Biventricular function in preterm infants with patent ductus arteriosus ligation: A three-dimensional echocardiographic study.

BACKGROUND: The detailed hemodynamics after patent ductus arteriosus (PDA) ligation in preterm infants remain unknown. We aimed to clarify the effect of surgical ligation on left ventricular (LV) and right ventricular (RV) volume and function. METHODS: Echocardiography was performed in 41 preterm infants (median gestational age: 25 weeks) before and after PDA ligation. Global longitudinal strain was determined using three-dimensional speckle-tracking echocardiography. These values were compared with those in 36 preterm infants without PDA (non-PDA). RESULTS: Preoperatively, the PDA group had greater end-diastolic volume (EDV) and cardiac output (CO) in both ventricles, a higher LV ejection fraction (LVEF) (53% vs 44%) and LV global longitudinal strain, and a lower RVEF (47% vs 52%) than the non-PDA group. At 4-8 h postoperatively, the two groups had a similar LVEDV and RVEDV. However, the PDA group had a lower EF and CO in both ventricles than the non-PDA group. At 24-48 h postoperatively, the RVEF was increased, but the LVEF remained decreased, and LVCO was increased. CONCLUSIONS: PDA induces biventricular loading and functional abnormalities in preterm infants, and they dramatically change after surgery. Three-dimensional echocardiography may be beneficial to understand the status of both ventricles. IMPACT: Preterm infants are at high risk of hemodynamic compromise following a sudden change in loading conditions after PDA ligation. Three-dimensional echocardiography enables quantitative and serial evaluation of ventricular function and volume in preterm infants with PDA. PDA induces biventricular loading and functional abnormalities in preterm infants, and they dramatically change after surgery.

Impaired tumor immune response in metastatic tumors is a selective pressure for neutral evolution in CRC cases.

A Darwinian evolutionary shift occurs early in the neutral evolution of advanced colorectal carcinoma (CRC), and copy number aberrations (CNA) are essential in the transition from adenoma to carcinoma. In light of this primary evolution, we investigated the evolutionary principles of the genome that foster postoperative recurrence of CRC. CNA and neoantigens (NAG) were compared between early primary tumors with recurrence (CRCR) and early primary tumors without recurrence (precancerous and early; PCRC). We compared CNA, single nucleotide variance (SNV), RNA sequences, and T-cell receptor (TCR) repertoire between 9 primary and 10 metastatic sites from 10 CRCR cases. We found that NAG in primary sites were fewer in CRCR than in PCRC, while the arm level CNA were significantly higher in primary sites in CRCR than in PCRC. Further, a comparison of genomic aberrations of primary and metastatic conditions revealed no significant differences in CNA. The driver mutations in recurrence were the trunk of the evolutionary phylogenic tree from primary sites to recurrence sites. Notably, PD-1 and TIM3, T cell exhaustion-related molecules of the tumor immune response, were abundantly expressed in metastatic sites compared to primary sites along with the increased number of CD8 expressing cells. The postoperative recurrence-free survival period was only significantly associated with the NAG levels and TCR repertoire diversity in metastatic sites. Therefore, CNA with diminished NAG and diverse TCR repertoire in pre-metastatic sites may determine postoperative recurrence of CRC.

Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma.

BACKGROUND: Driver alterations may represent novel candidates for driver gene-guided therapy; however, intrahepatic cholangiocarcinoma (ICC) with multiple genomic aberrations makes them intractable. Therefore, the pathogenesis and metabolic changes of ICC need to be understood to develop new treatment strategies. We aimed to unravel the evolution of ICC and identify ICC-specific metabolic characteristics to investigate the metabolic pathway associated with ICC development using multiregional sampling to encompass the intra- and inter-tumoral heterogeneity. METHODS: We performed the genomic, transcriptomic, proteomic and metabolomic analysis of 39-77 ICC tumour samples and eleven normal samples. Further, we analysed their cell proliferation and viability. RESULTS: We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case exhibited neutral evolution, regardless of their tumour stage. Upregulation of BCAT1 and BCAT2 indicated the involvement of 'Val Leu Ile degradation pathway'. ICCs exhibit the accumulation of ubiquitous metabolites, such as branched-chain amino acids including valine, leucine, and isoleucine, to negatively affect cancer prognosis. We revealed that this metabolic pathway was almost ubiquitously altered in all cases with genomic diversity and might play important roles in tumour progression and overall survival. CONCLUSIONS: We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions.

