Squamous metaplasia is an indicator of acute exacerbation in patients with usual interstitial pneumonia / idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbation (AE) is a potentially lethal event in patients with usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF). However, to date, no pathological predictors of AE have been identified. This retrospective study aimed to elucidate the pathological features that could predict AE in patients with UIP. METHODS: We reviewed the pathological findings of 91 patients with UIP/IPF and correlated these findings with AE events. Thirteen histological variables related to acute lung injury were evaluated by three independent observers and classified as positive or negative. The patients' clinical data during follow-up were collected and reviewed for AE. A recursive partition using the Gini index for the prediction of AE was performed, with each pathological finding as a candidate for branching. RESULTS: Twenty patients (22%) developed AE during the median follow-up duration of 40 months. Thirty-eight patients died (15 due to AE and 23 for other reasons). The median time interval from surgical lung biopsy to AE onset was 497 (interquartile range: 901-1657) days. Histologically, squamous metaplasia was positively associated with AE (odds ratio: 4.7, P = 0.015) and worse event-free survival in patients with UIP (P = 0.04). Leaf scoring based on the Gini index for recursive partition, including five positive findings (squamous metaplasia, neutrophilic infiltration, septal widening, Kuhn's hyaline, and fibrin), showed a sensitivity of 90% with a specificity of 74.7% (area under curve: 0.89). CONCLUSIONS: We found that squamous metaplasia is an important histopathological finding that predicts AE events and tends to unfavorable outcome in patients with UIP/IPF.

Focal Uptake in the Sternum on 18F-FDG-PET/CT Caused by G-CSF Therapy after Chemotherapy Mimicking Bone Metastasis of Breast Cancer.

A woman in her 70s was diagnosed with left breast cancer and left axillary lymph node metastasis by an ultrasound-guided biopsy. 18F-FDG-PET/CT showed strong FDG accumulation in the tumor in the left breast and a left axillary lymph node. Neoadjuvant chemotherapy (NAC) was administered in combination with a G-CSF injection to prevent febrile neutropenia. The post-treatment 18F-FDG-PET/CT showed the disappearance of the left breast tumor and left axillary lymph node and revealed a solitary new area of strong FDG accumulation in the sternum. To rule out the possibility of sternal metastasis, a sternal biopsy was performed at the same time as surgery, which revealed no malignant findings. Although very rare, focal uptake on 18F-FDG-PET/CT performed after anticancer drug therapy with G-CSF may mimic a solitary bone metastasis. A bone biopsy may be a useful technique to avoid an immediate misdiagnosis of bone metastasis.

[A Rapidly Growing Cardiac Calcified Amorphous Tumor in a Peritoneal Dialysis Patient:Report of a Case].

A calcified amorphous tumor( CAT) is a non-neoplastic cardiac tumor, which has been reported to be associated with hemodialysis dependent end-stage renal disease. We report a case of CAT attached to mitral annular calcification (MAC) in the posterior leaflet annulus of the mitral valve in a 56-year-old man who had been receiving peritoneal dialysis for three years. The CAT grew to 10 mm long in a half year. Peritoneal dialysis dependent end-stage renal disease is associated with MAC. Additionally, MAC-related CAT has been reported growing rapidly. We should perform periodic echocardiography not only for hemodialysis patients but also for peritoneal dialysis patients. When CAT is diagnosed, operation should be performed early to prevent embolism such as cerebral infarction.

[A Case of Recurrent Breast Cancer with Multiple Bone Metastasis Effectively Treated by CDK4/6 Inhibitor in Addition to Aromatase Inhibitor].

