ABSTRACT

BACKGROUND: Doxorubicin (Doxo) is a widely prescribed drug against many malignant cancers. Unfortunately, its utility is limited by its toxicity, in particular a progressive induction of congestive heart failure. Doxo acts primarily as a mitochondrial toxin, with consequent increased production of reactive oxygen species (ROS) and attendant oxidative stress, which drives cardiac dysfunction and cell death. A diet containing a special mixture of all essential amino acids (EAAs) has been shown to increase mitochondriogenesis, and reduce oxidative stress both in skeletal muscle and heart. So, we hypothesized that such a diet could play a favorable role in preventing Doxo-induced cardiomyocyte damage.

METHODS: Using transmission electron microscopy, we evaluated cells' morphology and mitochondria parameters in adult mice. In addition, by immunohistochemistry, we evaluated the expression of pro-survival marker Klotho, as well as markers of necroptosis (RIP1/3), inflammation (TNFα, IL1, NFkB), and defense against oxidative stress (SOD1, glutathione peroxidase, citrate synthase).

RESULTS: Diets with excess essential amino acids (EAAs) increased the expression of Klotho and enhanced anti-oxidative and anti-inflammatory responses, thereby promoting cell survival.

CONCLUSION: Our results further extend the current knowledge about the cardioprotective role of EAAs and provide a novel theoretical basis for their preemptive administration to cancer patients undergoing chemotherapy to alleviate the development and severity of Doxo-induced cardiomyopathy.

PMID:37242170 | PMC:PMC10222879 | DOI:10.3390/nu15102287

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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 potent chemotherapy drug. Despite its efficacy, Dox's clinical application is limited due to its association with significant complications, namely cardiotoxicity and the risk of heart failure. Recent intriguing findings by Ozcan et al. indicate that alternate-day fasting (ADF) significantly exacerbates the cardiotoxicity of Dox.

PMID:37246117 | DOI:10.1016/j.tem.2023.05.003

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PubMed articles on: Cardio-Oncology

Essential Amino Acids-Rich Diet Increases Cardiomyocytes Protection in Doxorubicin-Treated Mice

Nutrients. 2023 May 12;15(10):2287. doi: 10.3390/nu15102287.

 

ABSTRACT

Clinical application of doxorubicin (Dox) in cancer chemotherapy is limited by its cardiotoxicity. Present study aimed to demonstrate the effect and mechanism of hyperoside in Dox-induced cardiotoxicity. C57BL/6 mice were injected with 12 mg/kg of Dox, and 1 μM Dox was exposed to primary cardiomyocytes. Cardiac function was evaluated by echocardiographic and myocardial enzyme levels. Cardiomyocyts apoptosis was analyzed by TUNEL staining and flow cytometry. Network pharmacology and molecular docking were utilized to explore potential targets of hyperoside. Protein expressions were detected by western blot and enzyme activities were determined by colorimetry. Cardiac dysfunction and cardiomyocyte apoptosis induced by Dox were attenuated by hyperoside. Mechanism of hyperoside was mainly related to "oxidative stress" pathway. Hyperoside exhibited strong binding activities with nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs, the main source of ROS in cardiomyocytes) and cyclooxygenases (COXs). Experiments proved that hyperoside suppressed the ROS generation and the elevated activities of NOXs and COXs induced by Dox. Dox also triggered the activation of NLRP3 inflammasome, which was reversed by hyperoside. Hyperoside bound to NOXs and COXs, which prevents Dox-induced cardiotoxicity by inhibiting NOXs/ROS/NLRP3 inflammasome signaling pathway. Hyperoside holds promise as a therapeutic strategy for Dox-induced cardiotoxicity.

PMID:37246409 | DOI:10.1002/ptr.7900

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PubMed articles on: Cardio-Oncology

Alternate-day fasting exacerbates doxorubicin cardiotoxicity in cancer chemotherapy

Trends Endocrinol Metab. 2023 May 26:S1043-2760(23)00093-0. doi: 10.1016/j.tem.2023.05.003. Online ahead of print.

 

ABSTRACT

Venous thromboembolism (VTE) is a common and impactful complication of cancer. Several clinical prediction rules have been devised to estimate the risk of a thrombotic event in this patient population, however they are associated with limitations. We aimed to develop a predictive model of cancer-associated VTE using machine learning as a means to better integrate all available data, improve prediction accuracy and allow applicability regardless of timing for systemic therapy administration. A retrospective cohort was used to fit and validate the models, consisting of adult patients who had next generation sequencing performed on their solid tumor for the years 2014 to 2019. A deep learning survival model limited to demographic, cancer-specific, laboratory and pharmacological predictors was selected based on results from training data for 23,800 individuals and was evaluated on an internal validation set including 5,951 individuals, yielding a time-dependent concordance index of 0.72 (95% CI = 0.70-0.74) for the first 6 months of observation. Adapted models also performed well overall compared to the Khorana Score (KS) in two external cohorts of individuals starting systemic therapy; in an external validation set of 1,250 patients, the C-index was 0.71 (95% CI = 0.65-0.77) for the deep learning model vs 0.66 (95% CI = 0.59-0.72) for the KS and in a smaller external cohort of 358 patients the C-index was 0.59 (95% CI = 0.50-0.69) for the deep learning model vs 0.56 (95% CI = 0.48-0.64) for the KS. The proportions of patients accurately reclassified by the deep learning model were 25% and 26% respectively. In this large cohort of patients with a broad range of solid malignancies and at different phases of systemic therapy, the use of deep learning resulted in improved accuracy for VTE incidence predictions. Additional studies are needed to further assess the validity of this model.

PMID:37214902 | PMC:PMC10197737 | DOI:10.21203/rs.3.rs-2870367/v1

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Hyperoside prevents doxorubicin-induced cardiotoxicity by inhibiting NOXs/ROS/NLRP3 inflammasome signaling pathway

Phytother Res. 2023 May 28. doi: 10.1002/ptr.7900. Online ahead of print.

 

ABSTRACT

BACKGROUND: Atrial fibrillation (AF) is the most common arrythmia in patients with cancer, especially breast, gastrointestinal, respiratory, urinary tract, and hematological malignancies. Catheter ablation (CA) is a well-established, safe treatment option in healthy patients; however, literature regarding safety of CA for AF in patients with cancer is limited and confined to single centers.

OBJECTIVE: We aimed to assess the outcomes and peri-procedural safety of CA for AF in patients with certain types of cancer.

METHODS: The NIS database was queried between 2016 and 2019 to identify primary hospitalizations with AF and CA. Hospitalizations with secondary diagnosis of atrial flutter and other arrhythmias were excluded. Propensity score matching was used to balance the covariates between cancer and non-cancer groups. Logistic regression was used to analyze the association.

RESULTS: During this period 47,765 CA procedures were identified, out of which 750 (1.6%) hospitalizations had a diagnosis of cancer. After propensity matching, hospitalizations with cancer diagnosis had higher in-hospital mortality (OR 3.0, 95% CI 1.5-6.2, p=0.001), lower home discharge rates (OR 0.7, 95% CI 0.6-0.9, p<0.001)<0.001)

CONCLUSION: Patients with cancer who underwent CA for AF had significantly higher odds of in-hospital mortality, major bleeding, and pulmonary embolism. Further larger prospective observational studies are needed to validate these findings.

PMID:37224412 | DOI:10.1080/00325481.2023.2218188

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PubMed articles on: Cancer & VTE/PE

Application of Machine Learning to the Prediction of Cancer-Associated Venous Thromboembolism

Res Sq. 2023 May 8:rs.3.rs-2870367. doi: 10.21203/rs.3.rs-2870367/v1. Preprint.

