Increasing survivors of anthracycline-related cardiomyopathy with breast cancer in trastuzumab era: thirty-one-year trends in a Japanese Community.

BACKGROUND: Trastuzumab has improved breast cancer (BC) prognosis and reduced anthracycline use. However, the characteristic changes of anthracycline-related cardiomyopathy (ARCM) in patients with BC remain unclear. We aimed to update our understanding of ARCM in the trastuzumab era. METHODS: This retrospective observational cohort study included 2959 patients with BC treated with anthracyclines at three regional cancer centers in Niigata City between 1990 and 2020. Seventy-five patients (2.5%) developed ARCM and were categorized into two groups: pre- 2007 (early phase) and post-2007 (late phase), corresponding to before and during the trastuzumab era in Japan. RESULTS: ARCM incidence peaked at 6% in the 1990s, then decreased and stabilized at 2% until the 2010s. Survivors of anthracycline-treated BC increased more rapidly in the late phase, with four times as many patients with ARCM compared to the end of the early phase (26 and six, respectively). Although the rate of change in accumulation from the early phase to the late phase was slight in the anthracycline-treated BC group, it was more pronounced in the ARCM group (P < 0.001). Mean anthracycline use in the late phase was significantly lower than in the early phase (307 vs. 525 mg/m2, P < 0.001). Five-year survival rates in the late phase tended to be higher than early phase (45% and 28%, respectively. P = 0.058). Human epidermal growth factor receptor type 2 (HER2) positivity with trastuzumab therapy in the late phase was an independent predictor for mortality within 10 years (hazard ratio = 0.24, 95% confidence interval: 0.10-0.56; P = 0.001). CONCLUSIONS: HER2-positive patients with ARCM receiving trastuzumab therapy had a better prognosis than HER2-positive and HER2-negative patients with ARCM not receiving trastuzumab therapy, and this trend has been increasing in the trastuzumab era. These findings highlight the importance of HER2-targeted treatments in improving prognosis for BC patients with ARCM.

[Association of D-dimer Levels with Complications after Subcutaneous Implantable Central Venous Port Placement in Combination Chemotherapy with Bevacizumab for Colorectal Cancer].

Bevacizumab(BV)combination chemotherapy in colorectal cancer under subcutaneously implanted central venous port (CVP)implantation may cause complications after the implantation. Measurement of D-dimer is recommended to predict thromboembolism and other complications, but its relevance to complications after CVP implantation remains unclear. In this study, we investigated the association between D-dimer and complications after CVP implantation in 93 patients with colorectal cancer who received BV combination chemotherapy. Complications after CVP implantation occurred in 26 patients (28%), and those with VTE showed higher D-dimer values at the onset of the complication. The D-dimer values of the patients with VTE displayed a sharp increase at the onset of the disease, while those with an abnormal CVP implantation site showed a more variable course. Measurement of D-dimer levels appeared useful in estimating the incidence of VTE and abnormal CVP implantation sites in post-CVP implantation complications of BV combination chemotherapy for colorectal cancer. Further, monitoring not only the quantitative values but also the fluctuations over time is also important.

Relationship Between Medical Therapy, Long-Term Care Insurance, and Comorbidity in Elderly Patients With Heart Failure With Systolic Dysfunction.

BACKGROUND: Although guideline-directed medical therapy (GDMT), including ß-blockers, angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs), improves survival and quality of life, most patients with heart failure with reduced (HFrEF) and mildly reduced (HFmrEF) ejection fraction are treated with inadequate medications. We investigated the prescription patterns of GDMT in elderly patients with HFrEF and HFmrEF and their characteristics, including the certification of long-term care insurance (LTCI), which represents frailty and disability.Methods and Results: This retrospective cross-sectional study analyzed 1,296 elderly patients with symptomatic HFrEF and HFmrEF with diuretic use (median age 78 years; 63.8% male; median left ventricular ejection fraction 40%). Prescription rates of GDMT were inadequate (ACEi, ARBs, ß-blockers, and MRAs: 27.0%, 30.1%, 54.1%, and 41.9%, respectively). LTCI certification was independently associated with reduced prescription of all medications (ACEi/ARB: odds ratio [OR] 0.591, 95% confidence interval [CI] 0.449-0.778, P=0.001; ß-blockers: OR 0.698, 95% CI 0.529-0.920, P<0.001; MRAs: OR 0.743, 95% CI 0.560-0.985, P=0.052). Patients with LTCI certification also had a high prevalence of polypharmacy and prescription of diuretics. CONCLUSIONS: Vulnerable patients with LTCI may be an explanation for the challenges in implementing GDMT, and communicating is required for favorable heart failure care in this population.

