The present study aimed to determine the usefulness of contrast-enhanced ultrasonography (CEUS) with Sonazoid in evaluating the therapeutic response to sorafenib for hepatocellular carcinoma (HCC). ...In total, 26 patients with advanced HCC who received sorafenib and were followed up by CEUS were enrolled in the present study. CEUS was performed prior to and within 2-4 weeks of treatment, and the images of the target lesion in the post-vascular phase with a re-injection method were analyzed. The presence (+) or absence (−) of intratumoral necrosis and the intratumoral vascular architecture on micro-flow imaging (MFI) were compared prior to and subsequent to treatment. Target lesions that exhibited non-enhancement after re-injection were considered to indicate intratumoral necrosis. The intratumoral vascular architecture was classified into three groups, as follows: Vd, the intratumoral vessels visually narrowed or decreased; Vnc, the vessels remained unchanged; and Vi, the vessels were thickened or increased. Survival curves were estimated using the Kaplan-Meier method and compared using the log rank test between the intratumoral necrosis (+) and (−) groups, and among the Vd, Vnc and Vi groups. P<0.05 was considered to indicate a statistically significant difference. The number of patients in the intratumoral necrosis (+) and (−) groups was 8 and 18 patients, respectively, and the median survival time (MST) was 7.2 months 95% confidence interval (CI), 2.2-12.2 and 9.5 months (95% CI, 5.1-13.8), respectively (P=0.44). The MFI findings were observed in 11 patients in the Vd group, 10 patients in the Vnc group and 5 patients in the Vi group. The MSTs in the Vd, Vnc and Vi groups were 15.6 months (95% CI, 5.0-23.3), 11.0 months (95% CI, 3.5-17.6) and 3.6 months (95% CI: 1.2-6.0), respectively. The P-value for the differences between the Vd and Vnc groups, Vd and Vi groups, and Vnc and Vi groups were 0.78, 0.016 and 0.047, respectively, which indicated that the survival time decreased significantly in the Vi group. Evaluation of intratumoral vascular architecture using MFI demonstrates promise for assessing the therapeutic response to sorafenib in patients with HCC.
Introduction
Bronchial thermoplasty (BT) is a bronchoscopic procedure that involves the delivery of thermal radiofrequency energy to the bronchial wall for treating severe asthma. It has been ...suggested that too many radiofrequency activations could induce serious adverse events (SAEs) at an early stage. We aimed to examine the number of radiofrequency activations at each session and early lung function changes from baseline to determine whether these are related to SAEs.
Methods
We retrospectively investigated 13 consecutive patients who underwent three sessions each of BT for severe asthma from February 2015 to January 2016. Lung function tests were performed on the day before and after each BT procedure. Since we compared the number of activations and lung function changes from baseline after each session, a total of 39 sessions were reviewed. The relationship between the number of radiofrequency activations and each lung function change from baseline was also examined by linear regression analysis.
Results
A total of 10 SAEs (4 of pneumonia, 3 of atelectasis, 2 of bronchial asthma exacerbation and 1 of hemoptysis) were observed following the 39 BT sessions. When we compared sessions with and without SAEs, there were no differences in the number of activations (mean ± SD, 71.5 ± 28.6 times in sessions with SAEs; 66.5 ± 25.1 times in sessions without SAEs;
p
= 0.772) and lung function changes (mean changes in FVC/%FVC/FEV
1
/%FEV
1
/%PEF from baseline; − 0.49 l/− 14.2%/− 0.36 l/− 11.7%/− 9.6% in sessions with SAEs; − 0.43 l/− 13.3%/− 0.34 l/− 12.1%/− 9.4% in sessions without SAEs;
p
> 0.05 for all the above). Increase in the number of activations correlated with decreased FEV
1
(
R
2
= 0.17,
p
= 0.0088) and %FEV
1
(
R
2
= 0.11,
p
= 0.0357).
Conclusions
Increase in the number of radiofrequency activations during BT is related to a decrease in FEV
1
and %FEV
1
from baseline. The number of radiofrequency activations, however, is not associated with SAEs after BT.
