NSAID exposure, but also orchestrates the inflammatory responses associated with ulceration. Our study suggests that IND-induced inhibition of the ATX-LPAR2 axis is an early event in the pathogenesis of enteropathy

 

ABSTRACT

Cardiotoxicity linked with hematopoietic stem cell transplantation (HSCT) is a well-described phenomenon associated with an increased mortality risk; however, the majority of cardiac events present over 100 days following transfusion and are often attributed to graft-versus-host disease or pre-treatment conditioning by chemotherapy with or without radiation therapy. Here, we present the case of a 60-year-old female with a medical history of chronic lymphocytic leukemia complicated by a myelodysplastic syndrome that progressed to acute myeloid leukemia who developed chest pain immediately following an allogeneic HSCT. Electrocardiogram showed dynamic ST-depressions in leads V3-5 without evidence of reciprocal changes. Transthoracic echocardiography revealed pericardial effusion without signs of tamponade. The patient was thought to have acute pericarditis and was subsequently treated with high-dose intravenous methylprednisolone with a taper for two weeks. Her symptoms promptly subsided, and the pericardial effusion resolved on repeat echocardiography, which confirmed the diagnosis. Acute pericarditis is a rarely described complication of HSCT that is fatal if left untreated and prompts urgent management. This atypical case of acute pericarditis in the early post-transplant phase highlights the importance of cardiac stratification in patients with active malignancy undergoing treatment. It would suggest a potential benefit in closely monitoring high-risk individuals who have a history of coronary artery disease, smoking, or pericarditis in the pre-engraftment phase of transplantation.

PMID:37818511 | PMC:PMC10561524 | DOI:10.7759/cureus.44868

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PubMed articles on: Cardio-Oncology

Cardiac Safety of Pegylated Liposomal Doxorubicin After Conventional Doxorubicin Exposure in Patients With Sarcoma and Breast Cancer

Cureus. 2023 Sep 7;15(9):e44837. doi: 10.7759/cureus.44837. eCollection 2023 Sep.

ABSTRACT

BACKGROUND: Lifetime cumulative doses of conventional doxorubicin (>450 mg/m2) are associated with dose-dependent cardiotoxicity. In sarcoma and breast cancer, conventional doxorubicin is often utilized in the adjuvant setting, whereas pegylated liposomal doxorubicin (PLD) is typically reserved for recurrent and metastatic disease. PLD is believed to be associated with reduced cardiotoxicity compared to conventional doxorubicin. Limited data exists evaluating the cardiotoxicity associated with PLD treatment after conventional doxorubicin, especially when doxorubicin lifetime doses approach the established cumulative total lifetime dose of 450-550 mg/m2. This study aims to further qualify the cardiac safety of PLD use in patients who have had prior exposure to conventional doxorubicin.

METHODS: This was a single-center, observational, retrospective cohort study conducted in patients ≥18 years with sarcoma or breast cancer who were exposed to conventional doxorubicin from an earlier line of treatment before PLD between January 2010 to May 2022. Patients were evaluated for the presence of cardiac toxicity at any point in their treatment course. Cardiac toxicity was defined as ≥ 10% decrease in left ventricle ejection fraction (LVEF) or a new diagnosis of heart failure within six months after PLD cessation. The time interval between the last conventional doxorubicin exposure and PLD initiation and the time interval between PLD initiation and LVEF monitoring were also analyzed.

RESULTS: 494 patients were screened, and 50 met inclusion criteria: eight with sarcoma and 42 with breast cancer. The median lifetime cumulative conventional doxorubicin dose in patients with sarcoma was 450 mg/m2 with a maximum dose of 825 mg/m2 and 240 mg/m2 with a maximum dose of 300 mg/m2 in breast cancer patients. The median lifetime cumulative PLD dose was 105 mg/m2 (range: 35-150 mg/m2) in the sarcoma group and 105 mg/m2 (range: 35-510 mg/m2) in the breast cancer group. A decrease of ≥ 10% in LVEF was not observed in the sarcoma group. Patients with breast cancer had available LVEF data on PLD, and three of these patients experienced ≥ 10% in LVEF drop, with one of these patients diagnosed with heart failure. The average cumulative dose of PLD administered in patients with > 10% decrease in LVEF was 177 mg/m2 and had an average of 3.5 cycles. Five sarcoma patients initiated PLD treatment within two years after conventional doxorubicin exposure, while most breast patients initiated PLD treatment at least 10 years following conventional doxorubicin exposure. The average time from PLD initiation to first and second available LVEF monitoring was one and five months in the sarcoma group and three and eight months in the breast cancer group, respectively.

CONCLUSION: PLD administration in patients with prior exposure to conventional doxorubicin appears to be safe, with limited cardiotoxicity in patients with sarcoma and breast cancer. Future research is needed to determine if and how often routine cardiac monitoring is needed for patients on PLD without existing cardiac risk.

PMID:37809186 | PMC:PMC10559758 | DOI:10.7759/cureus.44837

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PubMed articles on: Cardio-Oncology

A dual role of lysophosphatidic acid type 2 receptor (LPAR2) in nonsteroidal anti-inflammatory drug-induced mouse enteropathy

Acta Pharmacol Sin. 2023 Oct 10. doi: 10.1038/s41401-023-01175-7. Online ahead of print.

ABSTRACT

Lysophosphatidic acid (LPA) is a bioactive phospholipid mediator that has been found to ameliorate nonsteroidal anti-inflammatory drug (NSAID)-induced gastric injury by acting on lysophosphatidic acid type 2 receptor (LPAR2). In this study, we investigated whether LPAR2 signaling was implicated in the development of NSAID-induced small intestinal injury (enteropathy), another major complication of NSAID use. Wild-type (WT) and Lpar2 deficient (Lpar2-/-) mice were treated with a single, large dose (20 or 30 mg/kg, i.g.) of indomethacin (IND). The mice were euthanized at 6 or 24 h after IND treatment. We showed that IND-induced mucosal enteropathy and neutrophil recruitment occurred much earlier (at 6 h after IND treatment) in Lpar2-/- mice compared to WT mice, but the tissue levels of inflammatory mediators (IL-1β, TNF-α, inducible COX-2, CAMP) remained at much lower levels. Administration of a selective LPAR2 agonist DBIBB (1, 10 mg/kg, i.g., twice at 24 h and 30 min before IND treatment) dose-dependently reduced mucosal injury and neutrophil activation in enteropathy, but it also enhanced IND-induced elevation of several proinflammatory chemokines and cytokines. By assessing caspase-3 activation, we found significantly increased intestinal apoptosis in IND-treated Lpar2-/- mice, but it was attenuated after DBIBB administration, especially in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. Finally, we showed that IND treatment reduced the plasma activity and expression of autotaxin (ATX), the main LPA-producing enzyme, and also reduced the intestinal expression of Lpar2 mRNA, which preceded the development of mucosal damage. We conclude that LPAR2 has a dual role in NSAID enteropathy, as it contributes to the maintenance of mucosal integrity after

NSAID exposure, but also orchestrates the inflammatory responses associated with ulceration. Our study suggests that IND-induced inhibition of the ATX-LPAR2 axis is an early event in the pathogenesis of enteropathy.

PMID:37816857 | DOI:10.1038/s41401-023-01175-7

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PubMed articles on: Cardio-Oncology

Papillary Adenocarcinoma: A Rare Subtype of Lung Adenocarcinoma

Cureus. 2023 Sep 7;15(9):e44838. doi: 10.7759/cureus.44838. eCollection 2023 Sep