 

ABSTRACT

Pulmonary arteriovenous malformations (PAVMs), particularly where feeding artery/arteries to PAVMs ≥ 3 mm can be treated with embolization. The treatment for hypoxemia resulting from multiple small or diffuse PAVMs remains unclear.We report a girl aged 5 years and 10 months presented with cyanosis and decreased activity after exercise (83-85% of pulse oxygen saturation, SpO2). She had 1 skin lesion on her face and 1 suspected hemangioma on her left upper extremity at birth and that gradually disappeared spontaneously. Physical examination revealed clubbed fingers, and abundant vascular networks on her back. Contrast-enhanced lung CT (slice thickness:1.25 mm) with vascular three-dimensional reconstruction and abdominal CT revealed increased bronchovascular bundles, increased diameter of the pulmonary artery and ascending aorta, and intrahepatic portosystemic venous shunts due to patent ductus venosus. Echocardiography revealed increased diameter of aortic and pulmonary artery. Transthoracic contrast echocardiography was highly positive (bubble appearing in the left ventricle after 5 cardiac cycles). Abdominal doppler ultrasound revealed hepatic-portal venous shunt. Magnetic resonance imaging, artery and vein of the brain revealed multiple malformations of venous sinuses. The patient received sirolimus for 2 years and 4 months. Her condition improved significantly. SpO2 gradually increased to 98%. Her finger clubbing gradually normalized.Our report implicates sirolimus might be a potential treatment option in persistent hypoxemia mainly due to intrapulmonary right-to-left shunt even small multiple or diffusive PAVMs in pediatric patients with multiple cutaneous and visceral vascular anomalies.

PMID:37226169 | PMC:PMC10206540 | DOI:10.1186/s13023-023-02732-3

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PubMed articles on: Cancer & VTE/PE

Safety of catheter ablation for atrial fibrillation in patients with cancer: a nationwide cohort study

Postgrad Med. 2023 May 24. doi: 10.1080/00325481.2023.2218188. Online ahead of print.

 

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

Effective long-term sirolimus treatment in hypoxemia mainly due to intrapulmonary right-to-left shunt in a patient with multiple vascular anomalies

Orphanet J Rare Dis. 2023 May 24;18(1):124. doi: 10.1186/s13023-023-02732-3.

 

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

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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

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

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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

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

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

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

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

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

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

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

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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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

(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 | PMC:PMC10222121 | DOI:10.3390/life13051106

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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: The incidence of venous thromboembolism (VTE; pulmonary embolism [PE] and/or deep vein thrombosis [DVT]) in Japan is increasing, but relatively small numbers of patients from Japan have been included in studies investigating rivaroxaban (a direct factor Xa inhibitor) for the treatment of VTE and preventing its recurrence.Methods and Results: An open-label, prospective, observational study (XASSENT [NCT02558465]) investigated the safety profile and effectiveness of rivaroxaban for ≤2 years in the treatment of VTE and prevention of its recurrence in Japanese clinical practice. Primary outcomes were major bleeding and symptomatic recurrent VTE. Statistical analyses were exploratory and descriptive. Overall, 2,540 patients were enrolled (safety analysis population [SAP], n=2,387; effectiveness analysis population [EAP], n=2,386). In the SAP, >80% of patients received the approved rivaroxaban dose, the mean (standard deviation) age was 66.6 (15.0) years, ≈74% were >50 kg, and 43% had a creatinine clearance ≥80 mL/min. PE+DVT, PE only, and DVT only were reported in 42%, 8%, and 50% of patients, respectively, and active cancer in 17% of patients. Major bleeding was reported in 69 patients (2.89%; 3.60%/patient-year; SAP) and symptomatic PE/DVT recurrence in 26 patients (1.09%; 1.36%/patient-year; EAP) during the treatment period.

CONCLUSIONS: XASSENT provided information on the expected proportions of bleeding and VTE recurrence during rivaroxaban treatment in Japanese clinical practice; no new concerns of safety or effectiveness were found.

PMID:37245989 | DOI:10.1253/circj.CJ-23-0104

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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

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

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PubMed articles on: Cancer & VTE/PE

Safety Profile and Effectiveness of Rivaroxaban for Patients With Venous Thromboembolism in Japan　- Results From Post-Marketing Surveillance (XASSENT)

Circ J. 2023 May 27. doi: 10.1253/circj.CJ-23-0104. Online ahead of print.

 

ABSTRACT

Cardiotoxicity represents an important acute or chronic adverse event of treatment modalities for childhood cancer. In the last two decades the emergence of novel cancer therapies has aimed to increase unaided or mostly in combination with conventional chemotherapy for the survival rates of pediatric cancer especially for those patients with relapsed and/or refractory disease. The use of emerging targeted therapies in combination with conventional chemotherapy is related to cardiovascular adverse events mostly reported in adults. The aim of our short review was to investigate the cardiotoxic side effects of targeted chemotherapeutic agents as monoclonal antibodies and small molecules in pediatric cancer patients.

PMID:37231721 | DOI:10.2174/1871520623666230525162147

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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: 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

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PubMed articles on: Cardio-Oncology

Cardiotoxicity of targeted therapies in children with haematological malignancies and solid tumors

Anticancer Agents Med Chem. 2023 May 25. doi: 10.2174/1871520623666230525162147. Online ahead of print.

 

ABSTRACT

Breast cancer is the most common type of malignancy in women and radiotherapy (RT) is an important part of treatment. Although it reduces cancer recurrence, it has been shown to cause accerelerated athnerosclerosis. This study aimed to compare the results of myocardial perfusion scintigraphy (MPS) for ischemia investigation with coronary angiography (CAG) findings and to investigate the effect of RT on the development of coronary artery disease in breast cancer patients who underwent RT. The results of 660 patients were analyzed and compared with each other in terms of clinical, demographic, laboratory parameters and MPS results. The mean age was 57.5 years and all of them were female. When the groups were compared, the Gensini score and marking of the left anterior descending artery (LAD) area as ischemic area localization were found more, but angiographically, the rate of severe stenosis in the area indicated by MPS was found to be lower in the RT group (p < 0.001). While the sensitivity of MPS in the RT group was 67.5% and non-RT group was 88.5% (p < 0.001), the result of our study shows that the sensitivity of the MPS test is significantly lower in the patient group receiving RT.

PMID:37232804 | PMC:PMC10217202 | DOI:10.3390/curroncol30050346

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PubMed articles on: Cardio-Oncology

PDE10A Inactivation Prevents Doxorubicin-Induced Cardiotoxicity and Tumor Growth

Circ Res. 2023 May 26. doi: 10.1161/CIRCRESAHA.122.322264. Online ahead of print.

 

ABSTRACT

[This corrects the article DOI: 10.3389/fmed.2023.1103842.].

PMID:37234241 | PMC:PMC10208720 | DOI:10.3389/fmed.2023.1205719

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PubMed articles on: Cardio-Oncology

Characterization of functioning in breast cancer survivors: an interpretive descriptive analysis study based on the International Classification of Functioning, Disability, and Health (ICF) and the Item-Perspective Classification Framework

Disabil Rehabil. 2023 May 26:1-19. doi: 10.1080/09638288.2023.2212915. Online ahead of print.

ABSTRACT

PURPOSE: Breast cancer survivors may experience a variety of disabilities that could potentially compromise their independent functioning. This study aimed to examine their perspectives and experts on their functioning and interpret concepts with the International Classification of Functioning, Disability, and Health (ICF) and the Item-Perspective Classification Framework (IPF).

METHODS: Interpretive descriptive methods were used with in-depth interviewing with 16 breast cancer survivors and 22 experts using a semi-structured interview guide. The interviews were recorded, transcribed, and qualitatively analyzed using thematic analysis. The extracted data were linked to the ICF Core Set for Breast cancer and were interpreted by the IPF.