Background We aimed to clarify associations between prior anticoagulation and short- or long-term clinical outcomes in ischemic stroke or transient ischemic attack patients with nonvalvular atrial ...fibrillation. Methods and Results A total of 1189 ischemic stroke or transient ischemic attack patients with nonvalvular atrial fibrillation who were hospitalized within 7 days after onset were analyzed. Of these, 813 patients (68.4%) received no prior anticoagulation, 310 (26.1%) received prior warfarin treatment with an international normalized ratio ( INR ) <2 on admission, 28 (2.4%) received prior warfarin treatment with an INR ≥2 on admission, and the remaining 38 (3.2%) received prior direct oral anticoagulant treatment. Prior warfarin treatment was associated with a lower risk of death or disability at 3 months compared with no prior anticoagulation ( INR <2: adjusted odds ratio: 0.58; 95% CI, 0.42-0.81; P=0.001; INR ≥2: adjusted odds ratio: 0.40; 95% CI, 0.16-0.97; P=0.043) but was not associated with a lower risk of death or disability at 2 years. Prior warfarin treatment with an INR ≥2 on admission was associated with a higher risk of ischemic events within 2 years compared with no prior anticoagulation (adjusted hazard ratio: 2.94; 95% CI, 1.20-6.15; P=0.021). Conclusions Prior warfarin treatment was associated with a lower risk of death or disability at 3 months but was not associated with a lower risk of death or disability at 2 years in ischemic stroke or transient ischemic attack patients with nonvalvular atrial fibrillation. Prior warfarin treatment with an INR ≥2 on admission was associated with a higher risk of ischemic events within 2 years. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01581502.
Abstract
Background Esophageal squamous cell carcinoma (ESCC) develops in close association with a chronic exposure to heavy drinking and smoking, frequently in a metachronous manner, suggesting a ...strong field effect on ESCC carcinogenesis. However, it is poorly understood how the field effect promotes clonal evolution in esophageal mucosa to induce dysplasia, eventually leading to the development of ESCC.
Patients & Methods A total of 221 samples were obtained by multiple sampling from cancer tissues (n = 53) as well as dysplastic (n = 12) and non-dysplastic (n = 156) mucosae from 49 cancer-bearing patients and 2 high-risk and 10 healthy patients either by endoscopy or surgery with different sampling sizes (regular size: 4 - 8 mm2 and small size: 0.2 or 0.8 mm2). All the samples were subjected to whole exome (WES) (n = 99) and/or targeted-capture (TS) (n = 221) sequencing. Copy number alterations (CNAs) were also investigated using SNP array- or sequencing-based karyotyping.
Results WES and TS in regular size samples revealed clonal proliferation in most of the non-dysplastic samples (98%), although the number of accompanying mutations and their clone size were significantly lower compared to those in samples from cancer and dysplasia (respectively, P = 0.021 and P < 0.001). Non-dysplastic samples were most frequently accompanied by NOTCH1 mutations (75%), followed by TP53 mutations (50%). By contrast, cancer and dysplasia samples showed much lower frequencies of NOTCH1 mutations (19% and 66%), but instead characterized by higher frequency of TP53 mutations (100% and 92%), and CNAs (83% and 17%), especially those focally involving CCND1, CDKN2A, PIK3CA, and EGFR, respectively. Mutation signatures also differed significantly between samples from non-dysplastic mucosa, and cancer/dysplasia tissues; cancer/dysplasia samples exhibited an enhanced APOBEC-related and decreased transcription-coupled repair-related signatures, compared to non-dysplastic samples. In non-dysplasia samples, both NOTCH1 and TP53 mutations were significantly enriched in heavy drinkers compared to non- or occasional drinkers (p < 0.001 and p = 0.023, respectively). To decipher the clonal architecture in more detail, we also sequenced 58 samples collected from non-dysplastic mucosae with a smaller sampling size. Clonal proliferation was confirmed in all the samples analyzed; NOTCH1 and TP53 mutations were found in 79% and 55% of the samples, where 78% and 27% of the mutated area showed biallelic alteration, respectively.
Conclusions Clonal proliferation in non-cancer esophageal epithelia is quite common even in non- or occasional drinkers and could be extensive in heavy drinkers. NOTCH1 and TP53 mutations as well as CNAs play major roles in clonal evolution but may have differential impacts on esophageal carcinogenesis, where TP53 mutation and CNAs are likely to make major contributions possibly under the influence of a higher APOBEC activity.