We report a case of recurrent breast cancer with multiple bone metastasis in a 62-year-old woman. Her breast cancer (invasive ductal carcinoma, T2N0M0, Stage ⅡA)was resected in 2001(partial mastectomy plus axillary lymph node dissection) with adjuvant chemotherapy(UFT)and irradiation to her left remnant breast. In February 2018, she complained of severe pain in right femoral joint and hip. CT scan showed a left cystic breast tumor(17 cm)and multiple bone metastasis. The core needle biopsy of the costal bone lesion and left mastectomy were performed. These pathological findings were recurrence of the breast cancer(ER+). The endocrine therapy(exemestane, aromatase inhibitor), the administration of denosumab and irradiation to painful bone lesions were performed, but it did not suppress tumor progression. The treatment of letrozole plus palbociclib(CDK4/6 inhibitor)were continued for 3 months from May 2018, and this therapy made her bone lesions smaller, but palbociclib were stopped due to its severe neutropenia. After that, the single administration of letrozole was continued, but the tumor marker did not become normal. In February 2019, abemaciclib was administered in addition to letrozole. One year later, her symptoms improved and her bone metastases have showed partial response.

[Assessment for Local Treatment for Elderly Breast Cancer Cases].

The number of elderly breast cancer patients has been increasing recently nevertheless the optimal treatment for the elderly breast cancer patients still remains controversial. In this study, 21 primary breast cancer cases who were equal or older than 85 years old at our hospital were examined their clinical and pathological features. These 21 cases were divided into 2 group; Group A; ten cases who received operations, Group B; eleven cases who did not receive operations. T categories, M categories and clinical stages in Group B were significantly higher than those of Group A. The main causing reason why Group B cases had not received operations was that their primary breast cancer were too advanced to perform operation. Instead of operation, most Group B cases received endocrine therapy or radiotherapy. Group A cases received standard operative procedures including partial or total mastectomy and biopsies or dissection of axillary lymph nodes. Besides, their post- operative courses were good and safe. These results suggest that even for elderly patients, early diagnosis and treatment could improve their prognosis and quality of life. In addition, careful surveillances for elderly breast cancer patients, those who tend to stop attending regular check up to their hospital, should be considered for further assessment for characteristics of elderly breast cancer patients.

[A Case of Ipsilateral Breast Cancer with Contralateral Axillary Node Recurrence after Right Breast Partial Mastectomy].

A female patient who was in her 50s visited our hospital complaining right breast tumor, 18 years after her right breast- conserving partial mastectomy with right axillary lymph nodes dissection. Ultrasonography revealed a right breast tumor and an enlarged lymph node at left axilla. Core needle biopsy(CNB)from the right breast tumor showed the recurrence of her breast cancer and fine-needle aspiration(FNA)from her left axillary lymph node showed Class Ⅴ. We concluded the recurrence of right breast cancer with left axillary metastasis. After neoadjuvant chemotherapy, she underwent right mastectomy and left axillary lymph node dissection. When the recurrence of residual breast is seen, the contralateral axillary lymph node might become a new sentinel lymph node.

Pharmacokinetic model of myocardial (99m)Tc-sestamibi washout.

OBJECTIVES: Technetium-99m sestamibi ((99m)Tc-MIBI) scintigraphy has been reported to be a functional imaging tool for in vivo detection of mitochondrial dysfunction in myocardium and multidrug resistance-associated protein expression in tumors. The purpose of this study was to propose a clinically applicable pharmacokinetic model with metabolic equilibrium of (99m)Tc-MIBI and to evaluate the accuracy of the model. METHODS: For this study, eight healthy men received (99m)Tc-MIBI scintigraphy. The planar images were obtained at 0.25, 0.5, 1, 2, 3, 4, 5, and 6 h after (99m)Tc-MIBI injection. The measured time series (99m)Tc-MIBI counts were fitted to our model by nonlinear regression analysis. The predictive performance of the model was determined by comparing the residuals between measured and predicted values. RESULTS: We obtained a good regression by fitting data from 0.25 to 6 h after (99m)Tc-MIBI injection, with excellent correlation between measured and predicted (99m)Tc-MIBI counts (R(2) = 0.9792) and a slope near unity. The 95% confidence interval of the mean prediction error included 0, which means that the prediction was not significantly biased. The precision of the prediction was also excellent. CONCLUSIONS: Our model shows good predictive capacity, with favorable bias and accuracy. By comparing the predictive values of this model with measured values, mitochondrial (99m)Tc-MIBI washout can be quantified. (99m)Tc-MIBI washout rates are reported to be a promising method for evaluating cardiac function in patients with cardiac diseases and P-glycoprotein expression in tumor cells. Therefore, this quantification could be useful for mitochondrial functional imaging, especially in patients with cardiac diseases or tumors.