RESULTS: Four main themes emerged to define the functioning of breast cancer survivors: body functioning, physical functioning, social functioning, and mental functioning. Three other factors were also categorized as modifiers of functioning personal, emotional, and environmental. The 592 extracted meaningful concepts were linked to 38 (47%) categories from the ICF: 16 Body Functions, 14 Activities and Participation, and 8 Environmental Factors. The IPF classified all the extracted concepts, and most rational appraisals fell in the biological (B) domain. The concepts that required emotional appraisal were classified in Psychology (P).

CONCLUSION: Psychological and emotional factors were pivotal in defining functioning in patients with BC.

PMID:37237439 | DOI:10.1080/09638288.2023.2212915

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PubMed articles on: Cardio-Oncology

Comparison of Myocardial Perfusion Scintigraphy and Coronary Angiography Results in Breast Cancer Patients Treated with Radiotherapy

Curr Oncol. 2023 Apr 28;30(5):4575-4585. doi: 10.3390/curroncol30050346.

 

ABSTRACT

INTRODUCTION: While abiraterone acetate (AA) has demonstrated survival benefit in advanced prostate cancer (APC), meaningful cardiotoxicity is observed. It is unclear whether the magnitude differs based on disease indication and concurrent steroid administration.

METHODS: We performed a systematic review and meta-analysis of phase II/III RCTs of AA in APC published as of August 11, 2020. Primary outcomes examined were all- and high-grade (grade ≥ 3) hypokalemia and fluid retention, and secondary outcomes included hypertension and cardiac events. We performed random effects meta-analysis comparing intervention (AA + steroid) and control (placebo ± steroid), stratified by treatment indication and whether patients received steroids.

RESULTS: Among 2,739 abstracts, we included 6 relevant studies encompassing 5901 patients. Hypokalemia and fluid retention were observed more frequently among patients receiving AA (odds ratio [OR] 3.10 [95% CI 1.69-5.67] and 1.41 [95% CI 1.19-1.66]). This was modified by whether patients in the control received steroids: trials where control patients did not demonstrated a larger association between AA and hypokalemia (OR 6.88 [95% CI 1.48-2.36] versus OR 1.86 [95% CI 4.97-9.54], P < .0001) and hypertension (OR 2.53 [95% CI 1.91-3.36] vs. OR 1.55 [95% CI 1.17-2.04], P = .1) than those where steroids were administered. We observed heterogeneity due to indication: there were greater effects on hypokalemia (P < 0001), hypertension (P = .03), and cardiac disorders (P = .01) among patients treated for mHSPC than mCRPC.

CONCLUSIONS: The magnitude of cardiotoxicity with AA differs based on trial design and disease indication. These data are valuable in treatment decisions and highlight utilization of appropriate data for counseling.

PMID:37236862 | DOI:10.1016/j.clgc.2023.04.007

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PubMed articles on: Cardio-Oncology

Corrigendum: D-dimer trends elaborate the heterogeneity of risk in hospitalized patients with COVID-19: a multi-national case series from different waves

Front Med (Lausanne). 2023 May 10;10:1205719. doi: 10.3389/fmed.2023.1205719. eCollection 2023.

 ABSTRACT

BACKGROUND: The aim of this study was to compare the efficacy, cardiotoxicity and factors affecting pathologic complete response (pCR) of neoadjuvant chemotherapy (NACT) regimen TCbHP (docetaxel/nab-paclitaxel, carboplatin, trastuzumab and pertuzumab) and AC-THP (doxorubicin, cyclophosphamide followed by docetaxel/nab-paclitaxel, trastuzumab and pertuzumab) for human epidermal growth factor receptor 2-positive (HER2+) early-stage breast cancer at a retrospective cohort.

METHODS: This retrospective study included the patients with HER2+ early-stage breast cancer who received NACT with the regimen TCbHP or AC-THP and then underwent surgery from 2019 to 2022. pCR rate and breast-conserving rate were calculated to evaluate the efficacy of the regimens. Left ventricular ejection fraction (LVEF) from echocardiograms and abnormal electrocardiographs (ECGs) were collected to evaluate the cardiotoxicity of the two regimens. Association between the characteristics of the breast cancer lesions by magnetic resonance imaging (MRI) and the pCR rate were also explored.

RESULTS: A total of 159 patients were enrolled, including 48 patients in the AC-THP group and 111 patients in the TCbHP group. The pCR rate of the TCbHP group 64.0% (71/111) was significantly higher than that of for the the AC-THP group 37.5% (18/48) (P=0.002). Estrogen receptor (ER) status (P=0.011, OR: 0.437, 95% CI: 0.231-0.829), progesterone receptor (PR) status (P=0.001, OR: 0.309, 95% CI: 0.157-0.608) and IHC HER2 status (P=0.003, OR: 7.167, 95% CI: 1.970-26.076) were significantly correlated with the pCR rate. LVEF decreased at 6 and 12 months after treatment in the AC-THP group (P=0.024 and 0.040), which only decreased after 6 months of treatment in the TCbHP group (P=0.048). Post-NACT MRI characteristics including mass features (P<0.001)<0.001)

CONCLUSIONS: Early-stage HER2+ breast cancer treated with the TCbHP regimen has a higher pCR rate than the AC-THP group. The TCbHP regimen appears to have lower cardiotoxicity than the AC-THP regimen in terms of LVEF. Mass features and enhancement type at post-NACT MRI significantly associated with the pCR rate of breast cancer patients.

PMID:37434677 | PMC:PMC10331454 | DOI:10.21037/tcr-22-2547

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ABSTRACT

OBJECTIVE: To investigate the relationship of lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and nutritional risk index (NRI) with the prognosis of non-small cell lung cancer (NSCLC).

METHODS: The clinical data of 400 NSCLC patients undergoing surgery at Shaoxing Shangyu Hospital of Traditional Chinese Medicine from January 2019 to June 2022 were collected for this retrospective analysis. The optimal cutoff values for NLR, PLR, LMR and NRI were determined using receiver operating characteristic (ROC) curves. The patients were grouped according to the optimal cutoff values, and the clinicopathological characteristics were compared between groups. The Kaplan-Meier survival curve and Cox risk model were used to identify the independent risk factors affecting the prognosis of patients with NSCLC. A nomogram risk prediction model was constructed and its effectiveness was verified.

RESULTS: ROC curve analysis revealed that the area under the curve (AUC) values for NLR, PLR, LMR and NRI in predicting overall survival of NSCLC patients were 0.827, 0.753, 0.719 and 0.770, respectively. The optimal cutoff values for NLR, PLR, LMR and NRI were 2.49, 126.32, 3.02 and 89, respectively. Survival analysis found that the survival time was shorter in patients with NLR>2.49, PLR>126.32, LMR>3.02 and NRI≤89. Results from Cox model indicated that TNM staging, NLR>2.49, LMR>3.02, NRI≤89, surgical method, intraoperative blood loss, postoperative complication, and adjuvant chemotherapy were risk factors affecting the prognosis of NSCLC patients. A nomogram was constructed based on the results of multivariate analysis. The AUC of the nomogram was 0.967 (95% CI: 0.943-0.992) and 0.948 (95% CI: 0.874-1) in the training set and the test set, respectively. The C-index was 0.90 and 0.89, respectively. The calibration curve demonstrated good agreement between the predicted values of the nomogram and the actual observed values.

CONCLUSION: NLR, LMR and NRI are significant predictors of the prognosis of patients with NSCLC. NLR>2.49, LMR>3.02, and NRI≤89 are risk factors for the prognosis of NSCLC patients.

PMID:37434819 | PMC:PMC10331693

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PubMed articles on: Cardio-Oncology

Efficacy, cardiotoxicity and factors affecting pathologic complete response of neoadjuvant chemotherapy with anthracycline-containing verses anthracycline-free regimens plus dual HER2 blockade for HER2-positive early-stage breast cancer: a retrospective study

Transl Cancer Res. 2023 Jun 30;12(6):1490-1502. doi: 10.21037/tcr-22-2547. Epub 2023 May 30.

