ABSTRACT

A 'classical' and a 'basal-like' subtype of pancreatic cancer have been reported, with differential expression of GATA6 and different dosages of mutant KRAS. We established in situ detection of KRAS point mutations and mRNA panels for the consensus subtypes aiming to project these findings to paraffin-embedded clinical tumour samples for spatial quantitative analysis. We unveiled that, next to inter-patient and intra-patient inter-ductal heterogeneity, intraductal spatial phenotypes exist with anti-correlating expression levels of GATA6 and KRASG12D . The basal-like mRNA panel better captured the basal-like cell states than widely used protein markers. The panels corroborated the co-existence of the classical and basal-like cell states in a single tumour duct with functional diversification, i.e. proliferation and epithelial-to-mesenchymal transition respectively. Mutant KRASG12D detection ascertained an epithelial origin of vimentin-positive cells in the tumour. Uneven spatial distribution of cancer-associated fibroblasts could recreate similar intra-organoid diversification. This extensive heterogeneity with functional cooperation of plastic tumour cells poses extra challenges to therapeutic approaches. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

PMID:37842959 | DOI:10.1002/path.6212

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PubMed articles on: Cancer & VTE/PE

Low-Dose Rivaroxaban to Prevent Recurrences of Venous Thromboembolism in Cancer: A Real-Life Experience with a Focus on Female Patients

J Clin Med. 2023 Oct 9;12(19):6427. doi: 10.3390/jcm12196427.

ABSTRACT

BACKGROUND: The way in which to prevent recurrent venous thromboembolism (VTE) is an unmet clinical need in cancer patients. International guidelines only provide conditional recommendations and do not specify which anticoagulant and dose should be used. In the last 2 years, we have been using low-dose rivaroxaban to prevent VTE recurrences in cancer patients. The results of this real-life experience are presented in this study.

METHODS: All patients had cancer and had previously completed a cycle of at least six months of full-dose anticoagulation for the treatment of a VTE index event, before receiving a prescription of low-dose rivaroxaban (10 mg once daily) for secondary prevention of VTE. Effectiveness and safety of this therapeutic regimen were evaluated in terms of VTE recurrences, major bleedings (MB), and clinically relevant non-major bleedings (CRNMB).

RESULTS: The analysis included 106 cancer patients. Their median age was 60 years (IQR 50-69). Metastatic cancer was present in 87 patients (82.1%). Six patients (5.7%) had brain metastases. Over a median follow-up time of 333 days (IQR 156-484), the incidence of VTE recurrences was 3.8% (95%CI 1.0-9.4), with a recurrence rate of 4.0 per 100 person-years (95%CI 1.1-10.2). We observed no MB (0.0%) and three CRNMB (2.8%) (95%CI 0.6-8.1).

CONCLUSIONS: Low-dose rivaroxaban is potentially effective and safe in cancer patients that require prevention of recurrent VTE. Large-scale studies are needed to confirm these findings.

PMID:37835070 | PMC:PMC10573527 | DOI:10.3390/jcm12196427

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PubMed articles on: Cardio-Oncology

ATP protects anti-PD-1/radiation-induced cardiac dysfunction by inhibiting anti-PD-1 exacerbated cardiomyocyte apoptosis, and improving autophagic flux

Heliyon. 2023 Oct 5;9(10):e20660. doi: 10.1016/j.heliyon.2023.e20660. eCollection 2023 Oct.