Long-Term Outcomes in Patients with Not-Retrieval Inferior Vena Cava Filter Under Anticoagulation.

Since permanent inferior vena cava (IVC) filters increase deep vein thrombosis (DVT), filter retrieval should be performed as possible. Despite the guideline recommendation, IVC filters are not always retrieved in clinical practice. To date, many patients with not-retrieval IVC filters have been prescribed anticoagulant therapy, but the long-term prognosis, including venous thromboembolism (VTE) and bleeding events, remains unknown. In this study, 195 patients who underwent IVC filter implantation between 2006 and 2017 at 3 institutions in Niigata City have been investigated about their deaths, VTE recurrence, and bleeding events. After peaking 2009, the number of IVC filter implantation gradually decreased. During observational period, there were 158 patients with not-retrieval IVC filters (the overall retrieval rate of 19.0%). The not-retrieval group included significantly older and more patients with cancer compared to the retrieval group. Anticoagulation therapy was continued in 88% of the not-retrieval group. During a mean follow-up of 5.0 years, 6 symptomatic DVT events associated with inadequate control of anticoagulation and 13 bleeding events were observed. A total of 52 patients died and only the presence of cancer was prognostic risk factor. Although long-term anticoagulation therapy may be associated with bleeding events, there were few recurrent VTE under optimal anticoagulation. It is anticipated that even if the IVC filter cannot be retrieved, appropriate anticoagulation is useful for prevention of DVT recurrence despite the risk of bleeding.

Incidence and Risk Factors of Future Need for Long-Term Care Insurance in Japanese Elderly Patients With Left Ventricular Systolic Dysfunction.

BACKGROUND: Heart failure in elderly people causes physical and cognitive dysfunction and often requires long-term care insurance (LTCI); however, among patients with left ventricular (LV) systolic dysfunction, the incidence and risk factors of future LTCI requirements need to be elucidated.Methods and Results:The study included 1,852 patients aged ≥65 years with an echocardiographic LV ejection fraction (LVEF) ≤50%; we referred to their LTCI data and those of 113,038 community-dwelling elderly people. During a mean 1.7-year period, 332 patients newly required LTCI (incidence 10.7 per 100 person-years); the incidence was significantly higher than that for the community-dwelling people (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.32-1.64). On multivariate analysis, the risk factors at the time of echocardiography leading to future LTCI requirement were atrial fibrillation (HR, 1.588; 95% CI, 1.279-1.971), history of stroke (HR, 2.02; 95% CI, 1.583-2.576), osteoporosis (HR, 1.738; 95% CI, 1.253-2.41), dementia (HR, 2.804; 95% CI, 2.075-3.789), hypnotics (HR, 1.461; 95% CI, 1.148-1.859), and diuretics (HR, 1.417; 95% CI, 1.132-1.773); however, the LVEF was not a risk factor (HR, 0.997; 95% CI, 0.983-1.011). CONCLUSIONS: In elderly patients with LV systolic dysfunction, the incidence of LTCI requirement was more common than that for community-dwelling people; its risk factors did not include LVEF, but included many other non-cardiac comorbidities and therapies, suggesting the need for interdisciplinary cooperation to prevent disabilities.

[Risk Factors of Thromboembolism in Colorectal Cancer Patients Receiving Combination Chemotherapy with Bevacizumab].

