Case report: A case of metastatic BRAFV600-mutated melanoma with heart failure treated with immune checkpoint inhibitors and BRAF/MEK inhibitors.

Background: Novel therapies, immune checkpoint inhibitors (ICIs), and BRAF/MEK inhibitors (BRAFi/MEKi) provide unprecedented survival benefits for patients with advanced melanoma. However, the management of drug-induced adverse events is problematic for both agents and, although rare, can cause serious cardiac dysfunction. Case report: A 42-year-old male patient with no significant medical history noticed a fading dark brown patch on his left anterior chest, which had been there for 20 years, after his second coronavirus disease 2019 (COVID-19) vaccination. The left axillary lymph node became swollen one week after a third booster vaccination. Thinking of it as an adverse reaction to the vaccine, but the swelling increased, so he visited a hospital. The patient presented with a brown macule with depigmentation on the left anterior chest and a 13 cm left axillary mass. A biopsy of the axillary mass showed a metastatic malignant melanoma. Positron emission tomography (PET) showed an accumulation only in the axillary lymph nodes. One month after the initial diagnosis, the axillary mass had further enlarged. In addition, pleural effusion, ascites, difficulty breathing, and systemic edema appeared, and he was diagnosed with heart failure (NYHA class III). Echocardiography showed an ejection fraction of 52% and electrocardiogram (ECG) showed no abnormal findings. Though it was (a life-threatening instead of the life-threatening) the life-threatening condition, we determined that the symptoms were associated with the current disease. Then nivolumab (nivo) plus ipilimumab (ipi) was initiated after explaining the risk of cardiac dysfunction associated with drug use to the patient. After initiation of ICIs, treatment was switched to BRAFi/MEKi (encorafenib/vinimetinib) after the patient tested positive for BRAF V600E. After one month of treatment, the tumor shrank significantly and achieved a complete remission after four months. Furthermore, as the tumor shrank, the patient's heart failure improved, and he was able to continue treatment without serious drug-induced cardiotoxicity. Conclusion: Both ICI and BRAFi/MEKi carry a risk of cardiac dysfunction. However, without any underlying cardiac disease or severe cardiac dysfunction, their administration should not necessarily be excluded if careful follow-up is provided.

Cytokine Release Syndrome Induced by Immune-checkpoint Inhibitor Therapy for Non-small-cell Lung Cancer.

Immune-related adverse events, including autoimmune toxicity, may develop as a consequence of immune-checkpoint inhibitor (ICI) cancer therapy. Cytokine release syndrome (CRS) is a severe and life-threatening cytokine-associated toxicity that can develop after adoptive T-cell therapy. We herein report a rare case of severe CRS after ICI therapy for advanced non-small-cell lung cancer. He presented with a prolonged high fever, cardiogenic shock, and disseminated intravascular coagulation after the first course of programed death ligand-1 inhibitor and platinum-based doublet chemotherapy. He recovered by steroid pulse therapy and tocilizumab. CRS is a rare but life-threatening adverse event of ICI therapy and therefore warrants awareness.

[Transfusion-associated circulatory overload with pulmonary alveolar hemorrhage following allogeneic bone marrow transplantation].

A 51-year-old man underwent allogeneic bone marrow transplantation (BMT) for recurrent acute myeloid leukemia. Although the patient developed slight edema, pleural effusion, and cardiac effusion 6 months after BMT, his clinical condition improved with furosemide treatment. The patient was transfused with red blood cells for the management of anemia 8 months after BMT. He developed acute respiratory failure with pulmonary alveolar hemorrhage 80 min after the transfusion. He was diagnosed with transfusion-associated circulatory overload (TACO) due to the presence of acute pulmonary congestion and depressed left ventricular systolic function. Reduced circulatory load due to sufficient furosemide led to ventilator weaning 3 days later. Other causes of pulmonary alveolar hemorrhage were excluded, and the patient's condition improved by cardiac failure treatment only. This clinical course indicated that pulmonary alveolar hemorrhage would breakdown the blood vessels due to acute pulmonary congestion. Chemotherapy and prolonged anemia are high risks for cardiac failure in patients with hematological malignancies. Therefore, the possibility of cardiac failure is considered when patients with hematological malignancies have fluid retention, such as cardiac enlargement, edema, and pleural effusion. Moreover, the body fluids should be monitored before and after blood transfusion.

Incidence of, and risk factors for, postoperative venous thromboembolism in patients with benign or malignant musculoskeletal tumors.