ABSTRACT

The synergy between radiotherapy and immunotherapy in treating thoracic cancers presents a potent therapeutic advantage, yet it also carries potential risks. The extent and nature of cumulative cardiac toxicity remain uncertain, prompting the need to discern its mechanisms and devise effective mitigation strategies. Radiation alone or in combination with an anti- Programmed cell death protein1 (PD-1) antibody significantly reduced cardiac function in C57BL/6J mice, and this pathologic effect was aggravated by anti-PD-1 (anti-PD-1 + radiation). To examine the cellular mechanism that causes the detrimental effect of anti-PD-1 upon cardiac function after radiation, AC16 human cardiomyocytes were used to study cardiac apoptosis and cardiac autophagy. Radiation-induced cardiomyocyte apoptosis was significantly promoted by anti-PD-1 treatment, while anti-PD-1 combined radiation administration blocked the cardiac autophagic flux. Adenosine 5'-triphosphate (ATP) (a molecule that promotes lysosomal acidification) not only improved autophagic flux in AC16 human cardiomyocytes, but also attenuated apoptosis induced by radiation and anti-PD-1 treatment. Finally, ATP administration in vivo significantly reduced radiation-induced and anti-PD-1-exacerbated cardiac dysfunction. We demonstrated for the first time that anti-PD-1 can aggravate radiation-induced cardiac dysfunction via promoting cardiomyocyte apoptosis without affecting radiation-arrested autophagic flux. ATP enhanced cardiomyocyte autophagic flux and inhibited apoptosis, improving cardiac function in anti-PD-1/radiation combination-treated animals.

PMID:37842574 | PMC:PMC10570000 | DOI:10.1016/j.heliyon.2023.e20660

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PubMed articles on: Cardio-Oncology

Evolving cardiac biomarkers for immune checkpoint inhibitor related myocarditis in cancer patients

Int J Cardiol Heart Vasc. 2023 Oct 8;49:101278. doi: 10.1016/j.ijcha.2023.101278. eCollection 2023 Dec.

NO ABSTRACT

PMID:37842144 | PMC:PMC10570005 | DOI:10.1016/j.ijcha.2023.101278

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PubMed articles on: Cancer & VTE/PE

Inhibition of Factor XI: A New Era in the Treatment of Venous Thromboembolism in Cancer Patients?

Int J Mol Sci. 2023 Sep 22;24(19):14433. doi: 10.3390/ijms241914433.

ABSTRACT

Direct oral anticoagulants against activated factor X and thrombin were the last milestone in thrombosis treatment. Step by step, they replaced antivitamin K and heparins in most of their therapeutic indications. As effective as the previous anticoagulant, the decreased but persistent risk of bleeding while using direct oral anticoagulants has created space for new therapeutics aiming to provide the same efficacy with better safety. On this basis, drug targeting factor XI emerged as an option. In particular, cancer patients might be one of the populations that will most benefit from this technical advance. In this review, after a brief presentation of the different factor IX inhibitors, we explore the potential benefit of this new treatment for cancer patients.

PMID:37833881 | PMC:PMC10572808 | DOI:10.3390/ijms241914433

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PubMed articles on: Cancer & VTE/PE

Enoxaparin for the long-term therapy of venous thromboembolism in patients with cancer and renal insufficiency

Thromb Haemost. 2023 Oct 13. doi: 10.1055/a-2191-7510. Online ahead of print.

ABSTRACT

BACKGROUND: The optimal therapy of venous thromboembolism (VTE) in cancer patients with renal insufficiency (RI) is unknown. Current guidelines recommend to use low-molecular-weight heparin over direct oral anticoagulants to treat VTE in cancer patients at high-risk for bleeding.

METHODS: We used the RIETE registry to compare the 6-month incidence rates of: 1) VTE recurrences vs. major bleeding; and 2) fatal pulmonary embolism (PE) vs. fatal bleeding in 3 subgroups (those with mild, moderate, or severe RI) of cancer patients receiving enoxaparin monotherapy.