We investigated the incidence of thromboembolism in patients receiving combination chemotherapy with bevacizumab (BV)for colorectal cancer and examined its association with clinical factors. Between July 2007 and April 2014, 250 patients with colorectal cancer received combination chemotherapy with BV. Thromboembolism occurred in 24 cases(9.6%). Five predictive risk factors(platelet count B350,000/µL, hemoglobin <10 g/dL, leukocyte count>11,000/mL, body mass index B25.3 kg/m2, and D-dimer B1.44 µg/mL)were set based on a previous report, and the corresponding number of risk factors for thromboembolism and incidence of thromboembolism were examined. The results of multivariate analysis showed that the occurrence of 3 or more risk factors conferred a significant risk for the incidence of thromboembolism. Due to the increased risk of developing thromboembolism in such patients, special attention during management is required.

The Impending Epidemic of Cardiovascular Diseases in Patients With Cancer in Japan.

Onco-cardiology, a new academic field, aims to improve the quality of life and prognosis of cancer patients and survivors with cardiovascular diseases (CVD). With the aging of the population, an epidemic of cancer with CVD is emerging in developed countries. Cancer and CVD share risk factors, pathophysiology, treatments, and preventive and rehabilitative measures. A multidisciplinary team-based approach is needed to support cancer treatment to maximize its effectiveness and minimize its cardiotoxic potential. Basic and clinical onco-cardiology are already being practiced harmoniously. However, systematization in academia and clinical practice and accumulation of evidence have just started. In this review, we present the epidemiology, common risk factors between cancer and CVD, future epidemic of CVD in patients with cancer, and the necessity for an onco-cardiological approach to managing the burden of CVD in cancer patients and survivors.

Correction to: Future projection of cancer patients with cardiovascular disease in Japan by the year 2039: a pilot study.

n the original publication, in a title of Table 2.

Future projection of cancer patients with cardiovascular disease in Japan by the year 2039: a pilot study.

BACKGROUND: The number of cancer patients in Japan is estimated to rise to 3.5 million by 2025. The disease burden may be further complicated by comorbidities caused by cardiovascular disease (CVD). Predicting the number of cancer patients with CVD can help anticipate future resource needs. METHODS: We used statistics derived from the Niigata Cancer Center CVD Study (2015) as well as population estimates from the National Cancer Center's Cancer Registry and Statistics survey of 2017 for convenience. We simply multiplied the projected number of cancer patients through the year 2039 by the CVD prevalence in 2015, with patients classified by sex, age, and cancer type to estimate the number of cancer patients with CVD. RESULTS: The total number of Japanese cancer patients with CVD was 253,000 in 2015 and is predicted to increase rapidly by 30,000 in 2020 and peak at 313,000 in 2030-2034. Men will dominate the CVD population at 2.5-fold the number of women. The growth rate of the population with both cancer and CVD will be greater than that of the cancer-only population (1.23 vs 1.18, P < 0.001), and will comprise notably high proportions of patients with prostatic, breast, and uterine cancers (1.80, 1.57, and 1.66, P < 0.001, respectively). CONCLUSION: Future cancer patients will be older and more likely to have CVD. Although men will continue to dominate this population, the increase in the number of women will be pronounced. Cancer care providers should be trained to recognize CVD and provide any necessary interventions concurrently with cancer therapy.

Successful Treatment of Acute Fulminant Eosinophilic Myocarditis in a Patient with Ulcerative Colitis Using Steroid Therapy and Percutaneous Cardiopulmonary Support.

A 47-year-old man with ulcerative colitis was transferred to our hospital due to progressive dyspnea. Electrocardiography on admission showed ST elevation in leads II, III, aVF, and V5-V6. Coronary angiography revealed no remarkable coronary stenosis, and left ventriculography showed a depressed left ventricular ejection fraction (EF) of 23%. Although the patient received percutaneous cardiopulmonary support, his EF progressively decreased (7-15%), and both ventricular tachycardia (VT) and high-degree atrial-ventricular block occurred. An endomyocardial biopsy showed eosinophilic infiltration in the myocardium. Steroid therapy improved the patient's EF. However, his severe inferior wall hypokinesis and non-sustained VT remained after the abovementioned treatment.