 

ABSTRACT

BACKGROUND: Giant cell arteritis (GCA) causes severe inflammation of the aorta and its branches and is characterized by intense effector T-cell infiltration. The roles that immune checkpoints play in the pathogenesis of GCA are still unclear. Our aim was to study the immune checkpoint interplay in GCA.

METHODS: First, we used VigiBase, the World Health Organization international pharmacovigilance database, to evaluate the relationship between GCA occurrence and immune checkpoint inhibitors treatments. We then further dissected the role of immune checkpoint inhibitors in the pathogenesis of GCA, using immunohistochemistry, immunofluorescence, transcriptomics, and flow cytometry on peripheral blood mononuclear cells and aortic tissues of GCA patients and appropriated controls.

RESULTS: Using VigiBase, we identified GCA as a significant immune-related adverse event associated with anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) but not anti-PD-1/PD-L1 treatment. We further dissected a critical role for the CTLA-4 pathway in GCA by identification of the dysregulation of CTLA-4-derived gene pathways and proteins in CD4+ T cells (and specifically regulatory T cells) present in blood and aorta of GCA patients versus controls. While regulatory T cells were less abundant and activated/suppressive in blood and aorta of GCA versus controls, they still specifically upregulated CTLA-4. Activated and proliferating CTLA-4+ Ki-67+ regulatory T cells from GCA were more sensitive to anti-CTLA-4 (ipilimumab)-mediated in vitro depletion versus controls.

CONCLUSIONS: We highlighted the instrumental role of CTLA-4 immune checkpoint in GCA, which provides a strong rationale for targeting this pathway.

PMID:37435729 | DOI:10.1161/CIRCRESAHA.122.322330

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Correlation of immune inflammatory indices and nutritional risk index with prognosis in patients with non-small cell lung cancer

Am J Transl Res. 2023 Jun 15;15(6):4100-4109. eCollection 2023.

 

ABSTRACT

Off target damage to vital organ systems is an unfortunate side effect of cancer chemotherapy and remains a major limitation to the use of these essential drugs in the clinic. Despite decades of research, the mechanisms conferring susceptibility to chemotherapy driven cardiotoxicity and hepatotoxicity remain unclear. In the livers of patients with a history of chemotherapy, we observed a twofold increase in expression of G protein regulator RGS7 and a corresponding decrease in fellow R7 family member RGS11. Knockdown of RGS7 via introduction of RGS7 shRNA via tail vein injection decreased doxorubicin-induced hepatic collagen and lipid deposition, glycogen accumulation, and elevations in ALT, AST, and triglycerides by approximately 50%. Surprisingly, a similar result could be achieved via introduction of RGS7 shRNA directly to the myocardium without impacting RGS7 levels in the liver directly. Indeed, doxorubicin-treated cardiomyocytes secrete the endocrine factors transforming growth factor β1 (TGFβ1) and TGFβ superfamily binding protein follistatin-related protein 1 (FSTL1). Importantly, RGS7 overexpression in the heart was sufficient to recapitulate the impacts of doxorubicin on the liver and inhibition of TGFβ1 signaling with the receptor blocker GW788388 ameliorated the effect of cardiac RGS7 overexpression on hepatic fibrosis, steatosis, oxidative stress, and cell death as well as the resultant elevation in liver enzymes. Together these data demonstrate that RGS7 controls both the release of TGFβ1 from the heart and the profibrotic and pro-oxidant actions of TGFβ1 in the liver and emphasize the functional significance of endocrine cardiokine signaling in the pathogenesis of chemotherapy drive multiorgan damage.

PMID:37440271 | DOI:10.1096/fj.202300094R

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PubMed articles on: Cardio-Oncology

CTLA-4 Pathway Is Instrumental in Giant Cell Arteritis

Circ Res. 2023 Jul 12. doi: 10.1161/CIRCRESAHA.122.322330. Online ahead of print.

 

ABSTRACT

PURPOSE: Clinical trials have shown a significant increase in pathologic complete response (pCR) with the addition of pertuzumab to neoadjuvant chemotherapy for patients with early-stage HER-2 positive breast cancer. To date, limited studies have examined comparative outcomes of neoadjuvant pertuzumab in real-world setting. The Neopearl study aimed to assess comparative real-life efficacy and safety of neoadjuvant pertuzumab for these patients.

METHODS: We conducted a nationwide retrospective analysis involving 17 oncology facilities with a certified multidisciplinary breast cancer treatment committee. We identified patients with HER-2 positive stage II-III breast cancer treated with neoadjuvant chemotherapy based on trastuzumab and taxanes with or without pertuzumab. All patients underwent breast surgery and received a comprehensive cardiologic evaluation at baseline and after neoadjuvant treatment. Patients who received the combination of pertuzumab, trastuzumab, and chemotherapy constituted case cohort (PTCT), whereas those treated with trastuzumab and chemotherapy accounted for control cohort (TCT). The pCR rate and 5-year event free survival (EFS) were the primary outcomes. Secondary end-points were rates of conversion from planned modified radical mastectomy (MRM) to breast conservation surgery (BCS) and cardiotoxicities.

RESULTS: From March 2014 to April 2021, we included 271 patients, 134 (49%) and 137 (51%) in TCT and PTCT cohort, respectively. Positive axillary lymph nodes and stage III were more frequent in PTCT cohort. The pCR rate was significantly increased in patients who received pertuzumab (49% vs 62%; OR 1.74, 95%CI 1.04-2.89) and with HER-2 enriched subtypes (16% vs 85%; OR 2.94, 95%CI 1.60-5.41). After a median follow-up of 5 years, the 5-year EFS was significantly prolonged only in patients treated with pertuzumab (81% vs 93%; HR 2.22, 95%CI 1.03-4.79). The same analysis performed on propensity score matched population showed concordant results. On univariate analysis, only patients with positive lymph nodes were found to benefit from pertuzumab for both pCR and 5-year EFS. The rates of conversion from MRM to BCS and cardiologic toxicities did not differ between the cohorts.

CONCLUSION: Our findings support previous data on improved outcomes with the addition of pertuzumab to trastuzumab-based neoadjuvant chemotherapy. This benefit seems to be more significant in patients with clinically positive lymph nodes.

PMID:37441419 | PMC:PMC10335743 | DOI:10.3389/fonc.2023.1177681

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PubMed articles on: Cardio-Oncology

Cardiac RGS7 and RGS11 drive TGFβ1-dependent liver damage following chemotherapy exposure

FASEB J. 2023 Aug;37(8):e23064. doi: 10.1096/fj.202300094R.

 

ABSTRACT

BACKGROUND: Many patients with breast cancer receive therapies with the potential to cause cardiotoxicity. Echocardiography and multiple-gated acquisition (MUGA) scans are the most used modalities to assess cardiac function during treatment in high-risk patients; however, the optimal imaging strategy and the impact on outcome are unknown.

METHODS: Consecutive patients with stage 0-3 breast cancer undergoing pre-treatment echocardiography or MUGA were identified from a tertiary care cancer center from 2010-2019. Demographics, medical history, imaging data and clinical events were collected from hospital charts and administrative databases. The primary outcome is a composite of all-cause death or heart failure event. Clinical and imaging predictors of outcome were evaluated on univariable and multivariable analyses.

RESULTS: 1028 patients underwent pre-treatment MUGA and 1032 underwent echocardiography. The groups were well matched for most clinical characteristics except patients undergoing MUGA were younger, had more stage 3 breast cancer and more HER2 over-expressing and triple negative cases. Routine follow-up cardiac imaging scan was obtained in 39.3% of patients with MUGA and 38.0% with echocardiography. During a median follow-up of 2448 (1489, 3160) days, there were 194 deaths, including 7 cardiovascular deaths, and 28 heart failure events with no difference in events between the MUGA and echocardiography groups. There were no imaging predictors of the primary composite outcome or cardiac events. Patients without follow-up imaging had similar adjusted risk for the composite outcome compared to those with imaging follow-up, hazard ratio 0.8 (95% confidence interval 0.5,1.3), p=0.457.

