BOD1L mediates chromatin binding and non-canonical function of H3K4 methyltransferase SETD1A.

The H3K4 methyltransferase SETD1A plays an essential role in both development and cancer. However, essential components involved in SETD1A chromatin binding remain unclear. Here, we discovered that BOD1L exhibits the highest correlated SETD1A co-dependency in human cancer cell lines. BOD1L knockout reduces leukemia cells in vitro and in vivo, and mimics the transcriptional profiles observed in SETD1A knockout cells. The loss of BOD1L immediately reduced SETD1A distribution at transcriptional start sites (TSS), induced transcriptional elongation defect, and increased the RNA polymerase II content at TSS; however, it did not reduce H3K4me3. The Shg1 domain of BOD1L has a DNA binding ability, and a tryptophan residue (W104) in the domain recruits SETD1A to chromatin through the association with SETD1A FLOS domain. In addition, the BOD1L-SETD1A complex associates with transcriptional regulators, including E2Fs. These results reveal that BOD1L mediates chromatin and SETD1A, and regulates the non-canonical function of SETD1A in transcription.

Cryo-EM structure of P-glycoprotein bound to triple elacridar inhibitor molecules.

P-glycoprotein (P-gp) is an ATP-binding cassette transporter known for its roles in expelling xenobiotic compounds from cells and contributing to cellular drug resistance through multidrug efflux. This mechanism is particularly problematic in cancer cells, where it diminishes the therapeutic efficacy of anticancer drugs. P-gp inhibitors, such as elacridar, have been developed to circumvent the decrease in drug efficacy due to P-gp efflux. An earlier study reported the cryo-EM structure of human P-gp-Fab (MRK-16) complex bound by two elacridar molecules, at a resolution of 3.6 Å. In this study, we have obtained a higher resolution (2.5 Å) structure of the P-gp- Fab (UIC2) complex bound by three elacridar molecules. This finding, which exposes a larger space for compound-binding sites than previously acknowledged, has significant implications for the development of more selective inhibitors and enhances our understanding of the compound recognition mechanism of P-gp.

Effect of previous infection with hepatitis B virus on the incidence of hepatocellular carcinoma after sustained virologic response in patients with chronic hepatitis C virus infection.

Previous infection with hepatitis B virus (HBV), which is assessed by HBV core antibody (HBcAb) or surface antibody (HBsAb) titres, has reportedly been associated with an increased risk of developing hepatocellular carcinoma (HCC). We investigated the influence of previous HBV infection on the incidence of HCC in patients with hepatitis C virus (HCV) infection who achieved eradication of HCV, that is sustained virologic response (SVR). Both HBcAb and HBsAb were measured in a total of 1214 patients with HCV infection who had not been coinfected with HBV, as determined by both negative HBs antigen and HBV DNA, and in whom SVR was confirmed. Patients were followed up for a median of 5.7 years, and the incidence of post-SVR HCC was compared based on HBcAb and/or HBsAb. In both univariate and multivariate analyses, the incidence of post-SVR HCC did not differ based on the presence of HBcAb or HBsAb. In conclusion, previous HBV infection has no impact on the incidence of HCC in patients with HCV after SVR.

Critical Role of Preoperative Hyperglycemia in Association with GFAT-1 Expression in Resected Pancreatic Cancer.

BACKGROUND: Hyperglycemia is involved in malignant transformation of pancreatic cancer via the hexosamine biosynthetic pathway (HBP). However, few studies have verified this mechanism based on clinical data. This study investigated the complementary effects of hyperglycemia and HBP on pancreatic cancer prognosis using detailed clinical data. METHODS: The study analyzed data of 477 patients with pancreatic cancer who underwent pancreatectomy between 2006 and 2020. The patients were divided into normoglycemia and hyperglycemia groups based on their HbA1c levels. Immunostaining for glutamine fructose-6-phosphate transaminase-1 (GFAT-1), the rate-limiting enzyme in HBP, CD4, CD8, and Foxp3, was performed to evaluate the association between survival outcomes, HBP, and local tumor immunity. RESULTS: Overall survival (OS) was significantly poorer in the hyperglycemia group than in the normoglycemia group (mean survival time [MST]: 35.0 vs. 47.9 months; p = 0.007). The patients in the hyperglycemia group with high GFAT-1 expression had significantly poorer OS than those with low GFAT-1 expression (MST, 49.0 vs. 27.6 months; p < 0.001). However, the prognosis did not differ significantly between the patients with high and low GFAT-1 expression in the normoglycemia group. In addition, the patients with hyperglycemia and high GFAT-1 expression had fewer CD4+ (p = 0.015) and CD8+ (p = 0.017) T cells and a lower CD8+/Foxp3+ ratio (p = 0.032) than those with hyperglycemia and low GFAT-1 expression. CONCLUSIONS: The patients with hyperglycemia and high GFAT-1 expression levels had an extremely poor prognosis. Furthermore, the tumors in these patients were characterized as immunologically cold tumors.