Citation Format: Akira Yokoyama, Hiromichi Suzuki, Tetsuichi Yoshizato, Yuusuke Shiozawa, Yusuke Sato, Kosuke Aoki, Nobuyuki Kakiuchi, Yasuhide Takeuchi, Yoichi Fujii, Hideki Makishima, Kenichi Yoshida, Keisuke Kataoka, Yaichi Shiraishi, Masashi Sanada, Shigeru Tsunoda, Sachiko Minamiguchi, Satoru Miyano, Manabu Muto, Seishi Ogawa. Differential role of mutations in clonal evolution in esophageal mucosa at risk for cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1437. doi:10.1158/1538-7445.AM2017-1437
During the COVID-19 pandemic in 2020, an 81-year-old afebrile woman was transported to our institute at 44 minutes after she was found to have global aphasia and weakness of the right extremities. ...The onset time was unclear. CT showed an occlusion of the left middle cerebral artery without early ischemic changes. MRI revealed a negative fluid-attenuated inversion recovery (FLAIR) pattern, in which several small acute infarcts were seen in diffusion-weighted images with no corresponding hyperintensity lesions on FLAIR. Accordingly, intravenous thrombolysis with alteplase (0.6 mg/kg, the dose approved in Japan) was administered at 1,660 minutes after the last known well and 116 minutes after the symptom recognition. An immediate internal carotid angiogram showed severe stenosis at the distal end of the horizontal portion of the left middle cerebral artery. In the follow-up angiogram at 164 minutes after the symptom recognition, the stenotic lesion almost resolved with the restoration of quick and nearly complete antegrade flow. Her symptoms also resolved promptly. Although the use of MRI is recommended to be minimized in the emergency stroke management during the COVID-19 pandemic, MRI is occasionally mandatory for patient selection, such as cases with unclear onset to perform intravenous thrombolysis. The individualized protected code stroke is essential and must be well considered by each institute for diagnosing patients by selecting appropriate modalities.
During the COVID-19 pandemic in 2020, an 81-year-old afebrile woman was transported to our institute at 44 minutes after she was found to have global aphasia and weakness of the right extremities. ...The onset time was unclear. CT showed an occlusion of the left middle cerebral artery without early ischemic changes. MRI revealed a negative fluid-attenuated inversion recovery (FLAIR) pattern, in which several small acute infarcts were seen in diffusion-weighted images with no corresponding hyperintensity lesions on FLAIR. Accordingly, intravenous thrombolysis with alteplase (0.6 mg/kg, the dose approved in Japan) was administered at 1,660 minutes after the last known well and 116 minutes after the symptom recognition. An immediate internal carotid angiogram showed severe stenosis at the distal end of the horizontal portion of the left middle cerebral artery. In the follow-up angiogram at 164 minutes after the symptom recognition, the stenotic lesion almost resolved with the restoration of quick and nearly complete antegrade flow. Her symptoms also resolved promptly. Although the use of MRI is recommended to be minimized in the emergency stroke management during the COVID-19 pandemic, MRI is occasionally mandatory for patient selection, such as cases with unclear onset to perform intravenous thrombolysis. The individualized protected code stroke is essential and must be well considered by each institute for diagnosing patients by selecting appropriate modalities.
Recent genetic studies have revealed frequent and specific pathway mutations involving multiple components of the RNA splicing machinery in myelodysplasia. Among these, SRSF2 mutations are more ...prevalent in CMML subtype and are associated with poor prognosis. Mutations showed a prominent hotspot involving proline 95, causing either P95H, P95L, or P95 conversion. Comprehensive analysis in our large cohort of MDS revealed that SRSF2 mutations showed a significant trend to coexist with TET2, STAG2, ASXL1 and RUNX1 mutations, while being mutually exclusive with EZH2 mutations. On the other hand, the molecular mechanism by which SRSF2 mutations lead to myelodysplasia remains largely unknown.
To elucidate the role of SRSF2 mutations in the development of myelodysplasia, we generated a heterozygous conditional knock-in mouse model of Srsf2 P95H mutation and crossed them with Vav1-Cre transgenic mice. Srsf2 P95H mutant mice exhibited macrocytic anemia, otherwise no significant changes in total peripheral blood (PB) cell counts compared to wild-type mice at 8-15 weeks after birth. There was no significant difference in lineage composition as well as blood cell morphology between wild-type and mutant mice in both bone marrow (BM) and PB. Flow cytometry of BM cells showed significant decrease of the number of hematopoietic stem cells (HSCs) and multipotent progenitor cells defined as Lin-Sca-1+Kit+ (LSK) fractions in Srsf2 P95H mice compared to wild-type mice. On the other hand, there were no significant differences in the number of more differentiated progenitor cells including common myeloid progenitors (CMPs), granulocyte/macrophage lineage-restricted progenitors (GMPs), megakaryocyte/erythrocyte lineage-restricted progenitors (MEPs), and common lymphoid progenitors (CLPs) between Srsf2 P95H and wild-type mice. These observations suggested that heterozygous Srsf2 mutation led to deregulation of hematopoietic stem cells, which however, is not sufficient for the development of MDS.
