Left atrial reservoir strain is a marker of atrial fibrotic remodeling in patients undergoing cardiovascular surgery: Analysis of gene expression.

Left atrial strain (LAS) measured by two-dimensional speckle tracking echocardiography (2DSTE) is considered to be a marker of LA structural remodeling, but it remains unsettled. We investigated the potential usefulness and clinical relevance of LAS to detect atrial remodeling including fibrosis by analyzing gene expression in cardiovascular surgery patients. Preoperative 2DSTE was performed in 131 patients (92 patients with sinus rhythm [SR] patients including paroxysmal AF [PAF], 39 atrial fibrillation [AF]) undergoing cardiovascular surgery. Atrial samples were obtained from the left atrial appendages, and mRNA expression level was analyzed by real-time reverse transcription polymerase chain reaction (RT-PCR) in 59 cases (24 PAF, 35 AF). Mean value of left atrial reservoir strain (mLASr) correlated with left atrial volume index (LAVI), and left atrial conduit strain (mLAScd). mLASr also correlated with left atrial contractile strain (mLASct) in SR patients including PAF. mLASr was significantly lower, and LAVI was higher, in the AF group, compared with SR patients including PAF. The expression of COL1A1 mRNA encoding collagen type I α1 significantly increased in AF patients (p = 0.031). mLASr negatively correlated with COL1A1 expression level, and multivariate regression analysis showed that mLASr was an independent predictor of atrial COL1A1 expression level, even after adjusting for age, sex, and BMI. But, neither mLAScd / mLASct nor LAVI (bp) correlated with COL1A1 gene expression. The expression level of COL1A1 mRNA strongly correlated with ECM-related genes (COL3A1, FN1). It also correlated ECM degradation-related genes (MMP2, TIMP1, and TIMP2), pro-fibrogenic cytokines (TGFB1 encoding TGFß1, END1, PDGFD, CTGF), oxidant stress-related genes (NOX2, NOX4), ACE, inflammation-related genes (NLRP, IL1B, MCP-1), and apoptosis (BAX). Among the fibrosis-related genes examined, univariable regression analysis showed that log (COL1A1) was associated with log (TGFB1) (adjusted R2 = 0.685, p<0.001), log (NOX4) (adjusted R2 = 0.622, p<0.001), log (NOX2) (adjusted R2 = 0.611, p<0.001), suggesting that TGFB1 and NOX4 was the potent independent determinants of COL1A1 expression level. mLASr negatively correlated with the ECM-related genes, and fibrosis-related gene expression level including TGFB1, NOX2, and NLRP3 in PAF patients. PAF patients with low mLASr had higher expression of the fibrosis-related gene expression, compared with those with high mLASr. These results suggest that LASr correlates with atrial COL1A1 gene expression associated with fibrosis-related gene expression. Patients with low LASr exhibit increased atrial fibrosis-related gene expression, even those with PAF, highlighting the utility of LAS as a marker for LA fibrosis in cardiovascular surgery patients.

Identification of a gene set that maintains tumorigenicity of the hepatocellular carcinoma cell line Li-7.

The identification and development of therapeutic targets in cancer stem cells that lead to tumor development, recurrence, metastasis, and drug resistance is an important goal in cancer research. The hepatocellular carcinoma cell line Li-7 contains functionally different types of cells. Cells with tumor-forming activity are enriched in cancer stem cell-like CD13+CD166- cells and this cell population gradually decreases during culture in conventional culture medium (RPMI1640 containing 10% fetal bovine serum). When Li-7 cells are cultured in mTeSR1, a medium developed for human pluripotent stem cells, CD13+CD166- cells, and their tumorigenicity is maintained. Here, we sought to identify the mechanisms of tumorigenicity in this sub-population. We compared gene expression profiles of CD13+CD166- cells with other cell sub-populations and identified nine overexpressed genes (ENPP2, SCGN, FGFR4, MCOLN3, KCNJ16, SMIM22, SMIM24, SERPINH1, and TMPRSS2) in CD13+CD166- cells. After transfer from mTeSR1 to RPMI1640 containing 10% fetal bovine serum, the expression of these nine genes decreased in Li-7 cells and they lost tumorigenicity. In contrast, when these genes of Li-7 cells were forcibly expressed in cultures using RPMI1640 containing 10% fetal bovine serum, Li-7 cells maintained tumorigenicity. A metabolome analysis using capillary electrophoresis-mass spectrometry showed that two metabolic pathways, "Alanine, aspartate and glutamate metabolism" and "Arginine biosynthesis" were activated in cancer stem-cell-like cells. Our analyses here showed potential therapeutic target genes and metabolites for treatment of cancer stem cells in hepatocellular carcinoma.

