Non-bacterial thrombotic endocarditis (NBTE) is a rare condition characterized by sterile thrombi on undamaged valves. We herein report a case of NBTE involving the Chiari's network and the mitral valve, related to a metastatic cancer, and occurring under non-vitamin K antagonist oral anticoagulant (NOAC).

CASE SUMMARY: A 74-year-old patient with metastatic pulmonary cancer was diagnosed with a right atrium mass during pre-treatment cardiovascular check-up. Transoesophageal echocardiography and cardiac magnetic resonance concluded that the mass was a Chiari's network. Two months later, the patient was admitted for a pulmonary embolism and started rivaroxaban. At 1-month follow-up, the patient underwent a new echocardiography, which showed an increased size of the right atrium mass and the presence of two new masses on the mitral valve. She suffered an ischaemic stroke. Infectious work-up was negative. Coagulation factor VIII was 419%. A NBTE with Chiari's network thrombosis and mitral valve involvement was suspected in the setting of a hypercoagulable state related to the active cancer, and intravenous heparin was started, bridged to vitamin K antagonist (VKA) after 3 weeks. All the lesions were fully resolved on follow-up echocardiography at 6 weeks.

DISCUSSION: This case highlights an atypical association of thrombosis on right and left heart chamber with systemic and pulmonary embolism, related to a hypercoagulable state. Chiari's network is an embryonic remnant with no clinical significance and is exceptionally thrombosed. Failure of treatment by NOAC highlights the complexity of cancer-related thrombosis, particularly in NBTE, and the necessity of heparin and VKA in our case.

PMID:37181468 | PMC:PMC10171835 | DOI:10.1093/ehjcr/ytad227

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PubMed articles on: Cancer & VTE/PE

"Risk of venous thromboembolism and bleeding after major surgery for ovarian cancer: standard in-hospital versus extended duration of thromboprophylaxis": Comment

J Thromb Haemost. 2023 Jun;21(6):1681-1683. doi: 10.1016/j.jtha.2023.02.032.

NO ABSTRACT

PMID:37179077 | DOI:10.1016/j.jtha.2023.02.032

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PubMed articles on: Cancer & VTE/PE

Role of circulating mitochondria in venous thrombosis in glioblastoma

J Thromb Haemost. 2023 May 11:S1538-7836(23)00397-5. doi: 10.1016/j.jtha.2023.04.036. Online ahead of print.

ABSTRACT

BACKGROUND: Many glioblastoma multiforme (GBM) patients develop deep venous thrombosis or pulmonary emboli. Cell-free circulating mitochondria increase after brain injury and are associated with coagulopathy.

OBJECTIVES: This study evaluated whether mitochondria play a role in the GBM-induced hypercoagulable state.

PATIENTS/METHODS: We examined the correlation between cell-free circulating mitochondria and venous thrombosis in GBM patients and the impact of mitochondria on venous thrombosis in mice with IVC stenosis.

RESULTS AND CONCLUSIONS: Using plasma samples of 82 patients with GBM, we found that GBM patients had a higher number of mitochondria in their plasma (GBM with VTE: 2.8 × 107 mitochondria/ml, GBM without VTE: 1.9 × 107 mitochondria/ml) than control healthy subjects (n=17)(0.3 × 107 mitochondria/ml). Interestingly, patients with GBM and VTE (n=41) had a higher mitochondria concentration than GBM patients without VTE (n=41). In a murine model of IVC stenosis, intravenous delivery of mitochondria resulted in an increased rate of venous thrombosis compared to controls (70% and 28%, respectively). Mitochondria-induced venous thrombi were neutrophil-rich and contained more platelets than control thrombi. Furthermore, as mitochondria are the only source of cardiolipin in circulation, we compared the concentration of anticardiolipin IgG in plasma samples of GBM patients and found a higher concentration in patients with VTE (OD = 0.69 ± 0.04) than those without VTE (OD: 0.51 ± 0.04). We concluded that mitochondria might play a role in the GBM-induced hypercoagulable state. We propose quantifying circulating mitochondria or anticardiolipin antibody concentrations in GBM patients might identify patients at increased risk for VTE.

PMID:37178770 | DOI:10.1016/j.jtha.2023.04.036

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PubMed articles on: Cancer & VTE/PE

Primary pulmonary artery chondrosarcoma: case report

29 May 2023

C

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Cardiotoxicity News

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PubMed articles on: Cardio-Oncology

p53 at the Crossroads between Doxorubicin-Induced Cardiotoxicity and Resistance: A Nutritional Balancing Act

Nutrients. 2023 May 10;15(10):2259. doi: 10.3390/nu15102259.