Burden of cardiovascular disease in Japanese cancer patients and survivors: a single cancer-center study in Niigata City.

BACKGROUND: Cardiovascular disease (CVD) and cancer are major causes of death in Japan. As most CVDs are chronic and often aggravate, long-term follow-up is necessary. Although some cancer patients and survivors have CVD, its prognostic significance and prevalence are unknown. Therefore, we conducted a retrospective study at our center to determine the prevalence of cancer patients with CVD. METHODS: In 2015, our 10-year (2005-2014) cancer registry was summarized. Comorbidities including left ventricular dysfunction, atrial fibrillation (AF), ischemic heart disease, aortic stenosis, venous thromboembolism (VTE), and elevation of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) were examined. RESULTS: In total, 26,235 de novo cancer patients were registered and 16,130 survived until January 1, 2015. The 5-year survival rate was 64.0% for all cancer patients and 44.2% for cancer patients with CVD. Cox proportional hazards analysis adjusting for age, cancer stage, and body mass index revealed that AF [hazard ratio (HR) 1.219, male; P = 0.038], VTE (HR 1.517, male; P = 0.003 and HR 2.089, female; P < 0.001), and NT-proBNP elevation (HR 1.861, female; P = 0.002) were significantly associated with death. The CVD prevalence among cancer survivors in 2015 was 8.7% vs 3.5% for males vs females. AF was the most common CVD (prevalence: male, 4.0%; female, 1.0%). The prevalence of most CVD in adults increased progressively with age, with male predominance (12.1% for male and 7.5% for female patients in the 80 s age group). CONCLUSIONS: One in 10 elderly cancer survivors has serious CVD. AF, VTE, and heart failure were critical comorbidities. Cardiologists and cancer-care providers should recognize CVD presence and monitor patients closely, providing medications or interventions concurrently with cancer therapy.

Prognosis of Cancer Patients with Aortic Stenosis Under Optimal Cancer Therapies and Conservative Cardiac Treatments.

Aortic stenosis (AS) is a life-threatening comorbidity of cancer patients. Aortic valve replacement (AVR) should be considered for some cancer patients, but neither the characteristics nor prognosis under conservative therapy is well known.We searched our echocardiography log (years 2005-2014) for cancer patients with AS, and 92 patients (54% female) were included in the study. To compare the survival curves, 470 control patients without AS were selected from our cancer registry.Mean age (± SD) was 77.6 ± 6.7 years for males and 81.6 ± 6.3 years for females. Mean aortic valve area (AVA) was 1.0 ± 0.3 cm2. Stomach, blood, and urinary bladder cancers were the major sites of current cancer. During the 5-year follow-up period, 44 patients with AS (48%) died; 26 (59%) due to cancer progression, 10 (23%) heart failure, and 4 (9%) stroke. Heart-failure death was significantly higher for patients with AS than for control patients (P < 0.001). Kaplan-Meier survival estimates were worse for stage I or II patients with AVA < 0.75 cm2 than for control patients (P = 0.016). Older age, advanced stages, absence of dyslipidemia, recent syncope, and chronic heart failure or AVA < 0.75 cm2 were significantly and independently associated with poor survival.Although the majority of cancer patients with AS died of cancer, a quarter died of heart failure. Careful follow-up is needed because cancer patients at earlier stages with symptomatic AS or AVA < 0.75 cm2 should be considered for AVR.

Characteristics of neoplastic cardiac tamponade and prognosis after pericardiocentesis: a single-center study of 113 consecutive cancer patients.