Safety and immunogenicity of mRNA COVID-19 vaccine in inpatients with muscular dystrophy.

INTRODUCTION/AIMS: Due to muscular weakness and cardiopulmonary dysfunction, patients with muscular dystrophy (MD) have an increased risk of serious complications from coronavirus disease-2019 (COVID-19). Although vaccination is recommended, COVID-19 vaccination safety and immunogenicity in these patients are unknown. We investigated reaction frequency, post-vaccine antibody titers after two mRNA COVID-19 vaccine doses, and clinical predictors of antibody response among patients with MD. METHODS: We recruited 171 inpatients with MD receiving two BNT162b2 mRNA COVID-19 vaccine doses from seven hospitals. Blood samples were obtained from 53 inpatients before the first dose and 28 to 30 days after the second dose, and antibody titers were measured. RESULTS: Overall, 104 (60.8%) and 115 (67.6%) patients had side effects after the first and second doses, respectively. These were generally mild and self-limited. Multiple logistic regression analysis showed that a bedridden state was associated with reduced side effects (odds ratio [OR] = 0.29; 95% confidence interval [CI], 0.12 to 0.71). The antibody titers of all participants changed from negative to positive after two vaccine doses. The geometric mean titer (GMT) of the inpatients was 239 (95% CI, 159.3 to 358.7). Older age (relative risk [RR] = 0.97; 95% CI, 0.95 to 0.99) and bedridden state (RR = 0.27; 95% CI, 0.14 to 0.51) were associated with a lower antibody titer. Patients with myotonic dystrophy type 1 (DM1) had a lower GMT than patients with other MDs (RR = 0.42; 95% CI, 0.21 to 0.85). DISCUSSION: COVID-19 vaccination is safe and immunogenic in inpatients with MD. Patients with DM1 appear to have a poorer COVID-19 antibody response than those with other MDs.

Death of children with Down syndrome by gestational age and cause.

BACKGROUND: We often encounter preterm infants with Down syndrome (DS) who die in the neonatal intensive care unit (NICU). In this study, we examined survival until NICU discharge and assessed the developmental prognosis of preterm infants with DS. METHODS: We retrospectively reviewed 416 infants with DS hospitalized during the past 27 years at our NICU. RESULTS: Death occurred in 8/20 (40%) infants at <32 weeks' gestation, 11/23 (48%) at 32-33 weeks, 9/99 (9%) at 34-36 weeks, and 9/274 (3%) at >36 weeks. In total, 84% of infants who died and 25% of those who survived had a non-reassuring fetal status (p < 0.001). Sex, small-for-gestational-age status, and postnatal transport were not associated with death. The main causes of death were bronchopulmonary dysplasia in 4/8 (50%) infants at <32 weeks' gestation, transient abnormal myelopoiesis in 11/20 (55%) and lymphatic dysplasia in 6/20 (30%) at 32-36 weeks, and varied causes at >36 weeks. Among survivors born at <34 weeks' gestation, 6/19 (32%) aged >2 years had moderate or severe cerebral palsy. CONCLUSIONS: These data on the high mortality and morbidity of preterm infants with DS may be useful for patient treatment and parent counseling in NICUs treating critically ill infants. IMPACT: Most infants with Down syndrome born at <34 weeks' gestation are born by cesarean section because of the non-reassuring fetal status. The mortality rate before discharge for infants with Down syndrome born at <34 weeks' gestation was 40%, and 30% of survivors developed moderate or severe cerebral palsy. The risk of death due to bronchopulmonary dysplasia and pulmonary hypertension was high in very preterm infants with Down syndrome despite the absence of chorioamnionitis. Infants with Down syndrome were born 1-2 weeks earlier than unaffected controls.