Gastric neuroendocrine carcinoma presenting complete durable response by nivolumab treatment for multiple metastases and radiotherapy to oligoprogressive metastasis.

Gastric neuroendocrine carcinomas (NEC) are highly aggressive cancer with dismal prognosis. Platinum-based chemotherapy is used as the first-line treatment for this entity. However, there are no established therapeutic guidelines for platinum-resistant gastric NEC. We herein report a patient with metastatic gastric NEC who achieved durable and complete response to nivolumab with radiotherapy for oligoprogressive metastasis. A 70-year-old male patient had recurrences of resected gastric NEC, involving the liver and lymph nodes. His disease became refractory to cisplatin and etoposide combination therapy, after which he was treated with nivolumab. All the tumors showed marked shrinkage. However, 1 year after starting nivolumab, one metastatic lesion of the liver began to enlarge, and radiotherapy was performed to the lesion. Thereafter, a complete response was obtained, which has been maintained without any treatment for the past 2 years.

Detection of left coronary ostial obstruction during transcatheter aortic valve replacement by coronary flow velocity measurement in the left main trunk by intraoperative transesophageal echocardiography.

BACKGROUND: Coronary obstruction is a rare but catastrophic complication of transcatheter aortic valve replacement (TAVR) and occurs mostly at the left coronary artery (LCA) ostium. However, some patients do not show any clinical findings, and thus, its detection is sometimes difficult. The peak diastolic flow velocity in left main coronary artery (LM) was reportedly increased in significant stenosis lesions. We evaluated the effectiveness of measuring blood flow velocities in LM by transesophageal echocardiography (TEE) for the detection of LCA ostial obstruction during a TAVR procedure. METHODS: A total of 1105 consecutive patients who underwent TAVR in Sendai Kousei Hospital between September 2014 and December 2020 were enrolled. The LM blood flow velocity was measured at pre- and post-valve implantation. RESULTS: Among the 1105 patients, 9 had LCA ostial obstruction. The peak LM blood flow velocity at post-TAVR [0.90 (0.39-1.15) vs. 0.37 (0.28-0.50) m/s; p = 0.0046) was significantly higher in 9 patients who had LCA ostial obstruction, compared with the remaining 1096 patients who had not (controls), although no significant difference was observed before the TAVR procedures between the two groups. The post- to pre-TAVR LM flow velocity ratio [2.26 (1.31-3.42) vs. 1.06 (0.82-1.36); p = 0.0030] was also significantly higher in patients with LCA obstruction, compared to the controls. Furthermore, the post- to pre-TAVR LM blood flow velocity ratio was >2.0 in all six hemodynamically stable patients with LCA obstruction, whereas <2.0 in all three patients with LCA obstruction who showed hemodynamic collapse at post-TAVR procedure. CONCLUSION: Coronary blood flow velocity in LM significantly increased in hemodynamically stable LCA obstruction patients. The intraprocedural TEE measurement of the LM flow velocities would be potentially useful to detect asymptomatic and hemodynamically stable LCA ostial obstruction.

Relationship between the serum GDF-15 concentration and muscle function in female patients receiving aortic valve replacement (TAVR, SAVR): Comparison with healthy elderly female subjects.