Clinical impact of carbonic anhydrase 9 expression on neoadjuvant chemoradiotherapy in pancreatic ductal adenocarcinoma.

BACKGROUND: PDAC cells upregulate carbonic anhydrase 9 (CA9) expression in order to survive in hypoxic tumor environments, which plays a key role in tumor progression. However, the relationship between CA9 expression and preoperative treatment has not been clarified. We evaluated the clinical impact of CA9 expression on the efficacy of neoadjuvant chemoradiotherapy (NACRT) in pancreatic ductal adenocarcinoma (PDAC). METHODS: We investigated CA9 expression in 273 surgical specimens and 20 serum samples obtained from patients with PDAC and evaluated their clinical outcomes. We analyzed the function of CA9 using human pancreatic cancer cell lines. RESULTS: CA9 was positively expressed in 36.2 % of patients who underwent NACRT, which was significantly lower than those who underwent upfront surgery (US) (58.9 %, p < 0.001). Interestingly, patients who were CA9-positive in the US group had a significantly poorer prognosis than that of those in the NACRT group (median survival time [MST], 21.5 months vs. 49.2 months, p < 0.001), while there was no significant difference between patients who were CA9-negative in the US and NACRT groups (MST, 45.8 months vs. 46.3 months, p = 0.357). Moreover, serum CA9 levels tended to correlate positively with CA9 expression in cancer tissues. In-vitro experiments demonstrated that CA9 expression was reduced after treatments with radiation and chemoradiation therapy (RT/CRT), and that CA9 knockdown suppressed the impact of RT/CRT on cancer cell proliferation. CONCLUSIONS: CA9 may act as a target molecule for RT/CRT, highlighting its clinical importance as a valuable biomarker for more stringent indications for NACRT.

Feasibility and efficacy of cell-free and concentrate ascites reinfusion therapy (CART) for advanced pancreatic cancer patients with massive malignant ascites.

BACKGROUND: The management of malignant ascites is critical for treating patients with advanced pancreatic cancer. The purpose of this study was to assess the safety of cell-free and concentrated ascites reinfusion therapy (CART) and its impact on the prognosis of patients with advanced pancreatic cancer who have massive malignant ascites. METHODS: This study analyzed 47 procedures in 29 patients who underwent CART for ascites caused by pancreatic cancer between 2015 and 2022. Among them, 7 patients who received chemotherapy following CART were classified as the chemotherapy group, while 22 patients without chemotherapy after CART were classified as the palliative care group. RESULTS: Among the 47 procedures, adverse events (AEs) were observed in 9 procedures (19 %). Grade 2 adverse events were observed only in one procedure, manifested as fever. There were no grade 3 or 4 AEs, nor were there any treatment-related deaths. The median survival time was 4.0 months in the chemotherapy group and 0.7 months in the palliative care group (p = 0.004). The albumin level in the chemotherapy group was significantly higher than that in the palliative care group. CONCLUSION: CART is feasible and might be the optimal option to enable prolonged use of chemotherapy to improve the prognosis for late-stage pancreatic cancer patients.

Impact of body mass index on the prognosis of unresectable HCC patients receiving first-line Lenvatinib or atezolizumab plus bevacizumab.