CONCLUSION: The selection of pretreatment echocardiography or MUGA did not influence the risk of death or heart failure in patients with early breast cancer. Many patients did not have any follow-up cardiac imaging and did not suffer worse outcomes. Cardiovascular deaths and heart failure event rates were low and the value of long-term cardiac imaging surveillance should be further evaluated.

PMID:37441421 | PMC:PMC10335844 | DOI:10.3389/fonc.2023.1168651

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PubMed articles on: Cardio-Oncology

Pathologic response and survival after neoadjuvant chemotherapy with or without pertuzumab in patients with HER2-positive breast cancer: the Neopearl nationwide collaborative study

Front Oncol. 2023 Jun 27;13:1177681. doi: 10.3389/fonc.2023.1177681. eCollection 2023.

 

ABSTRACT

In this study we aimed to evaluate and compare the overall performance of the Khorana, PROTECHT, and CONKO scores as predictive scores for the occurrence of venous thromboembolism (VTE) among ambulatory Hispanic patients with solid tumors. We included all outpatients with newly diagnosed solid tumors receiving systemic chemotherapy in Hospital San Juan Dios, San José, Costa Rica, from January to December 2021. For each patient the Khorana, PROTECHT, and CONKO scores were calculated at the beginning of treatment. The sixth-month cumulative incidence of VTE was estimated using the Fine & Gray competing risk model. The receiver operating characteristic (ROC) curve was used to assess the performance of each predictive tool through the analysis of the c-statistic, sensitivity, and specificity. A total of 708 patients were included in the research. After a median follow-up of 8.13 months, the cumulative VTE incidence at six months was 4.45% (95%CI: 3.25-6.91%) for the overall population. At the conventional positivity threshold of 3 points, these scores classified from 17.7 to 32.5% of all patients as high-risk for VTE. Patients belonging to the high-risk category of the Khorana, PROTECHT, and CONKO scores had significantly higher risk of VTE in comparison to low-risk patients (Khorana score: Hazard Ratio (HR): 2.66; 95%CI:1.20-5.89; p = 0.042; PROTECHT score: HR: 3.44; 95%CI:1.63-7.21; p = 0.001; CONKO score HR: 3.68; 95%CI:1.72-7.85; p = 0.001). The c-statistic of the ROC curve was: 0.62 (95%CI: 0.52-0.72), 0.62 (95%CI: 0.52-0.73), and 0.65 (95%CI: 0.56-0.76) for the Khorana, PROTECHT, and CONKO scores, respectively; with similar sensitivity (range: 67-70%) and specificity (range: 52-62%) among them. For Hispanic patients with solid tumors the Khorana, PROTECHT, and CONKO scores accurately categorize their risk of VTE. However, the overall discriminatory performance of these models remains poor (c-statistic from 0.62 to 0.65) for predicting all patients at risk for thromboembolic events.

PMID:37407771 | DOI:10.1007/s11239-023-02861-3

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Does cardiac imaging surveillance strategy influence outcomes in patients with early breast cancer?

Front Oncol. 2023 Jun 27;13:1168651. doi: 10.3389/fonc.2023.1168651. eCollection 2023.

 

ABSTRACT

BACKGROUND: Cancer is a well-known risk factor for venous thromboembolism (VTE). A combined strategy of D-dimer testing and clinical pre-test probability is usually used to exclude VTE. However, its effectiveness is diminished in cancer patients due to reduced specificity, ultimately leading to a decreased clinical utility. This review article seeks to provide a comprehensive summary of how to interpret D-dimer testing in cancer patients.

METHODS: In accordance with PRISMA standards, literature pertaining to the diagnostic and prognostic significance of D-dimer testing in cancer patients was carefully chosen from reputable sources such as PubMed and the Cochrane databases.

RESULTS: D-dimers have not only a diagnostic value in ruling out VTE but can also serve as an aid for rule-in if their values exceed 10-times the upper limit of normal. This threshold allows a diagnosis of VTE in cancer patients with a positive predictive value of more than 80%. Moreover, elevated D-dimers carry important prognostic information and are associated with VTE reoccurrence. A gradual increase in risk for all-cause death suggests that VTE is also an indicator of biologically more aggressive cancer types and advanced cancer stages. Considering the lack of standardization for D-dimer assays, it is essential for clinicians to carefully consider the variations in assay performance and the specific test characteristics of their institution.

CONCLUSIONS: Standardizing D-dimer assays and developing modified pretest probability models specifically for cancer patients, along with adjusted cut-off values for D-dimer testing, could significantly enhance the accuracy and effectiveness of VTE diagnosis in this population.

PMID:37409393 | DOI:10.1111/eci.14060

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PubMed articles on: Cancer & VTE/PE

Comparison among three predictive models for cancer-associated thromboembolism in a hispanic population

J Thromb Thrombolysis. 2023 Jul 6. doi: 10.1007/s11239-023-02861-3. Online ahead of print.

 

ABSTRACT

OBJECTIVES: Direct oral anticoagulants (DOACs) are effective in treating cancer-related thrombosis and are superior to low molecular weight heparin (LMWH) in terms of efficacy. The effects of DOACs or LMWH on intracranial hemorrhage (ICH) remain uncertain in individuals with brain tumors. We conducted a meta-analysis to compare the frequency of ICH in individuals with brain tumors treated with DOACs or LMWH.

METHODS: Two independent investigators reviewed all studies that compared the frequency of ICH in patients with brain tumors who received DOACs or LMWH. The primary outcome was the incidence of ICH. We used the Mantel-Haenszel method to estimate the combined effect and calculated 95% confidence intervals (CI).

RESULTS: This study encompassed six articles. The results indicated that cohorts treated with DOAC experienced much fewer instances of ICH compared to the LMWH cohorts (relative risk [RR] 0.39; 95% CI 0.23-0.65; P = 0.0003; I2 = 0%). The same effect was observed for the prevalence of major ICH (RR 0.34; 95% CI 0.12-0.97; P = 0.04; I2 = 0%), but there was no difference for fatal ICH. Subgroup analysis indicated that DOACs had a substantially reduced incidence of ICH in primary brain tumors (RR 0.18; 95% CI 0.06-0.50; P = 0.001; I2 = 0%), but had no impact on ICH with secondary brain tumors.

CONCLUSIONS: This meta-analysis showed that DOACs are associated with a lower risk of ICH than LMWH therapy in treating venous thromboembolism associated with brain tumors, especially in patients with primary brain tumors.

PMID:37413715 | DOI:10.1016/j.jstrokecerebrovasdis.2023.107243

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PubMed articles on: Cancer & VTE/PE

Unveiling the diagnostic enigma of D-dimer testing in cancer patients: Current evidence and areas of application

Eur J Clin Invest. 2023 Jul 6:e14060. doi: 10.1111/eci.14060. Online ahead of print.

 

ABSTRACT

BACKGROUND AND OBJECTIVE: Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Because of the limitations of clinical trials, which are not representative of large real-world populations, rare events and long-term safety concerns cannot be detected. The current study aimed to evaluate the adverse events of abemaciclib through data mining of the Food and Drug Administration Adverse Event Reporting System (FAERS).

METHODS: Reporting odds ratio and Bayesian confidence propagation neural network of information components were used to quantify the adverse event signals of abemaciclib from the third quarter of 2017 to the first quarter of 2022. Serious and non-serious cases were compared using the Mann-Whitney U test or Chi-squared test, and clinical priority was assigned to signals by scoring (range 0-10 points) five features using a rating scale.