BACKGROUND: Venous thromboembolism is a serious complication after surgery for malignant musculoskeletal tumors in the lower extremity. However, the incidence of postoperative venous thromboembolism in patients with benign musculoskeletal tumors and musculoskeletal tumors in the upper extremity or trunk remains unclear. Identifying risk factors may provide useful information for selecting patients who should receive chemoprophylaxis. METHODS: A retrospective study of 833 patients with musculoskeletal tumors who underwent surgery was conducted. Patients were divided into four groups: 364 patients with benign tumors in the upper extremity or trunk (group 1); 315 patients with benign tumors in the lower extremity or pelvis (group 2); 50 patients with malignant tumors in the upper extremity or trunk (group 3); and 104 patients with malignant tumors in the lower extremity or pelvis (group 4). The incidence of venous thromboembolism was investigated, and risk factors were examined for group 4. RESULTS: The incidence of postoperative venous thromboembolism was 0, 0.95, 0, and 4.8 % in groups 1, 2, 3, and 4, respectively. The incidence of venous thromboembolism in the malignant tumor group (groups 3 + group 4) was significantly higher than that in the benign tumor group (group 1 + group 2). The incidence of postoperative venous thromboembolism in the upper extremity or trunk group (group 1 + group 3) was significantly lower than that in the lower extremity or pelvis group (group 2 + group 4). In group 4, a higher incidence of postoperative venous thromboembolism was significantly correlated with a history of cerebrovascular disease and surgery in the prone position. CONCLUSIONS: Patients with malignant tumors in the lower extremity or pelvis, particularly those with a history of cerebrovascular disease and surgery in a prone position, were at high risk of venous thromboembolism. Patients with benign tumors in the lower extremity or pelvis were at intermediate risk. This is important information for predicting the incidence of postoperative venous thromboembolism and determining who should receive chemoprophylaxis after surgery for musculoskeletal tumors.

Improvement of a compressed inferior vena cava due to IgG4-related retroperitoneal fibrosis with steroid therapy.

A 79-year-old man had a 3.5-year history of edema of the lower extremities of unknown etiology. Abdominal computed tomography showed a soft tissue mass around the abdominal aorta, and the biopsy revealed dense fibrosis with abundant infiltration of IgG4-positive plasma cells. His serum IgG4 level was increased to 188 mg/dL. His lower extremity edema was induced by stenosis of the inferior vena cava (IVC) due to the mass. With a diagnosis of IgG4-related retroperitoneal fibrosis, he was treated with steroid, and the leg edema decreased with improvement of patency of the IVC and reduction of the soft tissue mass.

Elevated cardiac troponin T predicts adverse outcomes in hypertensive patients.

Ongoing myocardial damage detected as elevated serum cardiac troponin T (cTnT) indicates increased risk for future cardiac events in patients with chronic heart failure. Whether elevated cTnT is associated with adverse outcomes in patients with hypertension (HT) without left ventricular (LV) systolic dysfunction is unknown.We measured cTnT levels in 176 patients with essential HT without LV systolic dysfunction (LV ejection fraction ≤ 55%), renal failure, and prior cardiovascular or cerebrovascular diseases and 39 normal controls. Levels of cTnT were elevated (≥ 0.02 ng/mL) in 15 (9%) of the 176 patients and in 0 (0%) of the 39 normal controls (P = 0.04). The rate of diabetes mellitus (DM), the cardiothoracic ratio, plasma B-type natriuretic peptide (BNP) value, and LV mass index were significantly higher in patients with than without elevated cTnT (DM, 8/15 versus 29/161, P = 0.004; cardiothoracic ratio, 54.5 ± 4.5 versus 51.6 ± 5.2%, P = 0.04; BNP, 103.3 ± 142.3 versus 36.9 ± 50.7 pg/mL, P = 0.04; LV mass index, 227 ± 87 versus 152 ± 57 g/m(2), P = 0.0001). Kaplan-Meier analysis demonstrated that significantly fewer (P < 0.000001) patients with, than without elevated cTnT remained free of events (hospitalization due to cardiovascular or cerebrovascular disease, n = 34). Stepwise Cox multivariate analysis revealed that elevated cTnT (hazard ratio, 6.58; P = 0.000001) and smoking (hazard ratio, 2.24; P = 0.04) were independent predictors of events.The present findings indicate that cTnT is a novel and useful predictor of future cardiovascular or cerebrovascular events in hypertensive patients.

Elevated levels of both cardiomyocyte membrane and myofibril damage markers predict adverse outcomes in patients with chronic heart failure.