INTRODUCTION: Overweight is a negative prognostic factor in the general population in the long term. However, the role of body mass index (BMI) in the short-mid term in advanced tumours is unclear. The present analysis investigates the role of BMI weight classes in a large sample of patients affected by HCC and receiving atezolizumab plus bevacizumab or lenvatinib as first-line treatment. METHODS AND MATERIAL: The cohort included consecutive patients affected by BCLC-c and BCLC-B HCC patients from a multicenter international study group who received atezolizumab plus bevacizumab or lenvatinib as first-line therapy. Population was stratified according to the BMI in under-, over- and normal-weight according to the conventional thresholds. The primary objective of the study was to evaluate the prognostic and predictive impact of BMI in patients affected by advanced or intermediate HCC. Survival curves were estimated using the product-limit method of Kaplan-Meier. The role of stratification factors was analysed with log-rank tests. RESULTS: 1292 consecutive patients with HCC were analysed. 466 (36%) patients were treated with lenvatinib and 826 (64%) patients were treated with atezolizumab plus bevacizumab. In the atezolizumab plus bevacizumab arm, 510 (62%) patients were normal-weight, 52 (6%) underweight and 264 (32%) overweight. At the univariate analysis for OS, underweight patients had significantly shorter OS compared to normal-weight patients, whereas no differences were found between normal-weight versus overweight. Multivariate analysis confirmed that underweight patients had significantly shorter OS compared to normal-weight patients (HR: 1.7; 95% CI: 1.0-2.8; p = .0323). In the lenvatinib arm, 26 patients (5.6%) were categorized as underweight, 256 (54.9%) as normal-weight, and 184 (39.5%) as overweight. At the univariate analysis for OS, no significant differences were found between normal-weight versus underweight and between normal-weight versus overweight, which was confirmed at multivariate analysis. CONCLUSION: Our analysis highlighted a prognostic role of BMI in a cohort of patients with advanced HCC who received atezolizumab plus bevacizumab, while no prognostic role for low BMI was apparent in patients who received lenvatinib.

Clinical impact of atrial fibrillation progression in patients with heart failure with preserved ejection fraction: A report from the CHART-2 Study.

AIMS: Atrial fibrillation (AF) frequently coexists with heart failure with preserved ejection fraction (HFpEF), and clinical outcomes of patients with AF vary depending on its subtype. While AF progression, characterized by the transition from paroxysmal AF to persistent AF, is sometimes observed, the incidence and clinical impact of AF progression in patients with HFpEF remain to be explored. METHODS AND RESULTS: We enrolled patients with HFpEF and paroxysmal AF from the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study. AF progression was defined as the transition from paroxysmal AF to persistent AF. A total of 718 patients (median age: 72 years, 36% were female) were enrolled. For a median follow-up of 6.0 years (interquartile range: 3.0-10.2 years), AF progression occurred in 105 patients (14.6%), with a cumulative incidence of 16.7% at 10 years. In the multivariable Cox proportional hazards model, previous hospitalization for heart failure (hazard ratio [HR] 1.74, 95% confidence interval [CI] 1.16-2.60; P=0.007) and left atrial diameter (per 5-mm increase) (HR 1.37, 95% CI 1.20-1.55; P<0.001) were significantly associated with AF progression. Furthermore, AF progression was significantly linked to worsening heart failure (adjusted HR 1.68, 95% CI 1.18-2.40; P=0.004). Notably, 27 cases (26%) of worsening heart failure occurred within one year following AF progression. CONCLUSION: In patients with HFpEF, AF progression is significantly associated with adverse outcomes, particularly worsening heart failure. An increased risk is observed in the early phases following progression to persistent AF. REGISTRATION: ClinicalTrials.gov Identifier: NCT00418041.