The impact of adenosine pharmacologic stress combined with low-level exercise in patients undergoing myocardial perfusion imaging (BIWAKO adenosine-Ex trial).

BACKGROUND: The combination of adenosine infusion with low-level exercise has become a common approach for inducing stress during stress myocardial perfusion imaging (MPI). We investigated stress MPI performed by combined low-level exercise and adenosine infusion. This combined protocol can decrease adverse reactions and reduce the effect of scattered rays from the liver. METHODS AND RESULTS: Subjects were clinically referred for a 53-min rest-stress Tc-99m Sestamibi MPI procedure using BIWAKO PROTOCOL. Ninety-eight patients (44.5%) underwent adenosine infusion with ergometer exercise testing and 122 patients (55.5%) underwent adenosine infusion without exercise testing. We evaluated the liver/heart (L/H) uptake ratio, background activity in the upper mediastinum, and adverse reactions. RESULTS: The L/H ratio and background activity were lower in the adenosine-exercise group than in the adenosine-non-exercise group (1.8 ± 0.54 vs. 2.1 ± 0.62, P < 0.0056; 43.1 ± 12.2 vs. 61.5 ± 15.4, P < 0.0001). The adenosine-exercise group had fewer adverse reactions than the adenosine-non-exercise group (11.2 vs. 19.7%). All of the adverse reactions were minor, with the exception of severe back pain in one case. The incidence of adverse reactions in our study was lower than that in previous studies for unknown reason. CONCLUSION: Adenosine infusion in combination with low-level exercise seems to result in higher-quality images and fewer adverse reactions than adenosine infusion without exercise. The combined protocol decreases adverse reactions and improves the quality of myocardial perfusion images by decreasing background activity.

[Evaluation of a New Protocol for Two-isotope (123)I-BMIPP/(99m)Tc-TF Single Photon Emission Computed Tomography (SPECT) to Detect Myocardial Damage within One Hour].

Objective The present study aimed at establishing a new protocol using both (99m)Tc-Tetrofosmin (TF) and (123)I-BMIPP SPECT to detect myocardial damage within one hour. Methods Initial (123)I-BMIPP SPECT was immediately followed by (99m)Tc-TF SPECT. The influence of (123)I scattered rays on (99m)Tc energy windows set at 15% and 10% were measured using an RH-2 phantom. Participants in the study were patients with heart diseases who had provided written informed consent to undergo the new protocol. The patients maintained the MONZEN position throughout the procedure and an injection syringe was attached to the left arm for (99m)Tc-TF injection during (123)I-BMIPP SPECT. Results & Discussion The phantom study showed only slight (123)I contamination of (99m)Tc at the 10% window setting. The new method separated the (123)I and (99m)Tc energy windows well and neither crosstalk nor scatter correction were needed. Images obtained from dual (simultaneous) acquisition were contaminated, whereas contamination and influence of scattered rays were absent in images obtained by use of the new protocol. These images were thus useful for clinical diagnosis. Conclusion The new protocol is more convenient for patients and might improve the efficiency of detecting myocardial damage.

New protocol of myocardial SPECT imaging with technetium-99m sestamibi for reducing the time interval between rest and adenosine stress phases.

We have developed a new protocol of myocardial perfusion-gated single-photon emission computed tomography (SPECT), by use of technetium-99m sestamibi (MIBI), in which SPECT imaging at rest followed by SPECT imaging after adenosine with low level ergometer stress can be conducted by use of the Monzen position within a shortened total testing time of 1 h or less. The study group consisted of 137 patients who underwent this new imaging protocol. The diagnostic quality of the images was as good as that of images obtained with the conventional method (30-60 min after the injection of MIBI). The SPECT image quality for the 137 patients was evaluated, and the percentages of images rated as excellent, good, fair, and poor were 65.3, 27.4, 5.8, and 1.5% for the rest image, and 68.2, 21.9, 8.4, and 1.5% for the stress image, respectively. The shortened total testing time reduced the physical and mental burden on the patient compared with that of conventional myocardial perfusion imaging. Because this technique allows us to perform rest and stress myocardial imaging within a short period, it is expected to be very useful in the clinical setting.