Purpose: Sarcopenia is closely associated with postoperative prognosis in patients undergoing cardiovascular surgery. Growth differentiation factor (GDF)-15 is involved in the pathogenesis of cardiovascular disease. We examined the relationship between the serum GDF-15 concentration and muscle function in patients receiving aortic valve replacement and healthy elderly subjects. Methods: Forty-three female patients undergoing aortic valve surgery (79.9 ± 6.4 years; transcatheter aortic valve replacement [TAVR] n = 19, conventional surgical aortic valve replacement [SAVR] n = 24) and 64 healthy elderly female subjects (75.9 ± 6.1 years) were included. Walking speed, grip strength, and skeletal muscle mass index (SMI) by a multifrequency bioelectrical impedance analyzer were measured to determine the presence of sarcopenia. Preoperative serum GDF-15 concentration was measured by enzyme-linked immunosorbent assay. Results: The GDF-15 level was higher in patients receiving aortic valve replacement than in healthy elderly subjects (aortic valve replacement: 1624 ± 1186 pg/mL vs. healthy: 955 ± 368 pg/mL, p < 0.001). Multivariate linear regression analysis showed that the serum GDF-15 level determined grip strength independently of the high-sensitivity C-reactive protein level and eGFR, even after adjusting for age (ß = -0.318, p = 0.025). Sarcopenia was found in 12.5% of healthy elderly subjects, 83.3% of patients with TAVR, and 64.3% of patients with SAVR. The GDF-15 concentration that defined sarcopenia was 1109 pg/mL in subjects including patients receiving aortic valve replacement. Conclusions: The preoperative serum GDF-15 concentration, which was higher in female patients receiving aortic valve replacement than in healthy elderly subjects, may be a serum marker of sarcopenia.

En face view of the transcatheter heart valve from deep right-anterior-oblique cranial position for coronary access after transcatheter aortic valve implantation: a case series.

BACKGROUND: Coronary access after transcatheter aortic valve implantation (TAVI) is challenging due to the changes in aortic geometry. The perpendicular (long-axis) view of the transcatheter heart valve (THV) is usually used as the primary fluoroscopic angle. However, it does not always provide sufficient information on the rotational axis needed for selective coronary ostia engagement. The en face (short-axis) view from the deep right-anterior-oblique cranial position gives us additional information about three-dimensional spatial relationship of the THV and coronary ostia. CASE SUMMARY: We present three cases of coronary access after TAVI. We were successful in the use of the 'en face' view along with the perpendicular view in these cases. DISCUSSION: The use of the en face view complements that of the perpendicular long-axis view since it allows the understanding of the three-dimensional spatial relationship of the THV and the coronary ostia during fluoroscopy and control of catheter manipulation in two directions (up/down for perpendicular and clockwise/counterclockwise for en face view). We believe that the en face view helps improve the technical success of coronary access after TAVI.

Systemic chemotherapy combined with anti-epidermal growth factor receptor antibody therapy for RAS wild-type appendiceal signet-ring cell carcinoma: a series of three cases.

The effect of anti-epidermal growth factor receptor (EGFR) antibody-containing chemotherapy on appendiceal signet-ring cell carcinoma (SRCC) remains unknown. Herein, we report three patients, diagnosed as having synchronous metastases, who underwent this treatment for unresectable appendiceal SRCC with RAS wild type. Cases 1, 2, and 3 received FOLFOX with panitumumab, FOLFOX with cetuximab, and FOLFIRI with cetuximab, respectively, and their progression-free survival were 6.2, 7.2, and 18.7 months, respectively. The subsequent anti-vascular endothelial growth factor antibody-containing therapy was ineffective, and their overall survival was 8.2, 11.4, and 22.9 months, respectively. The anti-EGFR antibody-containing chemotherapy showed moderate efficacy for appendiceal SRCC. Further studies including molecular analysis should be needed.

Percutaneous transhepatic obliteration-related procedures for isolated gastric varices: experience of three cases.