BACKGROUND: Neoplastic cardiac tamponade (NCT) is a life-threatening complication of cancer. The interval between cancer diagnosis and NCT onset and the prognosis after pericardiocentesis may differ according to cancer type. METHODS AND RESULTS: We performed a retrospective study of 113 patients (54 % male) with NCT who underwent pericardiocentesis at Niigata Cancer Center Hospital between 1992 and 2013. Mean age at NCT was 61.2 years (range 15.9-94.8 years). The most common underlying cancers were lung cancer (59.2 %), breast cancer (21.2 %), lymphoma/leukemia (5.3 %), and gastric/esophageal cancer (5.3 %). The median time from cancer diagnosis to NCT onset was 9.0, 60.4, 5.6, and 8.0 months for lung cancer, breast cancer, lymphoma/leukemia, and gastric/esophageal cancer, respectively. Kaplan-Meier survival estimates were worse for breast cancer patients with NCT than for matched breast cancer patients without NCT (P < 0.0001). Median survival time after pericardiocentesis was 2.9, 4.2, 2.3, and 0.6 months for lung cancer, breast cancer, lymphoma/leukemia, and gastric/esophageal cancer, respectively; one-year survival after pericardiocentesis was 6.0, 16.7, 33.3, and 0 %, respectively. CONCLUSIONS: The interval between cancer diagnosis and NCT onset, the impact of NCT on prognosis, and the prognosis after pericardiocentesis differed according to cancer type. Healthcare practitioners caring for patients with NCT should recognize the differences between cancer types and customize their care accordingly.

[Left atrial giant myxoma incidentally discovered during endoscopic ultrasonography; report of a case].

A 49-year-old female patient with a symptom of dysphagia underwent endoscopic ultrasonography (EUS) of the upper gastrointestinal tract, which incidentally revealed a tumor compressing the esophagus from outside. Transthoracic echocardiography performed after EUS showed a giant tumor in the left atrium. The tumor, measuring 75×68×43 mm, weighing 105 g was successfully removed, and pathologically diagnosed as myxoma. Her symptom disappeared completely. When performing clinical studies, it is important to pay every attention not to miss any abnormal findings beyond the scope of targeted areas. We also mentioned an ambiguity of the term," giant" regarding the size and weight of myxoma.

[Risk factors for cardiotoxicity during fluorouracil and cisplatin combination chemotherapy].

We investigated the incidence of cardiovascular symptoms in patients treated with fluorouracil and cisplatin (FP) combination chemotherapy. Between April 2010 and March 2011, 61 patients were treated with FP therapy at the Department of Gastroenterology, Niigata Prefectural Cancer Center Hospital. Within 1 week of treatment and within the first or second course of therapy, six patients developed chest pain. To investigate the risk factors for cardiotoxicity following FP therapy, patients were divided into cardiotoxicity incidence and non-incidence groups. The prevalence of diabetes, hypertension, and heart disease was not significantly different between the two groups. Furthermore, serum sodium and potassium levels were not altered following FP therapy. Therefore, no definitive risk factors for cardiotoxicity were identified. These results suggest that while FP chemotherapy-induced nausea, vomiting, and renal damage are serious adverse effects, further attention should also be paid to the potential cardiotoxic effects of FP therapy.

A case of chemoradiotherapy-associated cardiotoxicity that developed into acute heart failure with progressive subendocardial fibrosis.

We describe the case of a 61-year-old Japanese woman who developed acute heart failure 5 years after chemoradiotherapy for breast cancer. The patient received less than the cardiotoxic dose of docetaxel, epirubicin, cyclophosphamide, and fluorouracil and experienced no cardiovascular complications in the 5 years between the onset of chemoradiotherapy and the onset of acute heart failure. Cardiac catheterization was performed and elevation of end diastolic pressure of both ventricles was observed. Endomyocardial biopsy showed progressive replacement fibrosis in the subendocardium. Normal thickness of the right endocardium is <20 µm. Surprisingly, our patient had a fibrous subendocardium that was 100-200 µm thick. Ultrastructural abnormalities similar to those observed in anthracycline cardiotoxicity were evident on electron micrographs. This case report demonstrates the unique pathophysiology of heart failure in a patient who received less than the cardiotoxic dose of antineoplastic agents. Recent protocols have decreased the dosage of cardiotoxic agents; however, even these reduced doses might not be safe for all Japanese individuals and may cause subclinical cardiovascular damage and late-onset heart failure. Clinicians should monitor cancer survivors carefully, even if antineoplastic agents were administered under the cardiotoxic dose. .