RESULTS: A total of 6125 reports of abemaciclib as the "primary suspected" and 72 significant adverse events of abemaciclib were identified. Common adverse events, such as diarrhea, neutropenia, alanine transaminase, aspartate transaminase, and serum creatinine increases, and other adverse events, including thrombosis, deep vein thrombosis, pulmonary embolism, interstitial lung disease, and pneumonitis were of high concern. Of note, 17 preferred terms were classified as unexpected adverse events that uncovered in the label. In addition, 1, 26, and 45 adverse events were identified as strong, moderate, and weak clinical priorities. The median time to onset for strong, moderate, and weak clinical priority signals was 49, 22, and 28 days, respectively. All of the disproportionality signals had early failure type features, suggesting that adverse events of abemaciclib gradually decreased over time.

CONCLUSIONS: The discovery of disproportionality signals could potentially prompt improved awareness of toxicities for abemaciclib, and the results of time to onset, serious and non-serious reports, and clinical priority analyses provided some supporting evidence for clinicians to manage adverse events.

PMID:37418089 | DOI:10.1007/s40264-023-01334-z

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PubMed articles on: Cancer & VTE/PE

Risk of intracranial hemorrhage with direct oral anticoagulation versus low molecular weight heparin in the treatment of brain tumor-associated venous thromboembolism: A meta-analysis

J Stroke Cerebrovasc Dis. 2023 Jul 4;32(8):107243. doi: 10.1016/j.jstrokecerebrovasdis.2023.107243. Online ahead of print.

 

ABSTRACT

Cancer-associated thrombosis (CAT) is common and associated with mortality. We estimated CAT rate by cancer sites and inherited factors among cancer patients from the UK Biobank (N =70,406). The 12-month CAT rate after cancer diagnosis was 2.37% overall but varied considerably among cancer sites. Among the 10 cancer sites classified as 'high-risk' of CAT by the National Comprehensive Cancer Network guidelines, 6 had CAT rate <5%.5%. For inherited risk factors, both known mutation carriers in two genes (F5/F2) and polygenic score for venous thromboembolism (VTE) (PGSVTE) were independently associated with increased CAT risk. While F5/F2 identified 6% patients with high genetic-risk for CAT, adding PGSVTE identified 13 % patients at equivalent/higher genetic-risk to CAT than that of F5/F2 mutations. Findings from this large prospective study, if confirmed, provide critical data to update guidelines for CAT risk assessment.

PMID:37419004 | DOI:10.1016/j.thromres.2023.06.023

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PubMed articles on: Cancer & VTE/PE

Disproportionality Analysis of Abemaciclib in the FDA Adverse Event Reporting System: A Real-World Post-Marketing Pharmacovigilance Assessment

Drug Saf. 2023 Jul 7. doi: 10.1007/s40264-023-01334-z. Online ahead of print.

 

ABSTRACT

Cancer-associated thrombosis (CAT) is common and associated with mortality. We estimated CAT rate by cancer sites and inherited factors among cancer patients from the UK Biobank (N =70,406). The 12-month CAT rate after cancer diagnosis was 2.37% overall but varied considerably among cancer sites. Among the 10 cancer sites classified as 'high-risk' of CAT by the National Comprehensive Cancer Network guidelines, 6 had CAT rate <5%.5%. For inherited risk factors, both known mutation carriers in two genes (F5/F2) and polygenic score for venous thromboembolism (VTE) (PGSVTE) were independently associated with increased CAT risk. While F5/F2 identified 6% patients with high genetic-risk for CAT, adding PGSVTE identified 13 % patients at equivalent/higher genetic-risk to CAT than that of F5/F2 mutations. Findings from this large prospective study, if confirmed, provide critical data to update guidelines for CAT risk assessment.

PMID:37419004 | DOI:10.1016/j.thromres.2023.06.023

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PubMed articles on: Cancer & VTE/PE

Disproportionality Analysis of Abemaciclib in the FDA Adverse Event Reporting System: A Real-World Post-Marketing Pharmacovigilance Assessment

Drug Saf. 2023 Jul 7. doi: 10.1007/s40264-023-01334-z. Online ahead of print.

 

ABSTRACT

BACKGROUND: Direct oral anticoagulant (DOAC) use in cancer-associated venous thromboembolism (CA-VTE) has increased due to updates in recent guidelines and literature. However, select guidelines caution against DOAC use in patients with gastrointestinal (GI) malignancies due to reported increased bleeding events. The objective of this study was to compare the safety and effectiveness of DOACs versus low-molecular-weight heparins (LMWHs) for CA-VTE treatment in patients with GI malignancies.

PATIENTS AND METHODS: This multicenter, retrospective cohort study included patients with primary GI malignancies who received therapeutic anticoagulation with a DOAC or LMWH for CA-VTE between January 1, 2018, and December 31, 2019. The primary outcome was the incidence rate of bleeding events (major, clinically relevant non-major, or minor bleeding events) within a 12-month period following the initiation of therapeutic anticoagulation. The secondary endpoint was the incidence rate of recurrent VTE events within a 12-month period following the start of therapeutic anticoagulation.

RESULTS: After screening, 141 patients met inclusion criteria. The incidence rate of all bleeding events significantly differed between DOAC (4.98 events/100 person-months) and LWMH (10.2 events/100 person-months) recipients. The corresponding incidence rate ratio (IRR) with the DOAC group serving as the reference was 2.05 (p = 0.01), with the majority of bleeds in both groups presenting as minor bleeds. No difference was found between the incidence rate of recurrent VTE within a 12-month period of starting therapeutic anticoagulation between groups (IRR 3.08, p = 0.06).

CONCLUSION: Our results suggest that DOACs do not pose an additional bleeding risk compared to LMWH in patients with certain GI malignancies. Careful selection of DOAC therapy with respect to bleeding risk is still warranted.

PMID:37421494 | DOI:10.1007/s11239-023-02858-y

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PubMed articles on: Cancer & VTE/PE

Cancer-associated thrombosis by cancer sites and inherited factors in a prospective population-based cohort

Thromb Res. 2023 Jun 26;229:69-72. doi: 10.1016/j.thromres.2023.06.023. Online ahead of print.

 

ABSTRACT

BACKGROUND: Colorectal cancer (CRC) is the third most prevalent cancer type. CRC-patients are at increased risk of venous and arterial thromboembolism (TE), but the magnitude of the risks, their predictors and consequences are not exactly known.

OBJECTIVES: We aimed to determine incidence, predictors and prognosis of TE after incident CRC in a large, unselected population.

METHODS: Using data from Statistics Netherlands and the Netherlands Comprehensive Cancer Organization, all incident CRC-patients were identified between 2013 and 2018 plus a sample of 1:2 age- and sex-matched control subjects. Incidence rates and cumulative incidences for TE were estimated. Predictor variables for TE were explored by univariable Cox regression. The association between TE and all-cause mortality was evaluated by multivariable time-dependent Cox regression.

RESULTS: 68,238 incident CRC-patients were matched to 136,476 controls. CRC-patients had a 1-year cumulative venous TE (VTE) incidence of 1.93 % (95%CI 1.83-2.04), versus 0.24 % (95%CI 0.21-0.27) in controls (HR 8.85; 95%CI 7.83-9.99). For arterial TE (ATE), this was 2.74 % (95%CI 2.62-2.87) in CRC versus 1.88 % (95%CI 1.81-1.95) in controls (HR 1.57; 95%CI 1.47-1.66). Cancer stage, surgery, chemotherapy and asthma were predictors for VTE, whereas age, prior ATE and Parkinson's disease were predictors for ATE. CRC patients with TE had an increased risk of all-cause mortality (VTE HR; 3.68 (95%CI 3.30-4.10, ATE HR; 3.05 (95%CI 2.75-3.39)) compared with CRC-patients without TE.

CONCLUSIONS: This Dutch nationwide cohort study adds detailed knowledge on the risk of VTE and ATE, their predictors and prognosis in CRC-patients. These findings may drive TE prophylactic management decisions.