Mast cells play a critical role in the pathogenesis of viral myocarditis.

BACKGROUND: Mast cells are powerful producers of multiple cytokines and chemical mediators playing a pivotal role in the pathogenesis of various cardiovascular diseases. We examined the role of mast cells in murine models of heart failure due to viral myocarditis, using 2 strains of mast cell-deficient mice. METHODS AND RESULTS: Two strains of mast cell-deficient mice, WBB6F1-Kit(W)/Kit(W-v) (W/W(V)) and WCB6F1-Kitl(Sl)/Kitl(Sl-d) (Sl/Sl(d)), were inoculated with 10 plaque-forming units of the encephalomyocarditis virus intraperitoneally. On day 14 after inoculation, survival of W/W(V) mice was significantly higher than that of their control littermates (77% versus 31%; P=0.03; n=13). On histological examination on day 7, myocardial necrosis and cellular infiltration were significantly less pronounced in W/W(V) and Sl/Sl(d) mice than in their control littermates (area of infiltration, 7.6+/-3.5% versus 29.3+/-15.6%; P=0.002; area of necrosis, 7.6+/-3.5% versus 30.0+/-17.2%; P=0.003; n=10). Histological examination showed more severe changes in mast cell-reconstituted than in -nonreconstituted W/W(V) and Sl/Sl(d) mice. The gene expressions of mast cell proteases were upregulated in the acute phase of viral myocarditis and rose further in the subacute phase of heart failure. Their activation coincided with the development of myocardial necrosis and fibrosis and correlated with the upregulation of gene expression of matrix metalloproteinase-9. The histamine H1-receptor antagonist bepotastine improved encephalomyocarditis viral myocarditis. CONCLUSIONS: These observations suggest that mast cells participate in the acute inflammatory reaction and the onset of ventricular remodeling associated with acute viral myocarditis and that the inhibition of their function may be therapeutic in this disease.

Reduction of infracardiac intestinal activity by a small amount of soda water in technetium-99m tetrofosmin myocardial perfusion scintigraphy with adenosine stress.

BACKGROUND: In technetium (Tc)-99m myocardial perfusion imaging (MPI), intestinal activity often interferes with the assessment of myocardial perfusion of the inferior wall. We examined whether a small amount of soda water prevents intestinal activity and improves image quality of the inferior wall in Tc-99m tetrofosmin MPI. METHODS AND RESULTS: Ninety-five patients referred for 1-day rest/stress Tc-99m tetrofosmin MPI were assigned to one of two groups automatically, according to the date when they underwent MPI: the soda water group (n = 63) ingested 100 mL soda water just before image acquisition after adenosine stress, and the control group (n = 32) underwent no intervention. The frequency of intestinal activity was assessed visually on planar images. The inferior myocardial wall and the abdominal activity adjacent to the myocardium were assessed quantitatively on three different planar images during stress, and the mean inferior wall-to-abdomen (I/A) count ratio was calculated. The frequency of intestinal activity was 69.8% in the soda water group, and 90.6% in the control group (P = .038). The I/A count ratio was significantly higher in the soda water group than in the control group (1.98 +/- 0.51 vs 1.50 +/- 0.35, respectively, P < .0001, +/- SD). CONCLUSIONS: The intake of 100 mL of soda water improves intestinal activity and improves the image quality of the inferior wall.

Exploring a technique for reducing the influence of scattered rays from surrounding organs to the heart during myocardial perfusion scintigraphy with technetium-99m sestamibi and technetium-99m tetrofosmin.

We have devised a new position (Monzen position) which can suppress the influence of scattered rays from surrounding organs (liver, etc.) when conducting myocardial imaging. Unlike the conventional techniques, which require a waiting period of 30-60 minutes before imaging can be started after the infusion of technetium-99m sestamibi or technetium-99m tetrofosmin, this position allows single-photon emission tomography to be started about 5-10 minutes after the infusion of the tracer. Therefore, with this technique the total time required for imaging is reduced and consequently the physical and mental burden of the patient is also reduced. Furthermore, the number of patients who can receive this test at any facility can be increased. This position may also be applicable in myocardial scintigraphy using some other tracers.