Esophageal cancer with an esophagopericardial fistula and purulent pericarditis.

We herein present the case of a 56-year-old Japanese woman who developed purulent pericarditis after undergoing chemoradiotherapy for esophageal cancer. She developed epigastralgia and a fever and was admitted to our hospital. A physical examination revealed hypotension, tachycardia and pericardial friction rub. Echocardiography revealed moderate pericardial effusion. Based on these observations, the patient was diagnosed with cardiac tamponade. Computed tomography confirmed the presence of an esophagopericardial fistula. Treatment with pericardiocentesis, drainage and short-term intrapericardial administration of antibiotics relieved the patient's symptoms. Daily rinsing through a catheter with normal saline prevented relapse of the purulent pericarditis. Esophagopericardial fistulas are so rare that their treatment is not well-established. We herein report successful palliative care of a malignant esophagopericardial fistula associated with purulent pericarditis.

Aneurysm of the internal mammary artery with cystic medial degeneration.

We herein report the histopathology of a rare case of an idiopathic internal mammary artery aneurysm in a 61-year-old asymptomatic woman. Chest radiography during an annual medical check-up incidentally revealed the aneurysm, which was initially mistaken for a mediastinal tumor. Given that a rupture of the aneurysm could have been life-threatening, it was removed surgically, and found to possess a paper-thin arterial wall with cystic medial degeneration.

A case of epirubicin-associated cardiotoxicity progressing to life-threatening heart failure and splenic thromboembolism.

We present the case of a 42-year-old Japanese woman who developed acute heart failure after chemotherapy with epirubicin for breast cancer. Echocardiography revealed a cardiac dysfunction with left ventricular thrombus. Serial serum troponin T tests were positive over a 5-week period, and an endomyocardial biopsy demonstrated ultrastructural lesions which were similar to those caused by cardiotoxicities due to doxorubicin. Although the patient developed splenic thromboembolism, her cardiac function recovered gradually, and she regained full range of her activities. This case report demonstrates that epirubicin-associated cardiotoxicity causes life-threatening heart failure and supportive care is important until the patient recovers from acute intoxication.

Force-frequency relationship as a predictor of long-term prognosis in patients with heart diseases.

Adequate evaluation of the nature of the residual failing myocardium, as well as the severity of myocardial injury, is important for managing patients with heart failure. The aim of this study was to investigate the myocardial function and the prognosis of patients with heart diseases using the force-frequency relationship (FFR). We enrolled 76 patients with sinus rhythm who had miscellaneous heart diseases and performed incremental right atrial pacing at the time of diagnostic cardiac catheterization. The first derivatives of left ventricular pressure (dP/dt) were recorded using a micro manometer-tipped catheter during the study. To represent properties of FFR, two parameters-the peak force rate (PFR) and force gain (FG)-were estimated. PFR was defined as the heart rate at which dP/dt became maximum. FG was defined as the difference between dP/dt at PFR and dP/dt at the basal heart rate. FG decreased as the severity of left ventricular (LV) dysfunction increased (372.0 ± 110.7, 209.5 ± 29.1 and 116.3 ± 13.1 mmHg/s for normal LV function, mild LV dysfunction and severe LV dysfunction groups, P < 0.05, respectively). PFR correlated with cardiac index (r = 0.375, P = 0.001). FG correlated with LV end systolic volume index (r = -0.297, P = 0.010) and LV ejection fraction (r = 0.539, P < 0.001). Furthermore, pulmonary arterial wedge pressure [hazard ratio (HR) 1.126, P < 0.01] and FG (HR 0.992, P = 0.061) tended to be independent predictors for cardiovascular death. Analysis of FFR, especially FG, seems to be useful to evaluate the nature of the failing myocardium and the prognosis of patients with heart diseases.