ABSTRACT

BACKGROUND: Cyclic nucleotides play critical roles in cardiovascular biology and disease. PDE10A (phosphodiesterase 10A) is able to hydrolyze both cAMP and cGMP. PDE10A expression is induced in various human tumor cell lines, and PDE10A inhibition suppresses tumor cell growth. Chemotherapy drug such as doxorubicin (DOX) is widely used in chemotherapy. However, cardiotoxicity of DOX remains to be a serious clinical complication. In the current study, we aim to determine the role of PDE10A and the effect of PDE10A inhibition on cancer growth and cardiotoxicity induced by DOX.

METHODS: We used global PDE10A KO (knockout) mice and PDE10A inhibitor TP-10 to block PDE10A function. DOX-induced cardiotoxicity was evaluated in C57Bl/6J mice and nude mice with implanted ovarian cancer xenografts. Isolated adult mouse cardiomyocytes and a human ovarian cancer cell line were used for in vitro functional and mechanistic studies.

RESULTS: We found that PDE10A deficiency or inhibition alleviated DOX-induced myocardial atrophy, apoptosis, and dysfunction in C57Bl/6J mice. RNA sequencing study revealed a number of PDE10A-regulated signaling pathways involved in DOX-induced cardiotoxicity. PDE10A inhibition increased the death, decreased the proliferation, and potentiated the effect of DOX on various human cancer cells. Importantly, in nude mice with implanted ovarian cancer xenografts, PDE10A inhibition attenuated tumor growth while protecting DOX-induced cardiotoxicity. In isolated cardiomyocytes, PDE10A contributed to DOX-induced cardiomyocyte death via increasing Top2β (topoisomerase 2β) expression, mitochondrial dysfunction, and DNA damage by antagonizing cGMP/PKG (protein kinase G) signaling. PDE10A contributed to cardiomyocyte atrophy via potentiating FoxO3 (forkhead box O3) signaling via both cAMP/PKA- (protein kinase A) and cGMP/PKG-dependent signaling.

CONCLUSIONS: Taken together, our study elucidates a novel role for PDE10A in cardiotoxicity induced by DOX and cancer growth. Given that PDE10A has been already proven to be a safe drug target, PDE10A inhibition may represent a novel therapeutic strategy in cancer therapy, with effects preventing DOX-induced cardiotoxicity and simultaneously antagonizing cancer growth.

PMID:37232184 | DOI:10.1161/CIRCRESAHA.122.322264

16:39

PubMed articles on: Cardio-Oncology

Preoptimisation in patients with acute obstructive colon cancer (PREOCC) - a prospective registration study protocol

BMC Gastroenterol. 2023 May 25;23(1):186. doi: 10.1186/s12876-023-02799-z.

ABSTRACT

BACKGROUND: Postoperative mortality and morbidity rates are high in patients with obstructing colon cancer (OCC). Different treatment options have been evaluated over the years, mainly for left sided OCC. Optimising the preoperative health condition in elective colorectal cancer (CRC) treatment shows promising results. The aim of this study is to determine whether preoptimisation is feasible in patients with OCC, with a special interest/focus on right-sided OCC, and if, ultimately, optimisation reduces mortality and morbidity (stoma rates, major and minor complications) rates in OCC.

METHODS: This is a prospective registration study including all patients presenting with OCC in our hospital. Patients with OCC, treated with curative intent, will be screened for eligibility to receive preoptimisation before surgery. The preoptimisation protocol includes; decompression of the small bowel with a NG-tube for right sided obstruction and SEMS or decompressing ileostomy or colostomy, proximal to the site of obstruction, for left sided colonic obstructions. For the additional work-up, additional nutrition by means of parenteral feeding (for patients who are dependent on a NG tube) or oral/enteral nutrition (in case the obstruction is relieved) is provided. Physiotherapy with attention to both cardio and muscle training prior surgical resection is provided. The primary endpoint is complication-free survival (CFS) at the 90 day period after hospitalisation. Secondary outcomes include pre- and postoperative complications, patient- and tumour characteristics, surgical procedures, total in hospital stay, creation of decompressing and/or permanent ileo- or colostomy and long-term (oncological) outcomes.

DISCUSSION: Preoptimisation is expected to improve the preoperative health condition of patients and thereby reduce postoperative complications.

TRIAL REGISTRATION: Trial Registry: NL8266 date of registration: 06-jan-2020.

STUDY STATUS: Open for inclusion.

PMID:37231376 | PMC:PMC10214621 | DOI:10.1186/s12876-023-02799-z

C

18:24

Cardiotoxicity News

18:24

In reply to this message

PubMed articles on: Cancer & VTE/PE

Hypercoagulability State Combined with Post-Treatment Hypofibrinolysis in Invasive Breast Cancer: A Seven-Year Follow-Up Evaluating Disease-Free and Overall Survival

Life (Basel). 2023 Apr 28;13(5):1106. doi: 10.3390/life13051106.