Percutaneous transhepatic obliteration (PTO) can facilitate antegrade embolization of variceal veins. We herein report three patients who underwent percutaneous transhepatic sclerotherapy (PTS) or percutaneous transportal outflow-vessel-occluded sclerotherapy (PTOS) for isolated gastric varices. PTS was performed in Cases 1 and 2, and PTOS was performed in Case 3. Technical success was achieved in all patients without a decline in liver function; however, lack of a therapeutic benefit with rupture of esophageal varices occurred in Case 3. Case 3 had a history of pylorus gastrectomy plus Billroth-I reconstruction for gastric cancer and multiple feeding veins existed. PTO-related procedures are good treatment options for isolated gastric varices, but clinicians should be aware of the risk of treatment failure, especially the cases which have multiple feeding veins.

A Durable Response after the Discontinuation of Nivolumab in an Advanced Gastric Cancer Patient.

A durable response after the discontinuation of immune checkpoint-inhibitor therapy has previously been reported in several cancers. We herein describe a patient with gastric cancer who maintained a durable response after the discontinuation of nivolumab. A 65-year-old man was treated with nivolumab as a sixth-line therapy for recurrent gastric cancer. After four cycles of nivolumab therapy, he showed a partial response. But the treatment was discontinued when two immune-related adverse events occurred after six cycles. Disease regression was sustained for approximately 2 years, without the re-administration of nivolumab. The characteristics leading to such responses are unclear, and further studies are warranted in this regard.

Effects of switching from clopidogrel to prasugrel at the chronic phase after coronary stenting on antiplatelet action and vascular endothelial function: Switch-Pras study.

Compared to clopidogrel, prasugrel has a lower incidence of ischemic events following percutaneous coronary intervention (PCI) because of an early reduction during the acute phase in P2Y12 reaction units (PRU). The objective of this study was to compare the antiplatelet effect and vascular endothelial function of both drugs during the chronic phase after PCI. Patients who had undergone PCI and were confirmed to have no restenosis by follow-up coronary angiography under dual anti-platelet therapy with clopidogrel (75 mg/day) and aspirin (100 mg/day) were randomized to either continue clopidogrel or switch to prasugrel (3.75 mg/day). At baseline, prior to randomization we determined the CYP2C19 genotype. At the baseline and 24 weeks after randomization, the P2Y12 reactivity unit (PRU) was measured using the VerifyNow™ P2Y12 assay. Endothelial function was evaluated by flow-mediated vasodilation (FMD) and reactive hyperemia peripheral arterial tonometry (RH-PAT), while and circulating CD34+/CD133+/CD45low progenitor cells were measured by flow cytometric analysis. Serum high-sensitivity C-reactive protein (hsCRP) level was also measured. The PRU was reduced significantly in the prasugrel group (P = 0.0008), especially in patients who were intermediate or poor metabolizers based on the CYP2C19 genotype (P < 0.0001). This reduction was not observed in the clopidogrel group. The number of CD34+/CD133+/CD45low cells increased in the clopidogrel group (P = 0.008), but not in the prasugrel group. The hsCRP, FMD and reactive hyperemia index measured by RH-PAT did not change in either group. Prasugrel is potentially better than clopidogrel for preventing thrombotic events, although clopidogrel may have an advantage over prasugrel in terms of preventing atherosclerotic events. Proper use of thienopyridine drugs based on the CYP2C19 genotype has promising clinical potential.

Phase Angle as an Indicator of Sarcopenia, Malnutrition, and Cachexia in Inpatients with Cardiovascular Diseases.

Malnutrition is associated with sarcopenia, cachexia, and prognosis. We investigated the usefulness of phase angle (PhA) as a marker of sarcopenia, cachexia, and malnutrition in 412 hospitalized patients with cardiovascular disease. We analyzed body composition with bioelectrical impedance analysis, and nutritional status such as controlling nutritional status (CONUT) score. Both skeletal muscle mass index (SMI) and PhA correlated with age, grip strength and knee extension strength (p < 0.0001) in both sexes. The SMI value correlated with CONUT score, Hb, and Alb in males. Phase angle also correlated with CONUT score, Hb, and Alb in males, and more strongly associated with these nutritional aspects. In females, PhA was correlated with Hb and Alb (p < 0.001). In both sexes, sarcopenia incidence was 31.6% and 32.4%; PhA cut-off in patients with sarcopenia was 4.55° and 4.25°; and cachexia incidence was 11.5% and 14.1%, respectively. The PhA cut-off in males with cachexia was 4.15°. Multivariate regression analysis showed that grip strength and brain natriuretic peptide (BNP) were independent determinants of SMI, whereas grip strength, BNP, and Hb were independent determinants of PhA. Thus, PhA appears to be a useful marker for sarcopenia, malnutrition, and cachexia in hospitalized patients with cardiovascular disease.