Right to left ventricular volume ratio is associated with mortality in congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is associated with high neonatal mortality. We performed this study to test the hypothesis that left ventricular (LV) and right ventricular (RV) volumes assessed by three-dimensional echocardiography may be associated with mortality in CDH. METHODS: This study was a single-center retrospective cohort study involving 35 infants with CDH. RV and LV end-diastolic volume (RVEDV and LVEDV, respectively) were measured by three-dimensional echocardiography and were corrected by birth body weight (BBW) on day 1. RVEDV/BBW, LVEDV/BBW, and LVEDV/RVEDV were compared between CDH survivors and non-survivors. Receiver-operating characteristic curve analysis was performed to assess the predictive ability for mortality of the echocardiographic parameters. RESULTS: Comparing CDH non-survivors (n = 6) with survivors (n = 29), respectively, RVEDV/BBW was significantly larger (2.54 ± 0.33 vs 1.86 ± 0.35 ml/kg; P < 0.01), LVEDV/BBW was significantly smaller (0.86 ± 0.21 vs 1.22 ± 0.33 ml/kg; P < 0.001), and LVEDV/RVEDV was significantly lower (0.34 ± 0.06 vs 0.66 ± 0.18; P < 0.001). The area under the curve for LVEDV/RVEDV was the largest (0.98). CONCLUSIONS: Three-dimensional echocardiographic volume imbalance between the RV and LV was remarkable in CDH non-survivors. The LVEDV/RVEDV ratio may be associated with mortality in CDH. IMPACT: Mortality with congenital diaphragmatic hernia (CDH) is high, and evaluating left and right ventricular structures and functions may be helpful in assessing the prognosis. Three-dimensional (3D) echocardiography indicated that the left ventricular end-diastolic volume/right ventricular end-diastolic volume ratio within 24 h after birth was associated with mortality in CDH infants. The usefulness of this ratio should be validated in prospective multicenter studies involving larger numbers of patients.

Use of ramucirumab for various treatment lines in real-world practice of patients with advanced hepatocellular carcinoma.

PURPOSE: Ramucirumab was shown to be effective as a second-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein levels > 400 ng/mL in a worldwide phase 3 trial. Ramucirumab is used in patients pretreated with various systemic therapies in clinical practice. We retrospectively examined the treatment outcomes of ramucirumab administered to advanced HCC patients after diverse systemic therapies. METHODS: Data were collected from patients with advanced HCC who received ramucirumab at three institutions in Japan. Radiological assessments were determined according to both Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and modified RECIST and the Common Terminology Criteria for Adverse Events version 5.0 was used to assess adverse events. RESULTS: A total of 37 patients treated with ramucirumab between June 2019 and March 2021 were included in the study. Ramucirumab was administered as second, third, fourth, and fifth-line treatment in 13 (35.1%), 14 (37.8%), eight (21.6%), and two (5.4%) patients, respectively. Most patients (29.7%) who received ramucirumab as a second-line therapy were pretreated with lenvatinib. We found grade 3 or higher adverse events only in seven patients and no significant changes in the albumin-bilirubin score during ramucirumab treatment in the present cohort. The median progression-free survival of patients treated with ramucirumab was 2.7 months (95% confidence interval, 1.6-7.3). CONCLUSION: Although ramucirumab is used for various lines of treatment other than second-line immediately after sorafenib, its safety and effectiveness were not significantly different from the findings of the REACH-2 trial.

Hyperprogressive disease during atezolizumab plus bevacizumab treatment in patients with advanced hepatocellular carcinoma from Japanese real-world practice.

