Real-world safety and effectiveness of anamorelin for cancer cachexia: Interim analysis of post-marketing surveillance in Japan.

BACKGROUND: Anamorelin was approved in Japan in 2021 to treat cancer cachexia associated with non-small cell lung, gastric, pancreatic, or colorectal cancers. Post-marketing surveillance is being conducted to evaluate the real-world safety and effectiveness of anamorelin. METHODS: This prospective, observational surveillance registered all patients who started treatment with anamorelin after April 21, 2021. Hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were defined as main safety specifications. Body weight (BW) and appetite were assessed as effectiveness specifications. RESULTS: This analysis was based on data as of January 21, 2023. The safety and effectiveness analysis sets included 6016 and 4511 patients, respectively. Treatment-related adverse events in ≥1% of patients were hyperglycemia (3.9%) and nausea (2.6%). The incidences of hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were 4.8%, 1.2%, and 1.1%, respectively. The mean changes (standard error [SE]) in BW from baseline to weeks 3, 12, 24, and 52 were 0.64 (0.05) kg, 1.19 (0.12) kg, 1.40 (0.21) kg, and 1.42 (0.39) kg, respectively. The mean changes (SE) in Functional Assessment of Anorexia/Cachexia Treatment 5-item Anorexia Symptom Scale total scores from baseline to weeks 3, 12, 24, and 52 were 3.2 (0.09), 4.8 (0.18), 5.2 (0.30), and 5.3 (0.47), respectively, exceeding the clinically meaningful improvement score (2.0 points). CONCLUSION: The overall safety of anamorelin raised no new safety concerns, although continued caution may be required for hyperglycemia and nausea. Improvements in BW and appetite were also observed in real-world clinical settings.

Lecompte maneuver for compressed left coronary artery after pulmonary artery banding.

A one-month-old baby boy with a complete atrioventricular septal defect underwent pulmonary artery banding. A high take-off of the left coronary artery, overlooked on the echocardiogram, was identified. It was compressed by the right pulmonary artery that was dilated owing to pulmonary artery banding. The patient developed severe heart failure, and a Lecompte maneuver was performed. The procedure helped effectively treat this congenital heart disease with a high take-off coronary artery compressed by the right pulmonary artery.

Total arch replacement for re-coarctation of the aorta after a Norwood procedure.

This is the first report of total arch replacement to repair re-coarctation. A 14-year-old boy with hypoplastic left heart syndrome developed re-coarctation, severe stenosis of neck vessels, and right ventricle dysfunction after a Norwood procedure. We performed total arch replacement; the postoperative course was unremarkable. He was followed up until 18 years of age and did not need re-intervention. Using artificial blood vessels in total arch replacement is rarely indicated but can be safely achieved when required. Mismatch between patient and graft size may be an issue in the future.

Is the QRS duration useful for determining the optimal timing of pulmonary valve replacement after tetralogy of Fallot repair?

OBJECTIVES: In pulmonary valve replacement (PVR) after tetralogy of Fallot (TOF) repair, the right ventricular end-diastolic and end-systolic volume index (RVEDVI and RVESVI) of cardiac magnetic resonance imaging (cMRI) are often used as indicators of the RV volume. We examined the utility of QRS duration, cardiothoracic ratio (CTR), and plasma brain natriuretic peptide (BNP) as indicators of the appropriate timing of cMRI to assess the RV volume and function before PVR. METHODS: We assessed the correlation of QRS duration, CTR, and BNP with RVEDVI and RVESVI on cMRI in 26 patients after TOF repair. Fifteen underwent PVR (age, 45.2 ± 11.4 years). Twelve underwent post-PVR cMRI. The RV volume change from before to after PVR was investigated. RESULTS: QRS duration, BNP, and CTR were positively correlated with RVEDVI and RVESVI after TOF repair. The post-PVR QRS duration was also positively correlated with post-PVR RVEDVI (p = 0.017) and RVESVI (p = 0.001). From before to after PVR, in 5 cases with QRS duration ≤ 160 ms, the QRS duration decreased from 110.4 ± 28.9 to 101.8 ± 30.5 ms (p = 0.063). Both RVEDVI and RVESVI decreased to the normal range in 4 of 5 cases. In contrast, in 7 cases with QRS duration > 160 ms, the QRS duration decreased from 183.0 ± 17.4 to 160.3 ± 23.8 ms (p = 0.013); however, RVESVI did not normalize in 6 of 7 cases. CONCLUSIONS: A prolonged QRS duration is a useful marker of RVEDVI and RVESVI enlargement after TOF repair. We recommend performing cMRI before the QRS duration reaches 160 ms due to normalization of the RV volume after PVR.

A simple mouse model of pericardial adhesions.