PMID:37421683 | DOI:10.1016/j.thromres.2023.06.028

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PubMed articles on: Cancer & VTE/PE

Evaluation of direct oral anticoagulants versus low molecular weight heparins for venous thromboembolism treatment in patients with gastrointestinal malignancies

J Thromb Thrombolysis. 2023 Jul 8. doi: 10.1007/s11239-023-02858-y. Online ahead of print.

 

ABSTRACT

INTRODUCTION AND OBJECTIVE: Several scoring systems have been developed for risk stratification in patients with acute pulmonary embolism (PE). The Pulmonary Embolism Severity Index (PESI) and its simplified version (sPESI) are among the most used, however the high number of variables hinder its application. Our aim was to derive an easy-to-perform score based on simple parameters obtained at admission to predict 30-day mortality in acute PE patients.

METHODS: Retrospective study in 1115 patients with acute PE from two institutions (derivation cohort n=835, validation cohort n=280). Primary endpoint was all-cause mortality at 30 days. Statistically and clinically relevant variables were selected for multivariable Cox regression analysis. We derived and validated a multivariable risk score model and compared to other established scores.

RESULTS: The primary endpoint occurred in 207 patients (18.6%). Our model included five variables weighted as follows: modified shock index ≥ 1.1 (hazard ratio [HR] 2.57, 1.68-3.92, p<0.001),<0.001),<0.001),<0.001),<0.001)<0.0001)

CONCLUSIONS: The PoPE score (https://tinyurl.com/ybsnka8s) is an easy tool with superior performance to predict early mortality in patients admitted for PE with non-high-risk PE.

PMID:37423312 | DOI:10.1016/j.repc.2023.04.011

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PubMed articles on: Cancer & VTE/PE

Venous and arterial thromboembolism after colorectal cancer in the Netherlands: Incidence, predictors, and prognosis

Thromb Res. 2023 Jul 4;229:90-98. doi: 10.1016/j.thromres.2023.06.028. Online ahead of print.

 

ABSTRACT

BACKGROUND: Postoperative venous thromboembolism (VTE) is a well-documented cause of morbidity and mortality in lung cancer patients. However, risk identification remains limited. In this study, we sought to analyze the risk factors for VTE and verify the predictive value of the modified Caprini risk assessment model (RAM).

METHODS: This prospective single-center study included patients with resectable lung cancer who underwent resection between October 2019 and March 2021. The incidence of VTE was estimated. Logistic regression was used to analyze the risk factors for VTE. Receiver operating characteristic (ROC) curve analysis was performed to test the ability of the modified Caprini RAM to predict VTE.

RESULTS: The VTE incidence was 10.5%. Several variables, including age, D-dimer, hemoglobin (Hb), bleeding, and patient confinement to bed were significantly associated with VTE after surgery. The difference between the VTE and non-VTE groups in the high-risk levels was statistically significant (P<0.001),

CONCLUSIONS: The risk-stratification approach of the modified Caprini RAM is not particularly valid after lung resection in our population. The use of the modified Caprini RAM combined with Hb and D-dimer levels shows a good diagnostic performance for VTE prediction in patients with lung cancer undergoing resection.

PMID:37426170 | PMC:PMC10323546 | DOI:10.21037/jtd-23-776

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PubMed articles on: Cancer & VTE/PE

Psychiatric disorders and subsequent risk of cardiovascular disease: a longitudinal matched cohort study across three countries

EClinicalMedicine. 2023 Jun 22;61:102063. doi: 10.1016/j.eclinm.2023.102063. eCollection 2023 Jul. ABSTRACTBACKGROUND: Several psychiatric disorders have been associated with increased risk of cardiovascular disease (CVD), however, the role of familial factors and the main disease trajectories remain unknown.

METHODS: In this longitudinal cohort study, we identified a cohort of 900,240 patients newly diagnosed with psychiatric disorders during January 1, 1987 and December 31, 2016, their 1,002,888 unaffected full siblings, and 1:10 age- and sex-matched reference population from nationwide medical records in Sweden, who had no prior diagnosis of CVD at enrolment. We used flexible parametric models to determine the time-varying association between first-onset psychiatric disorders and incident CVD and CVD death, comparing rates of CVD among patients with psychiatric disorders to the rates of unaffected siblings and matched reference population. We also used disease trajectory analysis to identify main disease trajectories linking psychiatric disorders to CVD. Identified associations and disease trajectories of the Swedish cohort were validated in a similar cohort from nationwide medical records in Denmark (N = 875,634 patients, same criteria during January 1, 1969 and December 31, 2016) and in Estonian cohorts from the Estonian Biobank (N = 30,656 patients, same criteria during January 1, 2006 and December 31, 2020), respectively.

FINDINGS: During up to 30 years of follow-up of the Swedish cohort, the crude incidence rate of CVD was 9.7, 7.4 and 7.0 per 1000 person-years among patients with psychiatric disorders, their unaffected siblings, and the matched reference population. Compared with their siblings, patients with psychiatric disorders experienced higher rates of CVD during the first year after diagnosis (hazard ratio [HR], 1.88; 95% confidence interval [CI], 1.79-1.98) and thereafter (1.37; 95% CI, 1.34-1.39). Similar rate increases were noted when comparing with the matched reference population. These results were replicated in the Danish cohort. We identified several disease trajectories linking psychiatric disorders to CVD in the Swedish cohort, with or without mediating medical conditions, including a direct link between psychiatric disorders and hypertensive disorder, ischemic heart disease, venous thromboembolism, angina pectoris, and stroke. These trajectories were validated in the Estonian Biobank cohort.

INTERPRETATION: Independent of familial factors, patients with psychiatric disorders are at an elevated risk of subsequent CVD, particularly during first year after diagnosis. Increased surveillance and treatment of CVDs and CVD risk factors should be considered as an integral part of clinical management, in order to reduce risk of CVD among patients with psychiatric disorders.

FUNDING: This research was supported by EU Horizon 2020 Research and Innovation Action Grant, European Research Council Consolidator grant, Icelandic Research fund, Swedish Research Council, US NIMH, the Outstanding Clinical Discipline Project of Shanghai Pudong, the Fundamental Research Funds for the Central Universities, and the European Union through the European Regional Development Fund; the Research Council of Norway; the South-East Regional Health Authority, the Stiftelsen Kristian Gerhard Jebsen, and the EEA-RO-NO-2018-0535.

PMID:37425374 | PMC:PMC10329128 | DOI:10.1016/j.eclinm.2023.102063

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PubMed articles on: Cancer & VTE/PE

PrOgnosis in Pulmonary Embolism (PoPE): 30-day mortality risk score based on five admission parameters

Rev Port Cardiol. 2023 Jul 7:S0870-2551(23)00376-1. doi: 10.1016/j.repc.2023.04.011. Online ahead of print.

 

ABSTRACT

BACKGROUND: Several biomarkers or risk factors have been identified and several prediction models exist. The major limitations inherent in these models include cost-ineffectiveness and lack of systematic stratification of risk factors resulting in the inclusion of clinically insignificant biomarkers in the models. This review aimed to systematically stratify the risk factors of lung cancer-associated venous thromboembolism (VTE) and determine the critical point for preemptive intervention.

METHODS: This systematic review was structured as per the Preferred Reporting Item for Systematic Reviews and Meta-analyses. We searched MEDLINE, PubMed, Cochrane Library, CINAHL, Academic Search Complete, and PsycINFO from the onset to June 2022. We included studies that reported the risk factors of lung cancer-associated VTE and corresponding risk estimates, irrespective of treatment status but studies were excluded if patients were on anti-VTE medications. We employed random effects models of meta-analysis and computed risk stability index and risk weight (Rw) to achieve the review objectives. The review protocol is registered with PROSPERO (CRD42022336476).