BACKGROUND: Hyperprogressive disease (HPD) is a phenomenon with greatly accelerated tumor growth and clinical deterioration rates compared to pre-therapy, in patients treated with immune checkpoint inhibitors (ICI). The aim of this study is to clarify the reality of HPD in patients with advanced hepatocellular carcinoma (HCC) who were treated with atezolizumab plus bevacizumab (Atez/Bev) using tumor dynamics. METHODS: Medical records of consecutive patients with advanced HCC who were treated with Atez/Bev were retrospectively reviewed. HPD was defined as a more than two- or fourfold increase in tumor growth rate (TGR) or tumor growth kinetics rate (TGKR) before and after treatment. Overall survival (OS) and baseline characteristics with or without HPD were analyzed. RESULTS: A total of 85 patients were included in the analysis. When HPD was defined as a twofold of TGR or TGKR, 8 patients (8/85, 9.4%) had HPD and 11 had PD without HPD. A total of 5 patients (5/85, 5.9%) were diagnosed with HPD and 14 with PD without HPD when HPD was defined as a fourfold of TGR or TGKR. No significant difference was observed in the baseline characteristics between HPD and non-HPD. CONCLUSION: The prevalence of HPD in patients with advanced HCC treated with Atez/Bev was lower than those treated with nivolumab monotherapy. The HPD mechanism in ICI combined with antibodies targeting vascular endothelial growth factor (VEGF) remains to be elucidated.

Common Blood Test Indices for Predicting Transient Abnormal Myelopoiesis-Related Mortality in Infants with Down Syndrome.

Transient abnormal myelopoiesis (TAM) can cause early death in children with Down syndrome, and liver failure is the most common cause of death. The aim of this single-center retrospective study was to identify a quantitative index for predicting TAM-related mortality at the time of diagnosis. Of the 462 children with Down syndrome admitted to our hospital from 1992 to 2021, we studied 12 infants with TAM-related death and 31 survivors who were diagnosed with TAM. In the death and survival groups, the median gestational ages were 34.9 and 37.1 weeks, respectively (p = 0.12). At diagnosis, the white blood cell (WBC) counts were 99.2 and 36.2 × 109/L (p = 0.011), the hemoglobin concentrations were 131 and 159 g/L (p = 0.009), and the serum albumin concentrations were 23 and 31 g/L (p < 0.001), respectively. The areas under the receiver operating characteristic curve for the abilities of the WBC count, hemoglobin, and serum albumin at diagnosis to predict survival were 0.75, 0.76, and 0.85, respectively. The serum albumin concentration threshold of 28 g/L at diagnosis had sensitivity of 0.79 and specificity of 0.82. Gestational age and serum albumin concentration were entered into a logistic regression model. The serum albumin concentration was an independent indicator of TAM-related death (adjusted odds ratio, 0.78; 95% confidence interval, 0.65-0.93; p = 0.005). In conclusion, a low serum albumin concentration at diagnosis may be a good predictor of TAM-related death.

A diet-induced murine model for non-alcoholic fatty liver disease with obesity and insulin resistance that rapidly develops steatohepatitis and fibrosis.

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide. Patients with NAFLD often suffer steatohepatitis, which can progress to cirrhosis and hepatocellular carcinoma. The presence of visceral obesity or type 2 diabetes mellitus (T2DM) is a major risk factor and potential therapeutic target for NAFLD. The establishment of animal models with these metabolic comorbidities and with the rapid progression of the disease is needed for developing treatments for NAFLD but remains to be archived. In the present study, KK-Ay mice, widely used as T2DM models, or C57BL6 mice were fed a high-fat, high-fructose, and high-cholesterol diet supplemented with cholic acid (NAFLD diet). The KK-Ay mice fed a NAFLD diet exhibited remarkable obesity and insulin resistance. A prominent accumulation of triglycerides and cholesterol in the liver was observed at 4 weeks. These mice developed steatohepatitis at 4 weeks and fibrosis at 12 weeks. In contrast, C57BL6 mice fed a NAFLD diet remained lean, although they still developed steatohepatitis and fibrosis. In summary, we established a diet-induced murine NAFLD model with the rapid development of steatohepatitis and fibrosis, bearing obesity and insulin resistance. This model could be useful as preclinical models for drug development of NAFLD.