Validation study of age-independent fibrosis score (Fibrosis-3 index) in patients with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIMS: Because the accuracy of the Fibrosis-4 (FIB-4) index for predicting liver fibrosis changes with age, the need for different cut-offs in various age groups has frequently been discussed. We developed the age-independent score, the Fibrosis-3 (FIB-3) index, and have shown its usefulness in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to validate the diagnostic ability of the FIB-3 index to predict fibrosis progression using a large new patient cohort. METHODS: The ability of the FIB-3 index to predict liver fibrosis was analyzed by comparing it with that of the FIB-4 index using data from 1398 patients with MASLD enrolled in the Asia-based clinical outcome NAFLD study. RESULTS: The areas under the receiver operating characteristic curves for predicting fibrosis stage F3 or higher were not different between the FIB-3 and FIB-4 indices in the entire cohort. Using the single ideal cut-offs of the indices (3.41 for FIB-3 index and 2.01 for FIB-4 index), the predictive accuracy of the FIB-3 index was not significantly different from that of the FIB-4 index among patients aged <60 years; however, the accuracy of the FIB-3 index was significantly higher than that of the FIB-4 index in those aged ≥60 years (0.645 and 0.529, respectively; p < 0.0001). CONCLUSION: The high ability of the FIB-3 index with a single cut-off to predict liver fibrosis in patients with MASLD was confirmed. The FIB-3 index could serve as a useful tool for assessing liver fibrosis regardless of age.

mADRES predicts hepatocellular carcinoma development in patients with hepatitis C virus who achieved sustained virological response.

BACKGROUND AND AIM: The study aims to develop a novel predictive model including the fibrosis (FIB)-3 index for hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C virus (HCV) who achieved sustained virological response (SVR) with direct-acting antiviral (DAA) therapy. METHODS: This study included 2529 patients in whom HCV was eradicated with DAA therapy. The after DAA recommendation for surveillance (ADRES) score, which is based on sex, FIB-4 index, and α-fetoprotein, was used to predict HCC development. We developed a modified ADRES (mADRES) score, in which the FIB-4 index was replaced by the FIB-3 index, and evaluated its usefulness in predicting HCC development compared with the ADRES score. RESULTS: In the training set (n = 1770), multivariate analysis with Cox proportional hazards modeling showed that male sex (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.48-3.01), FIB-3 index (HR, 1.36; 95% CI, 1.28-1.45), and α-fetoprotein (HR, 1.05; 95% CI, 1.03-1.07) are independently associated with HCC development. The incidence of HCC differed significantly by ADRES or mADRES score in multiple comparisons. Univariate Cox proportional hazards models showed that compared with the mADRES score 0 group, the HR for HCC development was 2.07 (95% CI, 1.02-4.19) for the mADRES score 1 group, 11.37 (95% CI, 5.80-22.27) for the mADRES score 2 group, and 21.95 (95% CI, 10.17-47.38) for the mADRES score 3 group. Similar results were obtained for mADRES score but not for ADRES score in the validation set (n = 759). CONCLUSION: The mADRES score is useful for predicting HCC development after SVR.

Comparison of six hepatocellular carcinoma prediction models in Japanese patients after sustained virologic response undergoing rigorous surveillance for hepatocellular carcinoma.

BACKGROUND AND AIM: While several predictive models for the development of hepatocellular carcinoma (HCC) have been proposed, including those for patients with chronic hepatitis C virus (HCV) infection who have achieved sustained virologic response (SVR), the best model may differ between regions. We compared the ability of six reported models to stratify the risk of post-SVR HCC in Japan, where rigorous surveillance and early detection of HCC is common. METHODS: A total of 6048 patients with no history of HCC who achieved SVR by oral direct-acting antiviral drugs were enrolled in this nationwide study. Patients continued HCC surveillance every 6 months after SVR. The incidence of post-SVR HCC was compared between risk groups using the aMAP score, FIB-4 index, Tahata model, GAF4 criteria, GES score, and ADRES score. RESULTS: During the observation period with a median duration of 4.0 years after SVR, post-SVR HCC developed in 332 patients (5.5%). All six models performed significantly at stratifying the incidence of HCC. However, Harrell's C-index was below 0.8 for all models (range, 0.660-0.748), indicating insufficient stratification ability. CONCLUSION: Although all six proposed models demonstrated a good ability to predict the development of post-SVR HCC, their ability to stratify the risk of post-SVRHCC was unsatisfactory. Further studies are necessary to identify the best model for assessing the risk of post-SVR HCC in regions where early detection of HCC is common.

Mortality in patients with chronic hepatitis B treated with tenofovir or entecavir: A multinational study.