RESULTS: From January 2009 through June 2022, 2,844 patients with RI received enoxaparin for ≥6 months: 1,432 (50%) had mild, 1,168 (41%) moderate, and 244 (8.6%) had severe RI. Overall, 68%, 62% and 12% respectively, received the recommended doses. Among patients with mild RI, the rates of VTE recurrences vs. major bleeding (4.6% vs. 5.4%) and fatal PE vs. fatal bleeding (1.3% vs. 1.2%) were similar. Among patients with moderate RI, VTE recurrences were half as common as major bleeding (3.1% vs. 6.3%), but fatal PE and fatal bleeding were close (1.8% vs. 1.2%). Among patients with severe RI, VTE recurrences were 3-fold less common than major bleeding (4.1% vs. 13%), but fatal PE was 3-fold more frequent than fatal bleeding (2.5% vs. 0.8%). During the first 10 days, fatal PE was 5-fold more common than fatal bleeding (2.1% vs. 0.4%).

CONCLUSIONS: Among cancer patients with severe RI, fatal PE was 5-fold more common than fatal bleeding. The recommended doses of enoxaparin in these patients should be revisited.

PMID:37832588 | DOI:10.1055/a-2191-7510

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PubMed articles on: Cardio-Oncology

CDK4/6 inhibitors: basics, pros, and major cons in breast cancer treatment with specific regard to cardiotoxicity - a narrative review

Ther Adv Med Oncol. 2023 Oct 11;15:17588359231205848. doi: 10.1177/17588359231205848. eCollection 2023.

ABSTRACT

Breast cancer is characterized by the uncontrolled proliferation of breast cells, with a high incidence reported in 2020 to have affected over 2 million women. In recent years, the conventional methods of treating breast cancer have involved radiotherapy and chemotherapy. However, the emergence of CDK4/6 inhibitors has shown potential as a promising cancer therapy. Cyclin-dependent kinases (CDK) inhibitors are a class of molecules that impede the formation of an active kinase complex, thereby hindering its activity and consequently halting the progression of the cell cycle. It was discovered that they have a significant impact on impeding the progression of the cancer. This is evident with the Food and Drug Administration's approval of drugs such as palbociclib, ribociclib, and abemaciclib for hormone receptor-positive metastatic breast cancer in combination with specific endocrine therapies. In spite of enormous success in breast cancer treatment, certain obstacles have emerged, such as therapy resistance, side effects, and most of all, cardiotoxicity. Some of these drawbacks have been successfully overcome by dosage reduction, different combinations of the drugs, and the assessment of each patient's condition and suitability prior to treatment. Yet other drawbacks still require tenacious research, especially certain cases of cardiotoxicities. This article delves into the biological mechanisms of CDK4/6 in the cell cycle and cancer, as well as the clinical advantages and most common adverse events (AEs) associated with CDK4/6 inhibitors. The primary objective of this review is to provide a comprehensive analysis of cardiotoxic AEs and elucidate the underlying pathophysiological mechanisms responsible for the cardiotoxicity of CDK4/6 inhibitors.

PMID:37841752 | PMC:PMC10571689 | DOI:10.1177/17588359231205848

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PubMed articles on: Cancer & VTE/PE

Implementation of routine venous thromboembolism prophylaxis during neoadjuvant chemotherapy for patients with ovarian cancer

Gynecol Oncol. 2023 Oct 11;178:89-95. doi: 10.1016/j.ygyno.2023.10.001. Online ahead of print.

ABSTRACT

OBJECTIVE: To compare the venous thromboembolism (VTE) rate in patients with ovarian cancer undergoing neoadjuvant chemotherapy before and after implementing routine thromboprophylaxis.

METHODS: This is a quasi-experimental pre-post study evaluating the VTE rate in patients with ovarian cancer who received neoadjuvant chemotherapy following a quality improvement initiative of routine thromboprophylaxis within a single healthcare system that started in January 2017. Patients were excluded if VTE was diagnosed before initiating chemotherapy. Patient factors and perioperative variables of interest were investigated for their association with VTE through univariate and multivariate models.