Changes in therapeutic options for hepatocellular carcinoma in Asia.

The incidence rate of hepatocellular carcinoma (HCC) is expected to increase, with most cases occurring in Asia. In some parts of Asia, the occurrence of HCC developing from metabolic-related liver disease has markedly increased in recent years, whereas the occurrence of HCC developing from viral-hepatitis-related liver disease has decreased. Advancements in the treatment of HCC over the past few decades has been remarkable, with most treatment strategies to remove or control liver tumours (hepatic resection, local ablation, radiation therapy, transarterial chemoembolisation, hepatic arterial infusion chemotherapy) primarily developing in Asia. In addition, recent progress in systemic therapies has prolonged the prognosis of advanced HCC. Nowadays, six regimens of systemic therapies have become available in most countries, according to phase III trials (atezolizumab plus bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab). In a global randomised phase III trial (IMbrave 150 trial), the most effective of the latest drug designs was newly emerged combination immunotherapy (atezolizumab plus bevacizumab), which has shown significantly prolonged overall survival compared with sorafenib, which was the first-line systemic therapy for more than a decade. Now, the treatment dynamics for HCC are undergoing a major transition as a result of two important changes: the replacement of viral-related HCC by metabolic-related HCC and the emergence of combination immune therapy.

Prostaglandin E-major urinary metabolite diagnoses mucosal healing in patients with ulcerative colitis in remission phase.

BACKGROUND AND AIM: Ulcerative colitis (UC) is usually detected by clinical symptoms, such as bleeding and diarrhea; however, it is rather difficult to assess during asymptomatic clinical remission (CR). Hence, there is a need for a biomarker that can reliably detect UC during remission. We previously reported on the utility of the prostaglandin E-major urinary metabolite (PGE-MUM) as a biomarker reflecting UC activity. In this study, we evaluated the effectiveness of the PGE-MUM in the diagnosis of endoscopic, histological, and histo-endoscopic mucosal remission of UC, comparing with fecal tests. METHODS: This prospective study was conducted at the Jikei University Hospital between August 2017 and January 2021. Patients with UC in CR scheduled to undergo colonoscopy were included. The association between the PGE-MUM with endoscopic remission (ER), histological remission (HR), and complete mucosal healing (CMH, defined as histo-endoscopic remission) was analyzed. We also compared the area under the curve (AUC) for the receiver operating characteristic curves between PGE-MUM, fecal calprotectin (FC), and fecal immunochemical test (FIT). RESULTS: In total, 128 patients were analyzed. PGE-MUM differed significantly in ER versus non-ER (14.5 vs 16.7, P = 0.028), HR versus non-HR (14.2 vs 17.4, P = 0.004), and CMH versus non-CMH (14.3 vs 16.7, P = 0.021). There were no significant differences between the AUCs for PGE-MUM, FC, and FIT for ER, HR, or CMH. CONCLUSIONS: The PGE-MUM can determine CMH in UC even during CR, regardless of the disease phenotype, indicating its clinical benefit for non-invasive monitoring.

Liver biopsy technique in the era of genomic cancer therapies: a single-center retrospective analysis.

BACKGROUND: With the evolution of personalized medicine in the field of oncology, which includes optimal treatment selection using next-generation sequencing-based companion diagnostic systems and tumor-agnostic treatments according to common biomarkers, a liver tumor biopsy technique that can obtain a sufficient specimen volume must be established. The current study aimed to evaluate the safety and availability of a liver tumor biopsy technique with multiple puncture sites made using a coaxial introducer needle and embolization with gelatin sponge particles. METHODS: Patients with primary or metastatic liver cancer who underwent liver tumor biopsies with puncture tract embolization using gelatin sponge (Spongel®) from October 2019 to September 2020 were included in the study. The complication and diagnostic rates were evaluated, and whether the specimen volume was sufficient for Foundation® CDx was investigated. RESULTS: In total, 96 patients were enrolled in this analysis. The median total number of puncture times per patient was 3 (range 1-8). The pathological diagnostic rate was 79.2%. Using the FoundationOne® CDx, specimens with a sufficient volume required for genomic medicine were collected in 84.9% of patients. The incidence rate of bleeding was 4.2% (n = 4), and only one patient presented with major bleeding requiring transfusion. CONCLUSIONS: Liver biopsy with puncture tract embolization using a gelatin sponge may be safe and effective for collecting specimens with a volume sufficient for modern cancer treatments.