BACKGROUND AND AIM: The benefits of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) in reducing the development of chronic hepatitis B (CHB)-related hepatocellular carcinoma remain controversial. Whether mortality rates differ between patients with CHB treated with ETV and those treated with TDF is unclear. METHODS: A total of 2542 patients with CHB treated with either ETV or TDF were recruited from a multinational cohort. A 1:1 propensity score matching was performed to balance the differences in baseline characteristics between the two patient groups. We aimed to compare the all-cause, liver-related, and non-liver-related mortality between patients receiving ETV and those receiving TDF. RESULTS: The annual incidence of all-cause mortality in the entire cohort was 1.0/100 person-years (follow-up, 15 757.5 person-years). Patients who received TDF were younger and had a higher body mass index, platelet count, hepatitis B virus deoxyribonucleic acid levels, and proportion of hepatitis B e-antigen seropositivity than those who received ETV. The factors associated with all-cause mortality were fibrosis-4 index > 6.5 (hazard ratio [HR]/confidence interval [CI]: 3.13/2.15-4.54, P < 0.001), age per year increase (HR/CI: 1.05/1.04-1.07, P < 0.001), alanine aminotransferase level per U/L increase (HR/CI: 0.997/0.996-0.999, P = 0.003), and γ-glutamyl transferase level per U/L increase (HR/CI: 1.002/1.001-1.003, P < 0.001). No significant difference in all-cause mortality was observed between the ETV and TDF groups (log-rank test, P = 0.69). After propensity score matching, no significant differences in all-cause, liver-related, or non-liver-related mortality were observed between the two groups. CONCLUSIONS: Long-term outcomes of all-cause mortality and liver-related and non-liver-related mortality did not differ between patients treated with ETV and those receiving TDF.

Predictability of noninvasive liver fibrosis score for cardiac events in patients with nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Patients with nonalcoholic fatty liver disease (NAFLD) have a higher risk of cardiac events. However, although the severity of liver fibrosis is related to worsening prognosis in patients with NAFLD, it is unclear whether the noninvasive liver fibrosis score has a predictive value for cardiac events. METHODS AND RESULTS: We evaluated 4071 patients with NAFLD diagnosed using ultrasonography. Liver fibrosis was assessed and divided into three groups based on the Fibrosis-4 (FIB4) index and NAFLD fibrosis score (NFS). The primary outcome of this study was major adverse cardiac events (MACE), including cardiac death, nonfatal myocardial infarction, and revascularization due to coronary artery disease. The median age of the evaluated patients was 61 (52-69) years, and 2201 (54.1%) were male. During the median follow-up period of 6.6 years, 179 (4.4%) patients experienced MACE. Kaplan-Meier survival analysis demonstrated that MACE increased progressively with the FIB4 index (log-rank, p < 0.001) and NFS (log-rank, p < 0.001). Multivariable analysis showed that the higher the FIB4 index, the higher the risk for MACE (low group as reference vs. intermediate group, hazard ratio [HR]: 1.860 [95% confidence interval (CI), 1.326-2.610; p < 0.001]; vs. high group, HR:3.325 [95% CI, 2.017-5.479; p < 0.001]), as well as NFS (low NFS group as reference vs. intermediate group, HR: 1.938 [95% CI, 1.391-2.699; p < 0.001]; vs. high group, HR: 3.492 [95% CI, 1.997-6.105; p < 0.001]). CONCLUSIONS: The FIB4 index and NFS are associated with the probability of MACE in patients with NAFLD. CLINICAL TRIALS: The study design was approved by the ethics review board of Ogaki Municipal Hospital (approval number: 20221124-12, registration date: November 28th, 2022). https://www.ogaki-mh.jp/chiken/kenkyu.html.

Outcomes of patients with cerebral microbleeds undergoing percutaneous coronary intervention and dual antiplatelet therapy.