RESULTS: Of the 136 patients in the pre-implementation group, 3.7% (n = 5) received thromboprophylaxis. Of the 154 patients in the post-implementation group, 65.6% (n = 101) received thromboprophylaxis. Provider compliance varied from 51% in 2019 to 79.3% in 2021. The overall rate of VTE, from the start of chemotherapy to the end of treatment, was 21.3% (n = 29) pre- and 8.4% (n = 13) in the post-implementation group (p < 0.01). There was no difference in major bleeding events between groups (0% vs. 0.68%, p = 0.63). On univariate analysis, thromboprophylaxis (OR 0.19; 95% CI 0.07-0.52) and post-implementation period (OR 0.34; 95% CI 0.17-0.69) were associated with a decreased risk of any VTE during primary treatment. On multivariate analysis, only thromboprophylaxis remained significantly associated with reduced VTE rates (aOR 0.19; 95% CI 0.07-0.53).

CONCLUSION: Routine thromboprophylaxis during neoadjuvant chemotherapy is associated with reduced risk of VTE throughout primary treatment and is not associated with increased bleeding events.

PMID:37832182 | DOI:10.1016/j.ygyno.2023.10.001

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PubMed articles on: Cardio-Oncology

Complications in patients with transfusion dependent thalassemia: A descriptive cross-sectional study

Health Sci Rep. 2023 Oct 11;6(10):e1624. doi: 10.1002/hsr2.1624. eCollection 2023 Oct.

ABSTRACT

BACKGROUND AND AIMS: One of the most common hemoglobinopathies globally related to blood transfusion and iron overload in the body is thalassemia syndrome. Increasing ferritin levels can cause severe damage to the patient's body organs. This study aims to evaluate the complications of iron overload on vital body organs in patients with transfusion-dependent beta-thalassemia.

METHODS: This descriptive cross-sectional study was performed in Iran University of Medical Sciences Hospitals on patients with a beta-thalassemia major with frequent blood transfusions. To evaluate the effect of iron overload on vital body organs, hematologic and blood analysis, echocardiography with measurement of pulmonary artery pressure (PAP) and ejection fraction (EF) tests, bone densitometry, and audiometric tests were performed for all patients.

RESULTS: Of the 1010 patients participating in this study, 497 (49%) were males, 513 were (51%) females aged 5-74 years, and the majority of participants (85%) were over 20 years old. This study demonstrated that increasing ferritin levels had no notable correlation with sex, cholesterol, low-density lipoprotein, parathyroid hormone, T4, and aspartate aminotransferase. However, elevating ferritin levels had significant correlations with increasing triglyceride, phosphorus, thyroid stimulating hormone, alkaline phosphatase, alanine transaminase, and PAP levels, age, hearing disorders, splenectomy, osteoporosis, and decreasing high-density lipoprotein, body mass index, calcium, and EF levels.

CONCLUSION: Improvement in beta-thalassemia patients' survival and quality of life can be due to multidisciplinary care in a comprehensive unit through regular follow-up and early complication detection.

PMID:37841947 | PMC:PMC10568004 | DOI:10.1002/hsr2.1624

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PubMed articles on: Cancer & VTE/PE

Risk of Thrombosis and Bleeding in Gynecologic Cancer Surgery: Systematic Review and Meta-Analysis

Am J Obstet Gynecol. 2023 Oct 10:S0002-9378(23)00735-4. doi: 10.1016/j.ajog.2023.10.006. Online ahead of print.

ABSTRACT

OBJECTIVE: To provide procedure-specific estimates of the risk of symptomatic venous thromboembolism (VTE) and major bleeding, in the absence of thromboprophylaxis, following gynecologic cancer surgery.

DATA SOURCES: We conducted comprehensive searches on Embase, MEDLINE, Web of Science, and Google Scholar for observational studies. We also reviewed reference lists of eligible studies and review articles. We performed separate searches for randomized trials addressing effects of thromboprophylaxis and conducted a web-based survey on thromboprophylaxis practice.