ABSTRACT

(1) Background: Cancer treatment, including chemotherapy, endocrine therapy, targeted therapy and radiotherapy, has been identified as an important independent risk factor for venous thromboembolism in cancer patients. The aim of the study was to evaluate the effect of adjuvant therapy on the coagulation and fibrinolysis components in invasive breast cancer. (2) Methods: Tissue factor pathway inhibitor (TFPI), tissue factor (TF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) antigen (concentration) and TFPI and TF activities were examined in the blood samples of 60 breast cancer patients treated by adjuvant chemotherapy, endocrine therapy, radiotherapy and immunotherapy. Blood samples were taken 24 h before primary surgery and 8 months after tumour removal surgery. (3) Results: Adjuvant therapy administrated to breast cancer patients significantly increased the concentration of plasma TF, the PAI-1 antigen and also the activity of TFPI and TF, but significantly decreased the level of the t-PA antigen. Combined chemotherapy and endocrine therapy, but not monotherapy, has an important effect on haemostatic biomarker levels. (4) Conclusions: Breast cancer patients receiving adjuvant therapy have an elevated risk of developing a hypercoagulability and hypofibrinolysis state leading to venous thromboembolism.

PMID:37240751 | DOI:10.3390/life13051106

18:24

18:24

In reply to this message

PubMed articles on: Cancer & VTE/PE

Phase 1 study of GSK3368715, a type I PRMT inhibitor, in patients with advanced solid tumors

Br J Cancer. 2023 May 26. doi: 10.1038/s41416-023-02276-0. Online ahead of print.

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

18:25

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

18:25

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

18:25

18:25

18:25

In reply to this message

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

18:25

18:25

18:25

18:25

18:25

In reply to this message

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

18:25

In reply to this message

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

18:25

In reply to this message

PubMed articles on: Cancer & VTE/PE

Ten-Year Multicenter Retrospective Study Utilizing Machine Learning Algorithms to Identify Patients at High Risk of Venous Thromboembolism After Radical Gastrectomy

Int J Gen Med. 2023 May 18;16:1909-1925. doi: 10.2147/IJGM.S408770. eCollection 2023.

ABSTRACT

PURPOSE: This study aims to construct a machine learning model that can recognize preoperative, intraoperative, and postoperative high-risk indicators and predict the onset of venous thromboembolism (VTE) in patients.

PATIENTS AND METHODS: A total of 1239 patients diagnosed with gastric cancer were enrolled in this retrospective study, among whom 107 patients developed VTE after surgery. We collected 42 characteristic variables of gastric cancer patients from the database of Wuxi People's Hospital and Wuxi Second People's Hospital between 2010 and 2020, including patients' demographic characteristics, chronic medical history, laboratory test characteristics, surgical information, and patients' postoperative conditions. Four machine learning algorithms, namely, extreme gradient boosting (XGBoost), random forest (RF), support vector machine (SVM), and k-nearest neighbor (KNN), were employed to develop predictive models. We also utilized Shapley additive explanation (SHAP) for model interpretation and evaluated the models using k-fold cross-validation, receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA), and external validation metrics.

RESULTS: The XGBoost algorithm demonstrated superior performance compared to the other three prediction models. The area under the curve (AUC) value for XGBoost was 0.989 in the training set and 0.912 in the validation set, indicating high prediction accuracy. Furthermore, the AUC value of the external validation set was 0.85, signifying good extrapolation of the XGBoost prediction model. The results of SHAP analysis revealed that several factors, including higher body mass index (BMI), history of adjuvant radiotherapy and chemotherapy, T-stage of the tumor, lymph node metastasis, central venous catheter use, high intraoperative bleeding, and long operative time, were significantly associated with postoperative VTE.

CONCLUSION: The machine learning algorithm XGBoost derived from this study enables the development of a predictive model for postoperative VTE in patients after radical gastrectomy, thereby assisting clinicians in making informed clinical decisions.

PMID:37228741 | PMC:PMC10202705 | DOI:10.2147/IJGM.S408770

18:25

In reply to this message

PubMed articles on: Cancer & VTE/PE

Ambulatory cancer patients: who should definitely receive antithrombotic prophylaxis and who should never receive

Intern Emerg Med. 2023 May 25. doi: 10.1007/s11739-023-03306-8. Online ahead of print.

ABSTRACT

Up to 15-20% of cancer patients experience one or more episodes of venous thromboembolism during cancer disease. Approximately 80% of all cancer-associated venous thromboembolic events occur in non-hospitalized patients. Routine thromboprophylaxis for outpatients with cancer who start new anticancer treatment is currently not recommended by the international guidelines due to the high heterogeneity of these patients in terms of VTE or bleeding risks, the difficulties in selecting patients at high risk, and the uncertainty of duration of prophylaxis. Although the international guidelines endorsed the Khorana score for estimating the thrombotic risk in ambulatory cancer patients, the discriminatory performance of this score is not completely convincing and varies according to the cancer type. Consequently, a minority of ambulatory patients with cancer receive an accurate screening for primary prophylaxis of VTE. The aim of this review is to provide support to physicians in identifying those ambulatory patients with cancer for whom thromboprophylaxis should be prescribed and those that should not be candidate to thromboprophylaxis. In absence of high bleeding risk, primary thromboprophylaxis should be recommended in patients with pancreatic cancer and, probably, in patients with lung cancer harboring ALK/ROS1 translocations. Patients with upper gastrointestinal cancers are at high risk of VTE, but a careful assessment of bleeding risk should be made before deciding on antithrombotic prophylaxis. Primary prevention of VTE is not recommended in cancer patients at increased risk of bleeding as patients with brain cancer, with moderate-to-severe thrombocytopenia or severe renal impairment.

PMID:37227679 | DOI:10.1007/s11739-023-03306-8

18:25

In reply to this message

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

18:25

18:25

18:25

18:25

18:25

18:25

C

20:43

Cardiotoxicity News

20:43

In reply to this message

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.