Changes in regional oxygen saturation of the kidney and brain of infants during hospitalization.

BACKGROUND: In pre-term infants, the postnatal changes in the regional oxygen saturation (rSO2) of the brain and kidney are unclear. METHODS: We performed a prospective observational study. We measured the cerebral/renal rSO2 ratio and recorded the associated clinical features of infants born at 23 to 41 weeks of gestation weekly from the early postnatal period to discharge. RESULTS: The median cerebral/renal rSO2 ratios (interquartile ranges) between birth and the expected date of birth were 1.13 (1.06-1.26) at 23-24 weeks (n = 7), 1.18 (1.10-1.32) at 25-26 weeks (n = 11), 1.24 (1.11-1.37) at 27-28 weeks (n = 9), 1.12 (1.05-1.19) at 29-30 weeks (n = 4), 1.11 (1.03-1.15) at 31-32 weeks (n = 5), 1.02 (0.98-1.06) at 33-34 weeks (n = 9), 0.98 (0.94-1.06) at 35-36 weeks (n = 19), and 0.95 (0.86-0.99) at 37-41 weeks of gestation (n = 22). The median cerebral/renal rSO2 ratio did not significantly change after birth, but with increasing gestational age, the cerebral/renal rSO2 ratio at the expected date of birth decreased (r = - 0.74, p < 0.001). Nephrotoxic drugs did not affect cerebral/renal rSO2 at the expected date of birth, after adjustment for clinical factors. CONCLUSIONS: Unlike in most infants born after the late pre-term period, the renal rSO2 remained lower than the cerebral rSO2 on the expected date of birth in infants born very pre-term.

Acquisition of mesenchymal-like phenotypes and overproduction of angiogenic factors in lenvatinib-resistant hepatocellular carcinoma cells.

Lenvatinib is one of the first-line drugs for patients with advanced hepatocellular carcinoma (HCC) and widely used around the world. However, the mechanisms underlying resistance to lenvatinib remain unclear. In this study, we conducted characteristic analyses of lenvatinib-resistant HCC cells. Lenvatinib-resistant HCC cell lines were established by exposure to serially escalated doses of lenvatinib over 2 months. The biological characteristics of these cells were examined by in vitro assays. To investigate the cytokine profile of lenvatinib-resistant HCC cells, the supernatant derived from lenvatinib-resistant Huh7 cells was subjected to nitrocellulose membrane-based sandwich immunoassay. Both activation of the MAPK/MEK/ERK signaling pathway and upregulation of epithelial mesenchymal transition markers were observed in lenvatinib-resistant cells. Concordant with these findings, proliferation and invasion abilities were enhanced in these cells compared with control cells. Screening of a cytokine array spotted with 105 different antibodies to human cytokines enabled us to identify 16 upregulated cytokines in lenvatinib-resistant cells. Among them, 3 angiogenic cytokines: vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and angiogenin, were increased significantly. Conditioned medium from lenvatinib-resistant cells accelerated tube formation of human umbilical vein cells. In conclusion, lenvatinib-resistant HCC cells were characterized by enhanced proliferation and invasion abilities. These findings might contribute to the establishment of new combination therapies with lenvatinib.

A Broad Range High-Throughput Assay for Lenvatinib Using Ultra-High Performance Liquid Chromatography Coupled to Tandem Mass Spectrometry With Clinical Application in Patients With Hepatocellular Carcinoma.