STUDY ELIGIBILITY CRITERIA: Observational studies enrolling ≥50 adult patients undergoing gynecologic cancer surgery procedures reporting absolute incidence for at least one of the following: symptomatic pulmonary embolism, symptomatic deep vein thrombosis, symptomatic VTE, bleeding requiring reintervention (including re-exploration and angioembolization), bleeding leading to transfusion or post-operative hemoglobin <70

STUDY APPRAISAL AND SYNTHESIS METHODS: Two reviewers independently assessed eligibility, performed data extraction, and evaluated risk of bias of eligible articles. We adjusted the reported estimates for thromboprophylaxis and length of follow-up and used the median value from studies to determine cumulative incidence at 4 weeks post-surgery stratified by patient VTE risk factors, and used the GRADE approach to rate evidence certainty.

RESULTS: We included 188 studies (398,167 patients) reporting on 37 gynecologic cancer surgery procedures. The evidence certainty was generally low to very low. Median symptomatic VTE risk (in the absence of prophylaxis) was <1%2.0% in 13 of 37 (35%). The risks of VTE varied from 0.1% in low VTE risk patients undergoing cervical conization to 33.5% in high VTE risk patients undergoing pelvic exenteration. Estimates of bleeding requiring reintervention varied from <0.1%<1%

CONCLUSIONS: VTE reduction with thromboprophylaxis likely outweighs increase in bleeding requiring reintervention in many gynecologic cancer procedures (e.g., open surgery for ovarian cancer and pelvic exenteration). In some procedures (e.g., laparoscopic total hysterectomy without lymphadenectomy), thromboembolism and bleeding risks are similar, and decisions depend on individual risk prediction and values and preferences regarding VTE and bleeding.

PMID:37827272 | DOI:10.1016/j.ajog.2023.10.006

12:13

PubMed articles on: Cardio-Oncology

Social disparities in cardiovascular mortality of patients with cancer in the USA between 1999 and 2019

Int J Cardiol Cardiovasc Risk Prev. 2023 Oct 3;19:200218. doi: 10.1016/j.ijcrp.2023.200218. eCollection 2023 Dec.

ABSTRACT

BACKGROUND: Temporal trends of the impact of social determinants on cardiovascular outcomes of cancer patients has not been previously studied.

OBJECTIVES: This study examined social disparities in cardiovascular mortality of people with and without cancer in the US population between 1999 and 2019.

METHODS: Primary cardiovascular deaths were identified from the Multiple Cause of Death database and grouped by cancer status. The cancer cohort was subcategorized into breast, lung, prostate, colorectal, and haematological. The number of cardiovascular deaths, crude cardiovascular mortality rate, cardiovascular age-adjusted mortality rate (AAMR), and percentage change in cardiovascular AAMR were calculated by cancer status and cancer type, and stratified by sex, race, ethnicity, and urban-rural setting.

RESULTS: 17.9 million cardiovascular deaths were analysed. Of these, 572,222 occurred in patients with a record of cancer. The cancer cohort were older and included more men and White racial groups. Regardless of cancer status, cardiovascular AAMR was higher in men, rural settings, and Black or African American races. Cardiovascular AAMR declined over time, with greater reduction in those with cancer (-51.6% vs -38.3%); the greatest reductions were in colorectal (-68.4%), prostate (-60.0%), and breast (-58.8%) cancers. Sex, race, and ethnic disparities reduced over time, with greater narrowing in the cancer cohort. There was increase in urban-rural disparities, which appeared greater in those with cancer.

CONCLUSIONS: While most social disparities narrowed over time, urban-rural disparities widened, with greater increase in those with cancer. Healthcare plans should incorporate strategies for reduction of health inequality equitable access to cardio-oncology services.

PMID:37841449 | PMC:PMC10568337 | DOI:10.1016/j.ijcrp.2023.200218

12:13

PubMed articles on: Cancer & VTE/PE

Accuracy of the ACS NSQIP Surgical Risk Calculator for Predicting Postoperative Complications in Gastric Cancer Following Open Gastrectomy

Am Surg. 2023 Oct 12:31348231206581. doi: 10.1177/00031348231206581. Online ahead of print.