We next performed noncompetitive transplantation experiments to assess the cell intrinsic effects of Srsf2 P95H mutations. In PB, decreased white blood cell counts and progressive anemia were observed in mutant mice, which were evident as early as one month after transplantation. Cytological analysis of PB revealed morphological abnormalities in mice reconstituted with Srsf2 mutated cells, including hypersegmentation in neutrophils and dysplasia in the erythroid lineage. Srsf2 mutant-reconstituted mice showed normo-to-hypercellular marrow, where abnormal megakaryocyte distribution adjacent to trabecular bone and erythroid dysplasia was observed. Flow cytometrical analysis revealed decreased numbers of HSCs, LSK fractions and CMPs, whereas there was no significant change in the number of MEPs, GMPs and CLPs in BM. The BM erythroid progenitors were decreased in mutant-reconstituted mice, whereas the mutant mice showed splenic erythropoiesis with increased erythroid progenitors, suggesting the presence of extramedullary hematopoiesis, which was not seen in wild-type Srsf2 transduced mice. These observations suggested that the Srsf2 mutation led to ineffective hematopoiesis and morphological abnormalities, which seemed to recapitulate the phenotype of MDS.
Subsequently, we assessed the reconstitution capacity of whole BM cells from Srsf2 mutant mice in competitive transplantation experiments. The donor chimerism of Srsf2 P95H-derived cells in PB was significantly lower than that of wild-type cells. At 4 months post transplantation, the chimerism of Srsf2 P95H-derived cells was remarkably lower than that of wild-type cells in the fractions of HSCs, MPPs, CMPs, MEPs, GMPs and CLPs in BM. Furthermore, the reduced donor chimerism for Srsf2 P95H mutants was recapitulated in secondary transplantation experiments.
In summary, our results demonstrated that heterozygous P95H mutation of Srsf2 led to deregulation of hematopoietic stem cells that was evident from reduced competitive repopulation and impaired hematopoietic differentiation. Whereas mice reconstituted with Srsf2 mutant BM cells developed MDS-like phenotype in non-competitive transplantation setting, Srsf2 mutation by itself does not seem to be sufficient to develop MDS without transplantation, raising the possibility that an additional genetic and/or epigenetic events was required for overt MDS phenotype.
No relevant conflicts of interest to declare.
Floating aortic arch thrombi —blood clots forming in an aorta without aneurysms or atherosclerosis —in a normal aorta are exceedingly rare. The etiology is unknown, and there are no guidelines for ...appropriate treatment strategies. We report a case of floating aortic arch thrombosis in a patient without coagulopathy that was treated surgically. As the mass could not be identified preoperatively as a tumor or thrombus, synthetic graft replacement was performed, allowing resection of the lesion site. Histopathological examination revealed erosion and fissures in the tunica intima of the aorta, which suggested vessel damage to the tunica intima as the cause.
The CyberKnife® is expected to be a novel local treatment for hepatocellular carcinoma (HCC), however, a long-term follow-up using dynamic computed tomography and magnetic resonance imaging is ...required to determine the effect of treatment in a number of the affected patients. Therefore, there is a requirement to evaluate procedures for early determination of the effect of CyberKnife treatment. The present study aimed to evaluate the changes in the hemodynamics of the tumors and the hepatic parenchyma surrounding the tumor prior to and following CyberKnife treatment for HCC. A total of 4 HCC patients were enrolled in this study. These patients underwent CyberKnife treatment and were evaluated by image analysis prior to and following treatment using contrast-enhanced ultrasonography (CEUS) with Sonazoid. CEUS was performed prior to treatment, at 2 and 4 weeks post-treatment, and every 4 weeks thereafter for as long as possible. The dynamics of the enhancement of the tumor and the hepatic parenchyma surrounding the tumor in the vascular phase, and the presence or absence of a hypoechoic area in the hepatic parenchyma surrounding the tumor in the post-vascular phase were assessed. Results showed that: i) In the patient with earlier changes, hemodynamic changes were evident in the tumor at 4 weeks and in the hepatic parenchyma surrounding the tumor at 2 weeks post-treatment, respectively; ii) the tumor showed hypoenhancement in all patients; and iii) with regard to findings in the hepatic parenchyma surrounding the tumor, strong hyperenhancement appeared in the vascular phase initially, followed by a hypoechoic area in the post-vascular phase. Evaluation of the hemodynamics of tumors and hepatic parenchyma surrounding the tumor using CEUS with Sonazoid may be therapeutically applicable, as it is less invasive than dynamic computed tomography (CT) and provides an early evaluation of the effectiveness of CyberKnife treatment.
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