Mediastinal Neuroendocrine Carcinoma Slowly Growing for 8 Years after Surgical Resection of Esophageal Squamous Cell Carcinoma.

A 70-year-old woman was referred to our department due to a solitary mediastinal tumor which gradually grew near the site of anastomosis for 8 years after radical surgery of esophageal squamous cell carcinoma. It was difficult to distinguish the lymph node recurrence of esophageal cancer from another tumor of unknown primary origin. Endoscopic ultrasound-guided fine-needle aspiration was performed, and the tumor was diagnosed to be neuroendocrine carcinoma. She received concurrent chemoradiotherapy with etoposide plus cisplatin. After the completion of chemoradiotherapy, the tumor disappeared. A solitary growing tumor which develops after radical resection of cancer would be better to be examined histologically in order to make an accurate diagnosis and select the most appropriate treatment.

Inflammatory myofibroblastic tumor of ileum with intussusception in adult.

A 62-year-old man was referred to our department with suspected intussusception due to an ileal tumor. Tumor markers including soluble interleukin-2 receptor were not elevated. Contrast-enhanced computed tomography and color Doppler ultrasonography showed a distinct ileal tumor without intratumoral blood flow or surrounding lymphadenopathies. Retrograde single-balloon enteroscopy revealed a submucosal tumor in the ileum that was hard and ulcerated. Partial intestinal resection was performed, and the lesion was diagnosed as an inflammatory myofibroblastic tumor. The patient had no recurrence over 2 years without additional treatment after surgery. This rare tumor should be kept in mind as a cause of ileal intussusception in adult and a multidisciplinary approach is vital to characterize it.

A case of advanced gastric cancer showing HER2 positivity after chemotherapy.

A 63-year-old man had advanced poorly differentiated gastric adenocarcinoma with para-aortic lymph node metastases. No HER2 expression was observed in four endoscopic biopsies from the primary tumor. Tumors shrunk after S-1 with cisplatin treatment, and he underwent simple gastrectomy due to stenosis. Interestingly, HER2 diffusely overexpressed in the resected surgical specimen. His disease was stable with trastuzumab-containing therapy for 6.4 months. This case may suggest a selection of HER2-positive cells that were insensitive to the chemotherapy, and further study is needed for the change of intratumoral HER2 heterogeneity after chemotherapy.

A case report: Long-term complete response of metastatic hepatocellular carcinoma obtained after discontinuation of 2-month sorafenib monotherapy.

A 69-year-old woman who had a history of chronic hepatitis C, autoimmune hemolytic anemia and myelodysplastic syndrome was treated with sorafenib at a daily dose of 400 mg for HCC with multiple lung metastases. Nonetheless, elevated serum tumor markers further increased (alpha fetoprotein from 121,100 to 348,660 ng/ml and protein induced by vitamin K absence/antagonist-II from 3435 to 29,357 mAU/ml), and lung metastatic lesions on chest X-ray showed no improvement after 2 months of sorafenib treatment. Sorafenib was discontinued because of adverse events with diarrhea, fatigue, and severe anemia due to bleeding from stomach telangiectasia. Hand-foot syndrome was mild. Thereafter, the tumor markers rapidly decreased to almost normal range, and the lung and liver tumors markedly shrunk and disappeared without any other cancer treatments. Her tumors remained in complete remission for 17 months until an intrahepatic recurrence occurred. This unique course of metastatic HCC indicated that antitumor mechanisms other than the direct anticancer effect of sorafenib contributed to tumor shrinkage.