INTRODUCTION: Cerebral microbleeds (CMBs) on brain magnetic resonance imaging (MRI) are predictive of intracerebral hemorrhage (ICH). However, the risk of ICH in patients with CMBs who undergo percutaneous coronary intervention (PCI) while receiving dual antiplatelet therapy (DAPT) is unclear. MATERIALS AND METHODS: We conducted a study on 329 consecutive patients with coronary artery disease who underwent PCI and were evaluated using a 3T MRI scanner. Based on T2*-weighted imaging, patients were classified into three groups: no CMBs, < 5 CMBs, or ≥ 5 CMBs. We determined the occurrence of ICH during follow-up. RESULTS: At least 1 CMB was found in 109 (33%) patients. The mean number of CMBs per patient was 2.9 ± 3.6. Among the 109 patients with CMBs, 16 (15%) had ≥ 5 CMBs. Coronary stent implantation was performed in 321 patients (98%). DAPT was prescribed for 325 patients (99%). During a mean follow-up period of 2.3 years (interquartile range, 1.9-2.5 years), ICH occurred in one patient (1.1%) with four CMBs. There were no significant differences in the incidence of ICH (0% vs. 1.1% vs. 0%; p = 0.28). However, the rate of DAPT at 6 months of follow-up was significantly lower in patients with ≥ 5 CMBs than in patients with no CMBs or < 5 CMBs (89% vs. 91% vs. 66%, p = 0.026). Furthermore, there were no significant differences in systemic blood pressure during follow-up (123 ± 16 vs. 125 ± 16 vs. 118 ± 11 mmHg; p = 0.40). CONCLUSION: Although a substantial number of patients who underwent PCI had cerebral microbleeds, at approximately two years of follow-up, intracerebral hemorrhage was very rare in our study population.

Evaluation of Atezolizumab Plus Bevacizumab Versus Modified Lenvatinib Therapy in Child-Pugh A Unresectable Hepatocellular Carcinoma.

Background/Aim: Atezolizumab/bevacizumab (Atez/BV) and lenvatinib (LEN) are the recommended first-line treatments for patients with unresectable hepatocellular carcinoma (HCC). Previous reports have suggested that the tolerability and therapeutic efficacy of LEN could be enhanced by modifying its administration method. Therefore, this study compared the efficacy and safety of Atez/BV, the standard LEN therapy (standard LEN), and modified LEN therapy (modified LEN). Patients and Methods: The overall survival (OS) and the rate of discontinuation due to adverse events (AEs) were compared between groups treated with Atez/BV (n=36), standard LEN (n=30), and modified LEN (n=11). Results: Discontinuation due to AEs was required in 22.2%, 23.3%, and 9.1% of patients in the Atez/BV, standard LEN, and modified LEN groups (p=0.485). The median OS for the Atez/BV, standard LEN, and modified LEN groups was 523 [95% confidence interval (CI)=163-818], 382 (95%CI=330-547), and 604 (95% CI=257-656) days, respectively (log-rank test, p=0.949). Conclusion: Atez/BV and the standard and modified LEN regimens showed comparable efficacy and safety.

Safety evaluation of lenvatinib treatment after atezolizumab plus bevacizumab therapy for patients with unresectable liver cancer: A comparison of lenvatinib as 1st­ or 2nd­line treatment.

Atezolizumab plus bevacizumab (Atez/BV) as first-line therapy and lenvatinib (LEN) as second-line therapy are the recommended treatments for patients with unresectable hepatocellular carcinoma. Adverse immune events caused by immune checkpoint inhibitors (such as Atez) generally only occur several months after administration; therefore, the potential influence of the first-line treatment on second-line treatment is not clear. The present study investigated the safety of second-line LEN treatment (2nd LEN) by comparing the adverse events (AEs) of 2nd LEN after first-line Atez/BV treatment for unresectable liver cancer, with those of first-line LEN treatment (1st LEN). Patients who received Atez/BV as first-line therapy and 2nd LEN, or those who received 1st LEN at Ogaki Municipal Hospital (Ogaki, Japan) between April 2018 and September 2023 were retrospectively evaluated for treatment duration and AEs. The median treatment duration for patients in the 1st LEN (n=39) and 2nd LEN (n=13) groups was 151.0 days [95% confidence interval (CI) 77-303 days] and 128.5 days (95% CI 68-270 days), respectively (P=0.385). A greater proportion of patients showed elevated aspartate aminotransferase/alanine aminotransferase levels in the 2nd LEN group (76.9%) compared with those in the 1st LEN group (46.2%) (P=0.016). Hypothyroidism was more common in those receiving 2nd LEN (46.2%) than 1st LEN (12.8%) (P=0.016). In addition, grade 1 (three patients) and grade 2 (three patients) hypothyroidism was observed in patients receiving 2nd LEN. For these six patients, during first-line Atez/BV treatment, four patients had grade 0 hypothyroidism and two patients had grade 1 hypothyroidism (P=0.025). In conclusion, patients receiving 2nd LEN after treatment with Atez/BV are at an increased risk of hypothyroidism.