BACKGROUND: Lenvatinib is increasingly being selected as the first-line treatment for unresectable hepatocellular carcinoma (HCC) based on the results of the REFLECT trial. However, early discontinuation of lenvatinib because of adverse effects is a frequent occurrence. Hence, lenvatinib is a difficult drug for use in the clinical setting. One of the causes is that the dose of lenvatinib is mainly determined by body weight alone, despite high interindividual variability. To overcome this problem, a dosing regimen of lenvatinib based on a population pharmacokinetic (PPK) model for HCC patients is proposed. The aim of this study was to develop a high-throughput quantification method for lenvatinib using ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) that can be applied to a PPK analysis of HCC patients in the future. METHODS: After a simple solid-phase extraction step using a 96-well plate, lenvatinib was analyzed by UHPLC-MS/MS in a positive electrospray ionization mode. RESULTS: The novel method fulfilled the requirements of the US Food and Drug Administration guidance on bioanalytical method validation. The calibration curve was linear over the 0.2-1000 ng/mL concentration range. The average recovery rate was 98.63 ± 4.55% (mean ± SD). The precision was below 6.05%, and the accuracy was within 12.96% for all quality control levels. The matrix effect varied between 103.33% and 134.61%. This assay was successfully applied to the measurement of plasma concentrations in 6 HCC patients receiving lenvatinib. CONCLUSIONS: A novel high-throughput UHPLC-MS/MS assay for quantification of lenvatinib in human plasma was successfully developed. This method can be applied to PPK analysis for patients receiving lenvatinib in the clinical setting.

Acute respiratory effect of transpyloric feeding for respiratory exacerbation in preterm infants.

OBJECTIVES: Gastroesophageal reflux may exacerbate chronic lung disease in preterm infants. We evaluated the short-term effects of transpyloric feeding on respiratory status in preterm infants during mechanical ventilation. METHODS: We retrospectively collected data from the hospital information management system. To evaluate the effect of transpyloric feeding on oxygenation, we compared changes in SpO2/FiO2 ratios before and after commencing transpyloric feeding by a piecewise linear regression model. RESULTS: We examined 33 infants (median gestational age, 25.4 weeks; median birth weight, 656 g) who underwent transpyloric feeding. All tubes were placed at the bedside without fluoroscopy. No cases of unsuccessful placement, gastroduodenal perforation, or tracheal misinsertion occurred. Transpyloric feeding began at a median age of 18 (interquartile range, 15-23) days. Mean SpO2/FiO2 (±SD) ratios were 391 (±49), 371 (±51), 365 (±56), and 366 (±53) 72-96 h before, 0-24 h before, 48-72 h after, and 96-120 h after starting transpyloric feeding, respectively. The rate of change per hour of SpO2/FiO2 ratios increased 48-120 h after compared with 0-96 h before transpyloric feeding (0.03 [95% confidence interval, -0.10 to 0.17] vs. -0.29 [-0.47 to -0.12]) (p=0.007). No apparent changes occurred in the mean airway pressure, amplitude pressure, or pCO2. CONCLUSIONS: Transpyloric feeding during mechanical ventilation can prevent the deterioration of oxygenation without major complications at the stage of respiratory exacerbation in preterm infants.

Sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a multicenter retrospective study in Japan.

Background Conversion from sorafenib to regorafenib is primarily an evidence-based treatment strategy in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the safety and efficacy of sequential therapy with sorafenib and regorafenib in patients with advanced HCC by analysis of outcomes in clinical practice with the aim to complement phase III findings. Methods The medical records of patients with advanced HCC receiving regorafenib were retrieved to collect data on sorafenib administration at seven Japanese institutions. Radiological responses and adverse events were evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Common Terminology Criteria for Adverse Events version 4.0, respectively. Results Before March 2018, 44 patients were administered regorafenib for advanced HCC. The median sorafenib treatment duration was 8.4 months. The most common adverse events were similar to those reported by the RESORCE trial. The median overall survival (OS) was 17.3 months (95% confidence interval [CI] 11.4-22.9), and 17 of 37 patients (45.9%) discontinued regorafenib and received sequential systemic therapy after regorafenib. These patients had significantly longer OS than those who were treated by the best supportive care or sub-optimal therapy (not reached versus 8.7 months [95% CI 5.8-11.7]; P < 0.001). Conclusion The results based on Japanese clinical practices verified the tolerability of regorafenib in advanced HCC. Major regorafenib-associated adverse events were similar to those related to sorafenib. OS was significantly longer than expected, which might be associated with the sequential systemic therapies after regorafenib, mainly lenvatinib.