ABSTRACT

INTRODUCTION: The prediction of complications before gastric surgery is of utmost importance in shared decision making and proper counseling of the patient in order to minimize postoperative complications. Our aim was to evaluate the predictive validity of American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) risk calculator in gastric cancer patients who underwent gastrectomy.

METHODS: Preoperative assessment data of 432 patients were retrospectively reviewed and manually entered into the calculator. The accuracy of the calculator was evaluated using Pearson's chi-squared test, C-statistic, Brier score, and Hosmer-Lemeshow test.

RESULTS: The lowest Brier scores were observed in urinary tract infection, renal failure, venous thromboembolism, pneumonia, and cardiac complications. Best results were obtained for predicting sepsis, discharge to rehabilitation facility, and death (low Brier scores, C-statistic >.7, and Hosmer-Lemeshow P > .05).

CONCLUSION: The calculator had a strong performance in predicting sepsis, discharge to the rehabilitation facility, and death. However, it performed poor in predicting the most commonly observed events (any or serious complication and surgical site infection).

PMID:37823864 | DOI:10.1177/00031348231206581

12:13

PubMed articles on: Cardio-Oncology

MRI-derived extracellular volume as a biomarker of cancer therapy cardiotoxicity: systematic review and meta-analysis

Eur Radiol. 2023 Oct 12. doi: 10.1007/s00330-023-10260-8. Online ahead of print.

ABSTRACT

OBJECTIVES: MRI-derived extracellular volume (ECV) allows characterization of myocardial changes before the onset of overt pathology, which may be caused by cancer therapy cardiotoxicity. Our purpose was to review studies exploring the role of MRI-derived ECV as an early cardiotoxicity biomarker to guide timely intervention.

MATERIALS AND METHODS: In April 2022, we performed a systematic search on EMBASE and PubMed for articles on MRI-derived ECV as a biomarker of cancer therapy cardiotoxicity. Two blinded researchers screened the retrieved articles, including those reporting ECV values at least 3 months from cardiotoxic treatment. Data extraction was performed for each article, including clinical and technical data, and ECV values. Pooled ECV was calculated using the random effects model and compared among different treatment regimens and among those who did or did not experience overt cardiac dysfunction. Meta-regression analyses were conducted to appraise which clinical or technical variables yielded a significant impact on ECV.

RESULTS: Overall, 19 studies were included. Study populations ranged from 9 to 236 patients, for a total of 1123 individuals, with an average age ranging from 12.5 to 74 years. Most studies included patients with breast or esophageal cancer, treated with anthracyclines and chest radiotherapy. Pooled ECV was 28.44% (95% confidence interval, CI, 26.85-30.03%) among subjects who had undergone cardiotoxic cancer therapy, versus 25.23% (95%CI 23.31-27.14%) among those who had not (p = .003).

CONCLUSION: A higher ECV in patients who underwent cardiotoxic treatment could imply subclinical changes in the myocardium, present even before overt cardiac pathology is detectable.

CLINICAL RELEVANCE STATEMENT: The ability to detect subclinical changes in the myocardium displayed by ECV suggests its use as an early biomarker of cancer therapy-related cardiotoxicity.

KEY POINTS: • Cardiotoxicity is a common adverse effect of cancer therapy; therefore, its prompt detection could improve patient outcomes. • Pooled MRI-derived myocardial extracellular volume was higher in patients who underwent cardiotoxic cancer therapy than in those who did not (28.44% versus 25.23%, p = .003). • MRI-derived myocardial extracellular volume represents a potential early biomarker of cancer therapy cardiotoxicity.

PMID:37823922 | DOI:10.1007/s00330-023-10260-8

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PubMed articles on: Cancer & VTE/PE

Measurement of adherence and health-related quality of life during anticoagulation therapy in cancer-associated venous thromboembolism (VTE): a multicenter quantitative study

Support Care Cancer. 2023 Oct 6;31(10):615. doi: 10.1007/s00520-023-08073-y.