A case report of refractory multivessel coronary spasm associated with hypereosinophilic syndrome: one cell, one disease?

Background: Hypereosinophilic syndrome (HES) is characterized by moderate to severe eosinophilia, exclusion of neoplastic or secondary origins of eosinophilia, and systemic involvement with end-organ damage. Coronary arteries can be affected to cause vasospastic angina (VSA); however, the association of the two diseases is not well recognized. Case summary: A 55-year-old woman who had a history of multiple allergic disease such as bronchial asthma and chronic sinusitis with nasal polyps was hospitalized due to attacks of chest pain at rest. During a spontaneous attack of chest pain, ECG revealed ST-segment elevation in the inferior leads and emergency coronary angiography showed focal spasms of the right and left anterior descending coronary arteries, both of which were relieved after intracoronary administration of nitroglycerine. She was diagnosed with VSA according to the Japanese Circulation Society guidelines. Despite conventional vasodilator therapies, her resting angina remained refractory. Laboratory findings were notable for moderate eosinophilia. A comprehensive evaluation to uncover the underlying cause of refractory VSA led to the diagnosis of HES, concomitant with eosinophilic pneumonia and eosinophilic chronic rhinosinusitis. Pericoronary inflammation by fat attenuation index (FAI) was increased in the proximal segment of the right coronary artery. Treatment was initiated with oral prednisolone at a starting dose of 30 mg/day. The response to treatment was rapid, with her symptoms disappearing and a regression of eosinophilia observed the following day. Discussion: Hypereosinophilic syndrome manifests with refractory VSA, and eosinophil-suppressing corticosteroid therapy proves effective in improving both conditions along with reduction of the pericoronary inflammation by FAI.

Prognostic significance of growth differentiation factor-15 across age in chronic heart failure.

AIMS: Growth differentiation factor-15 (GDF15), a cytokine in the transforming growth factor family, is up-regulated in stress and inflammatory conditions and is elevated in patients with heart failure (HF). However, the age-specific attributes and prognostic significance of GDF15 across age remain unknown in chronic HF (CHF). METHODS AND RESULTS: Serum levels of GDF15 were examined in 942 hypertensive patients (median 68 years) with CHF from the SUPPORT trial across the four age groups [under 50 (n = 73), 51-59 (n = 158), 60-69 (n = 296), and 70-79 years (n = 415)] and in the continuous spectrum. Clinical correlates of GDF15 were explored using the classic stepwise and LASSO (least absolute shrinkage and selection operator) regression approaches. Interaction terms with age were tested in the LASSO regression approach. The associations with the composite outcome of HF hospitalization or all-cause death were investigated across ages. Median GDF15 levels (pg/mL) increased along with aging, from 691 in under 50 years to 855 in 51-59 years, 1114 in 60-69 years, and 1516 in 70-79 years (trend P < 0.001). Age, sex, systolic blood pressure, history of diabetes, ischaemic heart disease, left ventricular (LV) end-systolic dimension, LV ejection fraction, estimated glomerular filtration rate, haemoglobin, N-terminal pro-brain natriuretic peptide (NT-proBNP), troponin, C-reactive protein, and the use of angiotensin-converting enzyme inhibitors, diuretics, and statins were mutually selected as clinical covariates of GDF15. The LASSO regression analysis identified significant interactions between age and the history of diabetes and NT-proBNP, with particularly robust associations in patients aged between 60 and 70 years. During the mean follow-up of 8.6 years, 474 composite endpoints of HF hospitalization or death occurred. GDF15 was associated with a higher risk of HF hospitalization or all-cause death [adjusted hazard ratio 1.84 (95% confidence interval 1.45-2.33)], with a particularly heightened risk in patients aged around 70 years (Pinteraction = 0.0008). The model with GDF15 on top of other established risk factors yielded marginally higher C-statistics compared with the model without GDF15 (0.803 and 0.796, P = 0.045). The additive value of GDF15 on top of other established risk factors appeared similar across ages. A universal cut-off value of 1400 pg/mL performed well in discriminating between those with and without HF hospitalization or death. CONCLUSIONS: Some clinical correlates of GDF15 have an interaction with age. GDF15 is an important determinant of cardiovascular endpoints, particularly in patients aged around 70 years. The additive value of GDF15 appeared consistent across ages, suggesting the use of a universal cut-off value.