Long-term administration of Tolvaptan to patients with decompensated cirrhosis.

Aim: Tolvaptan, an oral vasopressin-2 antagonist, sometimes improves hepatic edema including ascites in patients with decompensated cirrhosis. In this study, we examined the effectiveness and survival advantage in patients with the long-term administration of tolvaptan. Methods: A total of 115 patients with refractory ascites who were treated with tolvaptan were retrospectively analyzed based on their clinical records. Patients with a decrease in body weight of ≥1.5 kg from the baseline on day 7 were determined as responders. Re-exacerbation was defined as a return to the baseline BW, dose escalation of conventional diuretics, or abdominal drainage. Results: Of the 115 patients, 84 were included in this analysis. Response to tolvaptan treatment was observed in 55 out of the 84 patients (65.5%), with a mean weight reduction of 2.52 kg. Multivariate analyses demonstrated that body mass index (≥24) and urinary specific gravity (≥1.018) were significant predictors of the response to tolvaptan. However, cumulative re-exacerbation rates in responders at 6 and 12 months were 42.4 and 60.1%, respectively. Child-Pugh (classification C), HCC complication, and serum sodium levels (≥133 mEq/L) were determined as independent prognostic factors impacting overall survival (OS). Although there were no significant differences in OS between tolvaptan responders and non-responders, the responders without re-exacerbation within 3 months showed significantly longer OS than those with re-exacerbation within 3 months. Conclusion: A persistent therapeutic response, but not early response to tolvaptan, was associated with favorable survival of decompensated cirrhotic patients.

Serum fibroblast growth factor 19 serves as a potential novel biomarker for hepatocellular carcinoma.

BACKGROUND: Abnormal autocrine fibroblast growth factor 19 (FGF19) production has been observed in several types of cancers, including hepatocellular carcinoma (HCC). In this study, we investigated the potential of serum FGF19 as a novel tumor marker of HCC based on a sandwich enzyme-linked immunosorbent assay (ELISA). METHODS: The serum FGF19 levels of 304 patients with HCC was measured by ELISA. The serum levels of existing markers, including alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) were determined by chemiluminescence enzyme immunoassay. Both diagnostic value of FGF19 and its changes after curative ablation therapy was further examined. RESULTS: The median FGF19 levels in controls, chronic liver disease patients, and primary HCC patients, were 78.8 pg/mL, 100.1 pg/mL, and 214.5 pg/mL, respectively. The subsequent receiver operating characteristic curves (ROC) successfully determined an optimal cut-off value of 200.0 pg/mL. The area under the ROC curve (AUC) of FGF19 for HCC detection was comparable to those of AFP and DCP. Of importance, FGF19 showed higher sensitivity for the detection of small HCC (solitary cancer with diameter < 20 mm) than those of existing markers. In addition, 43 out of 79 cases (54.4%) with normal AFP and DCP (so-called "double negative HCC") exhibited serum FGF19 level ≥ 200 pg/mL. In 45 HCC patients treated with curative ablation therapy, serum FGF19 levels changed from 257.4 pg/mL to 112.0 pg/mL after the treatment. CONCLUSION: Our findings reveal that FGF19 can be a potential novel biomarker for HCC. Although FGF19 is not necessarily a substitute for existing markers, it may help improve the prognosis in HCC patients owing to its resourceful use in various aspects of HCC management and treatment.