Mast cell tryptase in mast cell granules enhances MCP-1 and interleukin-8 production in human endothelial cells.

OBJECTIVE: Recent studies have highlighted the pathogenetic importance of chronic inflammation in cardiovascular disorders such as congestive heart failure and atherosclerosis. Mast cells release a wide variety of immune mediators that may initiate inflammatory responses, whereas endothelial cells (ECs) play a prominent role in the pathogenesis of cardiovascular diseases by secreting cytokines. The purpose of this study was to clarify the role of mast cells as an activator of ECs. METHODS AND RESULTS: ECs harvested from human umbilical cord veins were stimulated with mast cell granules (MCGs) prepared from sonicated human leukemic mast cells. The supernatants and total RNA from cells were collected. Levels of interleukin (IL)-1beta, tumor necrosis factor-alpha, and granulocyte colony-stimulating factor remained unchanged up to 24 hours. In contrast, levels of monocyte chemoattractant protein-1 (MCP-1) and IL-8 increased significantly within 6 hours. Northern blot analysis revealed an increase in MCP-1 and IL-8 mRNA expression in MCG-treated ECs. Induction of these chemokines was attenuated by antitryptase neutralizing antibody. Furthermore, MCP-1 and IL-8 were induced in ECs by incubation with human mast cell tryptase, but not with chymase. CONCLUSIONS: These results indicate that the production of MCP-1 and IL-8 in ECs was induced by MCG and amplified by tryptase.

[Tumor microembolism presenting as characteristic patterns of pulmonary perfusion on lung scanning: a case report].

A 55-year-old man presented with tumor microembolism manifesting as characteristic patterns of pulmonary perfusion on lung scanning. He had a 2-week history of dyspnea and general fatigue. Echocardiography demonstrated right ventricular enlargement. Computed tomography of the chest was normal. Lung perfusion imaging showed multiple subsegmental peripheral defects, which were characteristic of tumor embolism. Ultrasonography and computed tomography of the abdomen revealed multiple enlargement of the lymph nodes. Upper gastrointestinal panendoscopy showed gastric cancer. At 10 days after admission, he suffered cardiac arrest and died despite resuscitative efforts. Histological examination revealed pulmonary arterial obstruction with tumor cells, and poorly differentiated adenocarcinoma in the stomach and lymph nodes. This case emphasizes the need to include tumor microembolism in the differential diagnosis of dyspnea, even if there is no evidence of an underlying malignant tumor.

Suppression of cytokines and nitric oxide production, and protection against lethal endotoxemia and viral myocarditis by a new NF-kappaB inhibitor.

BACKGROUND: Nuclear factor kappa B (NF-kappaB) is activated by several factors, which increase the inflammatory response, and this activation, in turn, leads to the expression of several genes such as cytokines, and may play an important role in cardiovascular diseases. AIMS: The aim of the study is to examine the effect of SUN C8079, a newly synthesized NF-kappaB inhibitor in vitro and in vivo. METHODS: We examined the effects of SUN C8079 on the transcriptional responses of NF-kappaB, on activation of NF-kappaB in electrophoretic mobility shift assay, and on the gene expressions of tumor necrosis factor (TNF)-alpha and iNOS. We also studied effects of SUN C8079 on lethal endotoxemia and viral myocarditis in mice. RESULTS: SUN C8079 inhibited the lipopolysaccharide (LPS)-induced expression of the genes of TNF-alpha and iNOS by inhibiting the activation of NF-kappaB in vitro. SUN C8079 inhibited the systemic release of TNF-alpha and improved mortality in LPS-treated mice. In addition to protecting mice against lethal endotoxemia, SUN C8079 prevented the development of myocarditis due to the encephalomyocarditis virus (EMCV), and inhibited the expressions of proinflammatory cytokines and the iNOS gene in cardiac tissues. CONCLUSION: These findings suggest that the activation of NF-kappaB plays an important role in the pathogenesis of endotoxemia and viral myocarditis, and that the NF-kappaB inhibitor, SUN C8079, may be therapeutic in these disorders.