Pathophysiology and diagnostic pathway of myocardial infarction with non-obstructive coronary arteries.

Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a heterogeneous and diverse disease entity, which accounts for about 6 % of all acute myocardial infarction (AMI) cases. In patients with chest pain and acute myocardial injury detected by a highly sensitive troponin assay, the absence of epicardial coronary stenosis of 50 % or greater on angiography leads to the working diagnosis of MINOCA. The updated JCS/CVIT/JCC 2023 Guideline described MINOCA as a new disease concept and recommended a multimodality approach to uncovering the underlying causes of MINOCA. Cardiac magnetic resonance (CMR) is useful in not only making a definite diagnosis of MINOCA, but also excluding non-ischemic causes that mimic AMI such as takotsubo cardiomyopathy and myocarditis. Meanwhile, intracoronary imaging, particularly optical coherence tomography (OCT), enables us to evaluate precisely intracoronary morphological alterations including plaque disruption and spontaneous coronary artery dissection which are not revealed by angiographic findings alone. Recent studies have shown that an initial workup with the combination of CMR and OCT could provide a definite diagnosis in a significant percentage of patients suspected of MINOCA. Consecutively, patients with inconclusive results of a series of CMR and OCT implementation are eligible for assessing the potential for coronary functional abnormalities or blood coagulopathy as another factor involved in the development of MINOCA. Although uncovering the pathogenesis of MINOCA might be essential for establishing an individualized treatment approach, significant knowledge gaps in terms of secondary prevention strategies for MINOCA focusing on the improvement of long-term prognosis remain to be overcome. In this review, we summarize our current understanding of MINOCA and highlight contemporary diagnostic approaches for patients with suspected MINOCA.

Optimal treatment conditions for low-intensity pulsed ultrasound therapy for Alzheimer's disease: applications from mice to humans.

PURPOSE: We previously developed a novel therapy with low-intensity pulsed ultrasound (LIPUS) that ameliorates cognitive decline through upregulation of endothelial nitric oxide synthase (eNOS) in mouse models of Alzheimer's disease (AD). In a randomized, double-blind, placebo-controlled pilot trial, we demonstrated that whole-brain LIPUS therapy is safe and tends to suppress the cognitive decline in early AD patients. We herein report the findings of our basic experiments that we performed for the pilot trial in order to apply whole-brain LIPUS therapy to humans, as well. METHODS: First, we examined the relationship between bone density/thickness and ultrasound transmittance using human temporal bone. Next, based on the results of ultrasound transmittance, we further examined mRNA expression of VEGF, FGF2, and eNOS in response to variable ultrasound frequencies, duty cycles, and sound pressures. RESULTS: There was a significant correlation between bone thickness and transmittance (1.0 MHz, P < 0.001), while there was no significant correlation between bone density and transmittance (1.0 MHz, P = 0.421). At a frequency of 0.5 MHz, the optimum duty cycle was considered to be up to 20%. When the tissue amplitude was in the range of 0.05-0.5 MPa, VEGF, FGF2, and eNOS were significantly upregulated by LIPUS. Thus, the conditions necessary for LIPUS therapy for the human brain were identified as sound pressure just below the probe 1.3 MPa (tissue amplitude 0.15 MPa), duty cycle 5%, and frequency 0.5 MHz. CONCLUSION: We successfully identified the optimal treatment conditions for LIPUS therapy for patients with AD.