ABSTRACT

Doxorubicin (DOX) is a highly effective chemotherapeutic drug, but its long-term use can cause cardiotoxicity and drug resistance. Accumulating evidence demonstrates that p53 is directly involved in DOX toxicity and resistance. One of the primary causes for DOX resistance is the mutation or inactivation of p53. Moreover, because the non-specific activation of p53 caused by DOX can kill non-cancerous cells, p53 is a popular target for reducing toxicity. However, the reduction in DOX-induced cardiotoxicity (DIC) via p53 suppression is often at odds with the antitumor advantages of p53 reactivation. Therefore, in order to increase the effectiveness of DOX, there is an urgent need to explore p53-targeted anticancer strategies owing to the complex regulatory network and polymorphisms of the p53 gene. In this review, we summarize the role and potential mechanisms of p53 in DIC and resistance. Furthermore, we focus on the advances and challenges in applying dietary nutrients, natural products, and other pharmacological strategies to overcome DOX-induced chemoresistance and cardiotoxicity. Lastly, we present potential therapeutic strategies to address key issues in order to provide new ideas for increasing the clinical use of DOX and improving its anticancer benefits.

PMID:37242146 | PMC:PMC10222243 | DOI:10.3390/nu15102259

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PubMed articles on: Cardio-Oncology

Prognostic Impact of Global Longitudinal Strain and NT-proBNP on Early Development of Cardiotoxicity in Breast Cancer Patients Treated with Anthracycline-Based Chemotherapy

Medicina (Kaunas). 2023 May 15;59(5):953. doi: 10.3390/medicina59050953.

ABSTRACT

Background. The most important anthracycline side effect is cardiotoxicity, resulting in congestive heart failure (HF). Early detection of cardiac dysfunction and appropriate treatment can improve outcomes and reduce the progression of HF. The aim of our study was to evaluate changes in clinical data, echocardiographic parameters, and NT-proBNP, as well as their associations with early anthracycline-induced cardiotoxicity (AIC) in patients treated with anthracycline-based chemotherapy. Methods and Materials. Patients with breast cancer were prospectively assessed with echocardiography, as well as NT-proBNP testing at baseline, (T0), after two cycles (T1) and four cycles (T2) of chemotherapy. AIC was defined as a new decrease in the LVEF of 10 percentage points, to a value below the lower limit of normal. Results.We evaluated 85 patients aged 54.5 ± 9.3 years. After a cumulative dose of 237.9 mg/m2 of doxorubicin, 22 patients (25.9%) met the criteria of AIC after chemotherapy. Patients who subsequently progressed to cardiotoxicity had demonstrated a significantly larger impairment in LV systolic function compared to those who did not develop cardiotoxicity (LVEF: 54.0 ± 1.6% vs. 57.1 ± 1.4% at T1, p< 0.001, and 49.9 ± 2.1% vs. 55.8 ± 1.6% at T2, p< 0.001; GLS: -17.8 ± 0.4% vs. -19.3 ± 0.9% at T1, p< 0.001, and -16.5 ± 11.1% vs. -18.5 ± 0.9% at T2, p< 0.001, respectively). The levels of NT-proBNP increased significantly from 94.8 ± 43.8 ng/L to 154.1 ± 75.6 ng/L, p< 0.001. A relative decrease in GLS ≤ -18.0% (sensitivity: 72.73%; specificity: 92.06%; AUC, 0.94; p< 0.001) and a relative increase in NT-proBNP > 125 ng/L (sensitivity: 90.0%; specificity: 56.9%; AUC, 0.78; p< 0.001) from baseline to T1 predicted subsequent LV cardiotoxicity at T2. Conclusions. Decrease in GLS and elevation in NT-proBNP were significantly associated with AIC, and these could potentially be used to predict subsequent declines in LVEF with anthracycline-based chemotherapy.

PMID:37241185 | PMC:PMC10224214 | DOI:10.3390/medicina59050953

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PubMed articles on: Cardio-Oncology

Echocardiographic Findings in Asymptomatic Mediastinal Lymphoma Survivors Years after Treatment Termination

J Clin Med. 2023 May 12;12(10):3427. doi: 10.3390/jcm12103427.