Preformed angiotensin II is present in human mast cells.

PURPOSE: The density of mast cells increases in the myocardium of patients suffering from heart failure. However, their function remains unclear. In this study, preformed angiotensin II (ANG II), a potent growth factor, was found to be contained in, and released by, human mast cells. METHODS: The human mast cell line (HMC-1) was incubated with 0 to 10(-6) M calcitonin gene-related peptide (CGRP) or culture medium. The expression of renin-angiotensin system mRNA was examined using RT-PCR analysis. ELISA and immunohistochemistry with monoclonal antibody against human ANG II were performed to detect the presence of ANG II in HMC-1. The effect of CGRP on the expression of angiotensinogen mRNA was examined by quantitative RT-PCR analysis. RESULTS: Preformed ANG II was detected in a human mast cell line (HMC-1) which is a neoplastic cell line of mast cells by ELISA and immunohistochemistry. Presence of mRNA of angiotensinogen and renin was confirmed by polymerase chain reaction in HMC-1, while mRNA of angiotensin converting enzyme (ACE) was undetectable. Since myocardial mast cells are interfaced with nerve fibers and functionally associated with CGRP, the effect of CGRP on ANG II release from HMC-1 was examined. CGRP induced the release of ANG II and increased angiotensinogen mRNA in HMC-1. CONCLUSIONS: The presence of preformed ANG II and gene expression of the renin-angiotensin system were detected in human mast cells. The release and synthesis of ANG II in mast cells was regulated by CGRP.

Gene expression of cardiac mast cell chymase and tryptase in a murine model of heart failure caused by viral myocarditis.

This study examined the gene expression of mouse mast cell proteases to clarify their role in the pathophysiology of viral myocarditis. Male DBA/2 mice were inoculated intraperitoneally with the encephalomyocarditis virus and the gene expression of mast cell chymase, mouse mast cell protease (mMCP)-4 and -5, and tryptase, mMCP-6, matrix metalloproteinase (MMP)-9 and type-I procollagen was measured by real-time quantitative RT-PCR analysis. The gene expression of mMCP-4, -5 and -6 mRNA was increased at 5 days, and continued to increase to day 14, coinciding with a prominent inflammatory reaction and extensive myocardial necrosis and fibrosis. The gene expression of MMP-9 was also increased, and there was a significant correlation between upregulation of mast cell proteases and MMP-9. The gene expression of type-I procollagen was increased at 5 days and continued to increase to day 14, suggesting that a fibrotic process had already begun during the acute stage of viral myocarditis. These findings suggest that mast cell chymase and tryptase participate in the acute inflammation and remodeling process of viral myocarditis.

Evidence for a role of mast cells in the evolution to congestive heart failure.

Mast cells are believed to be involved in the pathophysiology of heart failure, but their precise role in the process is unknown. This study examined the role of mast cells in the progression of heart failure, using mast cell-deficient (WBB6F1-W/W(v)) mice and their congenic controls (wild-type [WT] mice). Systolic pressure overload was produced by banding of the abdominal aorta, and cardiac function was monitored over 15 wk. At 4 wk after aortic constriction, cardiac hypertrophy with preserved left ventricular performance (compensated hypertrophy) was observed in both W/W(v) and WT mice. Thereafter, left ventricular performance gradually decreased in WT mice, and pulmonary congestion became apparent at 15 wk (decompensated hypertrophy). In contrast, decompensation of cardiac function did not occur in W/W(v) mice; left ventricular performance was preserved throughout, and pulmonary congestion was not observed. Perivascular fibrosis and upregulation of mast cell chymase were all less apparent in W/W(v) mice. Treatment with tranilast, a mast cell-stabilizing agent, also prevented the evolution from compensated hypertrophy to heart failure. These observations suggest that mast cells play a critical role in the progression of heart failure. Stabilization of mast cells may represent a new approach in the management of heart failure.