BACKGROUND: Recent studies have shown the presence of ongoing myocardial damage in patients with chronic heart failure (CHF) detected by myofibril and membrane damage markers, cardiac troponin T (TnT) and heart-type fatty acid-binding protein (H-FABP), which identifies patients at increased risk of a future cardiac event (CE: death or rehospitalization because of worsening CHF). There is a difference between TnT and H-FABP in their release kinetics following myocardial damage. METHODS AND RESULTS: TnT and H-FABP were measured in 103 patients with CHF and in 31 controls. Patients were classified into 4 groups based on detectable (>or=0.01 ng/ml) or undetectable TnT (TnT+ or TnT-) and H-FABP >or= or <4.5 ng/ml (mean + 2 standard deviations in controls) (high-H-FABP or low-H-FABP). Kaplan-Meier analysis showed that the CE-free rate (n=43) was significantly lower in patients with TnT+ and high-H-FABP than in patients in the other 3 groups (patients with TnT+ and low-H-FABP, TnT- and high-H-FABP, and TnT- and low-H-FABP; p=0.02, p=0.001 and p=0.0002, respectively). In stepwise multivariate Cox proportional hazard analysis, TnT+ (p=0.01) and high-H-FABP (p=0.04) were independent predictors of future CE. CONCLUSIONS: Elevated levels of both TnT and H-FABP predict adverse outcomes in CHF patients.

Oxidative stress in the Dahl salt-sensitive hypertensive rat.

Oxidative stress has been proposed as important in the pathogenesis of hypertension. Measurement of 8-iso prostaglandin F2alpha (8-ISO) is introduced for evaluating oxidative stress in vivo. 8-ISO is the major urinary metabolite of F2-isoprostanes and is formed nonenzymatically from the attack of superoxide radicals on arachidonic acid. We examined the oxidative stress level in the Dahl salt-sensitive (Dahl-S) rats and the Dahl salt-resistant (Dahl-R) rats. Dahl-S and Dahl-R rats were fed either a high salt diet (8% NaCl; HS) or low salt diet (0.3% NaCl; LS) for 3 weeks, and systolic blood pressure (SBP) and 24-hr urinary excretion of 8-ISO (U-8-ISO) were measured. In Dahl-S rats, the high salt diet induced hypertension (139 +/- 3 mmHg in LS versus 186 +/- 2 mmHg in HS, p < .05) and significantly increased the U-8-ISO (24.9 +/- 3.6 ng/24 hr in LS versus 63.2 +/- 14.6 ng/24 hr in HS, p < .05). No significant difference in blood pressure or U-8-ISO was observed between high-salt and low-salt treated Dahl-R rats. U-8-ISO concentration was correlated with SBP in all four experimental groups (r = 0.866). Moreover, urinary 8-hydroxy-2'-deoxyguanosine (U-8-OHdG), which is one of the most commonly used markers for evaluation of oxidative stress, was higher in Dahl-S-8% rats than in Dahl-S-0.3% rats (136.1 +/- 48.4 ng/24 hr in LS versus 322.8 +/- 46.7 ng/24 hr in HS, p < .05), and U-8-OHdG was correlated with SBP (r = 0.681) in Dahl-S rats. These results suggest oxygen radicals are involved in the pathogenesis of hypertension.

Effect of morning and bedtime dosing with cilnidipine on blood pressure, heart rate, and sympathetic nervous activity in essential hypertensive patients.

Cilnidipine has a blocking action against N-type calcium channels as well as L-type calcium channels. We studied the effect of morning and bedtime dosing on circadian variation of blood pressure (BP), heart rate (HR), and activity of the autonomic nervous system, using an open randomized crossover study in 13 essential hypertensive patients. An automated device allowed 24-hour monitoring of ambulatory BP and HR and the power spectrum of the R-R interval, at the observation period, the morning dosing regimen, and the bedtime dosing regimen. Morning dosing and bedtime dosing with cilnidipine reduced the average systolic BP over 24 hours, during daytime, and during nighttime. The average HR and the average LF/HF ratio over 24 hours, during daytime, and during nighttime, were similar for the three periods. Both morning and bedtime dosing reduced the maximum systolic BP in the early morning and suppressed the morning rise of BP, which were accompanied by partial inhibition of the increase in LF/HF ratio. Our results show that cilnidipine administered once daily is an efficient antihypertensive drug regardless of the time of dosing, without reflex tachycardia and increase in sympathetic nervous activity, and with partial inhibition of the morning activation of the sympathetic nervous system.