RESULTS: The clinically significant risk factors of VTE in lung cancer patients were D-dimer (odds ratio [OR] = 5.510, 95% CI = 2.6-11.7; Rw = 5.0), albumin (OR = 2.2, 95% CI = 1.0-4.8; Rw = 1.79), leukocyte (OR = 2.48, 95% CI = 1.9-3.2; Rw = 1.77), histological type (OR = 1.69 , 95% CI = 1.2-2.4; Rw = 1.3), age (OR = 1.56; Rw = 0.99), and hemoglobin (OR = 1.85, 95% CI = 1.3-2.6; Rw = 0.92). Based on the distribution of Rw across risk factors, the critical point (upper third of the upper quartile class) was 4.5 and may mark the point at which preemptive intervention should be commenced.

CONCLUSIONS: Targeted screening for VTE in lung cancer patients could be patient-specific and should be based on a combination of the most significant risk factors required to meet the critical point, provided that such a combination is affordable as illustrated in the ALBAH model.

REGISTRATION: The review protocol is registered with PROSPERO (ID: CRD42022336476).

PMID:37426681 | PMC:PMC10328178 | DOI:10.1177/11795549231175221

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PubMed articles on: Cancer & VTE/PE

Risk assessment for postoperative venous thromboembolism using the modified Caprini risk assessment model in lung cancer

J Thorac Dis. 2023 Jun 30;15(6):3386-3396. doi: 10.21037/jtd-23-776. Epub 2023 Jun 26.

ABSTRACT

BACKGROUND: In recent years, osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has been recommended as a first-line treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC). A phase III study (AENEAS) to assess the efficacy and safety of aumolertinib, another third-generation EGFR-TKI, vs.gefitinib as a first-line treatment in patients with locally advanced or metastatic NSCLC harboring EGFRmutations has also achieved positive results. Despite the improvements in progression-free survival (PFS) and overall survival (OS) of third- vs.first-generation EGFR-TKIs, combined treatment strategies to postpone drug resistance and further prolong survival benefits remain to be explored.

METHODS: We conducted a nonrandomized phase II trial (ChiCTR2000035140) of an oral multitarget antiangiogenic TKI (anlotinib) with third-generation EGFR-TKIs (osimertinib or aumolertinib) in untreated patients with EGFRmutation and advanced NSCLC. Anlotinib and the third-generation EGFR-TKIs were orally administrated (anlotinib at a dose of 12 mg once every other day and osimertinib at 80 mg once daily or aumolertinib at 110 mg once daily). The primary end point of the study was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), OS, PFS, and safety of the combined treatment.

RESULTS: Enrollment was ceased due to treatment-related adverse events (trAEs) after 11 of 35 planned patients were treated. Among these 11 patients, two were lost to follow-up, and the treatment of five of the remaining nine patients was discontinued due to trAEs, including stomachache, rash, hyponatremia, pulmonary embolism, and interstitial pneumonia. AEs of grade 3 or worse were observed in five patients, but no treatment-related death occurred in these patients.

CONCLUSIONS: Combining anlotinib and third-generation EGFR-TKIs in untreated EGFR-mutant patients with advanced NSCLC demonstrated significantly increased toxicity, suggesting that the combined treatment strategy was an inappropriate therapeutic choice in this setting.

PMID:37425401 | PMC:PMC10326784 | DOI:10.21037/tlcr-23-175

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PubMed articles on: Cancer & VTE/PE

Stratification of Risk Factors of Lung Cancer-Associated Venous Thromboembolism and Determining the Critical Point for Preemptive Intervention: A Systematic Review With Meta-analysis

Clin Med Insights Oncol. 2023 Jun 28;17:11795549231175221. doi: 10.1177/11795549231175221. eCollection 2023. 

 

ABSTRACT

INTRODUCTION: Tranexamic acid (TXA) is an antifibrinolytic drug that has been shown to reduce blood loss following surgery. The use of TXA during orthopedic procedures has gained widespread acceptance, with multiple clinical studies demonstrating no increase in thrombotic complications. While TXA has been shown to be safe and effective for several orthopedic procedures, its use in orthopedic sarcoma surgery is not well established. Cancer-associated thrombosis remains a significant cause of morbidity and mortality in patients with sarcoma. It is unknown if intraoperative TXA use will increase the risk of developing a postoperative thrombotic complication in this population. This study aimed to compare the risk of postoperative thrombotic complications in patients who received TXA during sarcoma resection to patients who did not receive TXA.

METHODS: A retrospective review was performed of 1099 patients who underwent resection of a soft tissue or bone sarcoma at our institution between 2010 and 2021. Baseline demographics and postoperative outcomes were compared between patients who did and did not receive intraoperative TXA. We evaluated 90-day complication rates, including: deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI), cerebrovascular accident (CVA), and mortality.

RESULTS: TXA was used more commonly for bone tumors (p < 0.001), tumors located in the pelvis (p = 0.004), and larger tumors (p < 0.001). Patients who received intraoperative TXA were associated with a significant increase in developing a postoperative DVT (odds ratio [OR]: 2.22, p = 0.036) and PE (OR: 4.62, p < 0.001), but had no increase in CVA, MI, or mortality (all p > 0.05) within 90 days of surgery, following univariate analysis. Multivariable analysis confirmed that TXA was independently associated with developing a postoperative PE (OR: 10.64, 95% confidence interval: 2.23-50.86, p = 0.003). We found no association with DVT, MI, CVA, or mortality within 90 days postoperatively, following intraoperative TXA use.

CONCLUSION: Our results demonstrate a higher associated risk of PE following TXA use in sarcoma surgery and caution is warranted with TXA use in this patient population.

PMID:37428014 | DOI:10.1002/jso.27391

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PubMed articles on: Cancer & VTE/PE

A pilot study of anlotinib with third-generation epidermal growth factor receptor tyrosine kinase inhibitors in untreated EGFR-mutant patients with advanced non-small cell lung cancer

Transl Lung Cancer Res. 2023 Jun 30;12(6):1256-1263. doi: 10.21037/tlcr-23-175. Epub 2023 Jun 21.

 

ABSTRACT

Cancer patients are at higher risk for venous thromboembolism (VTE). Several risk assessment models (RAM), including the Khorana and COMPASS-CAT, were developed to help predict the occurrence of VTE in cancer patients on active anti-cancer therapy. We aim to study the prevalence and predictors of VTE among patients with non-small cell lung cancer (NSCLC) and compare both RAMs in predicting VTE in patients with NSCLC were retrospectively reviewed. Variables known to increase the risk of VTE were collected and risk of VTE was assessed using both Khorana and COMPASS-CAT RAM. A total of 508 patients (mean age ± SD, 58.4 ± 12.2 years) were enrolled. Most (n = 357, 70.3%) patients had adenocarcinoma, and 333 (65.6%) patients had metastatic disease. VTE were confirmed in 76 (15.0%) patients. Rates were higher among patients with metastatic disease (19.8%, p < 0.001), adenocarcinoma (17.4%, p = 0.01) and those treated with immunotherapy (23.5%, p = 0.014). VTE rates were 21.2%, 14.1% and 13.9% among those with high (n = 66), intermediate (n = 341) and low (n = 101) Khorana risk scores, respectively (p = 0.126). On the other hand, 190 (37.4%) were classified as high risk by the COMPASS-CAT RAM; 52 (27.4%) of them had VTE compared to 24 (7.5%) of the remaining 318 (62.6%) classified as Low/Intermediate risk level, p < 0.001. In conclusion, patients with NSCLC are at high risk for VTE, especially those with adenocarcinoma, metastatic disease and when treated with immunotherapy. Compared to Khorana RAM, COMPASS-CAT RAM was better in identifying more patients in high-risk group, with higher VTE rate.

PMID:37430158 | DOI:10.1007/s11239-023-02860-4

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Intravenous tranexamic acid is associated with an increased risk of pulmonary embolism following sarcoma resection

J Surg Oncol. 2023 Jul 10. doi: 10.1002/jso.27391. Online ahead of print.