BACKGROUND: Postoperative pericardial adhesions are considered a risk factor for redo cardiac surgery. Several large- and medium-size animal models of pericardial adhesions have been reported, but small animal models for investigating the development of anti-adhesion materials and molecular mechanisms of this condition are lacking. In this study, we aimed to establish a simple mouse model of pericardial adhesions to address this gap. METHODS: We administered blood, minocycline, picibanil, and talc into the murine pericardial cavity via one-shot injection. Micro-computed tomography analyses of contrast agent-injected mice were carried out for methodological evaluation. We investigated various dosages and treatment durations for molecules identified to be inducers of pericardial adhesion. The adhesive grade was quantified by scoring the strength and volume of adhesion tissues at sacrificed time points. Histological staining with hematoxylin and eosin and Masson's trichrome, and immunostaining for F4/80 or αSMA was performed to investigate the structural features of pericardial adhesions, and pathological features of the pericardial adhesion tissue were compared with human clinical specimens. RESULTS: Administration of talc resulted in the most extensive pericardial adhesions. Micro-computed tomography imaging data confirmed that accurate injection into the pericardial cavity was achieved. We found the optimal condition for the formation of strong pericardial adhesions to be injection of 2.5 mg/g talc for 2 weeks. Furthermore, histological analysis showed that talc administration led to an invasion of myofibroblasts and macrophages in the pericardial cavity and epicardium, consistent with pathological findings in patients with left ventricular assistive devices. CONCLUSIONS: We successfully established a simple mouse model of talc-induced pericardial adhesions, which mimics human pathology and could contribute to solving the clinical issues related to pericardial adhesions.

Biochemical and histological evidence of deteriorated bioprosthetic valve leaflets: the accumulation of fibrinogen and plasminogen.

Calcification of bioprosthetic valves (BVs) implanted in aortic position can result in gradual deterioration and necessitate aortic valve replacement. The molecular mechanism of calcium deposition on BV leaflets has been investigated, but remains to be fully elucidated. The present study aimed to identify explanted bioprosthetic valve (eBV)-specific proteins using a proteomics approach and to unveil their biochemical and histological involvements in calcium deposition on BV leaflets. Calcification, fibrosis, and glycosylation of the valves were histologically assessed using Von Kossa, Masson's Trichrome and Alcian Blue staining, as well as immunostaining. Protein expression in the explanted biological valves was analysed using proteomics and western blotting. In a histological evaluation, αSMA-positive myofibroblasts were not observed in eBV, whereas severe fibrosis occurred around calcified areas. SDS-PAGE revealed three major bands with considerably increased intensity in BV leaflets that were identified as plasminogen and fibrinogen gamma chain (100 kDa), and fibrinogen beta chain (50 and 37 kDa) by mass analysis. Immunohistochemistry showed that fibrinogen ß-chain was distributed throughout the valve tissue. On the contrary, plasminogen was strongly stained in CD68-positive macrophages, as evidenced by immunofluorescence. The results suggest that two important blood coagulation-related proteins, plasminogen and fibrinogen, might affect the progression of BV degeneration.

Refractory ventricular fibrillations after surgical repair of atrial septal defects in a patient with CACNA1C gene mutation - case report.

BACKGROUND: Congenital long QT syndrome (LQTS) can cause ventricular arrhythmic events with syncope and sudden death resulting from malignant torsades de pointes (TdP) followed by ventricular fibrillations (VFs). However, the syndrome is often overlooked prior to the development of arrhythmic events in patients with congenital heart diseases demonstrating right bundle branch block on electrocardiogram (ECG). We present a case of an adult patient with congenital heart disease who developed VFs postoperatively, potentially due to his mutation in a LQTS related gene, which was not identified on preoperative assessment due to incomplete evaluation of his family history. CASE PRESENTATION: A 64-year-old man was diagnosed as having multiple atrial septal defects. He presented with no symptoms of heart failure. His preoperative ECG showed complete right bundle branch block (CRBBB) with a corrected QT interval time of 478 ms. He underwent open-heart surgery to close the defects through median sternotomy access. Three hours after the operation, he developed multiple events of TdP and VFs in the intensive care unit. Cardiopulmonary resuscitation and multiple cardioversions were attempted for his repetitive TdP and VFs. He eventually reverted to sinus rhythm, and intravenous beta-blocker was administered to maintain the sinus rhythm. After this event, his family history was reviewed, and it was confirmed that his daughter and grandson had a medical history of arrhythmia. A genetic test confirmed that he had a missense mutation in CACNA1C, p.K1580 T, which is the cause for type 8. CONCLUSIONS: This case highlights the importance of paying attention to other ECG findings in patients with CRBBB, which can mask prolonged QT intervals.

Proteomics-based analysis of lung injury-induced proteins in a mouse model of common bile duct ligation.

BACKGROUND: Lung injury is a life-threatening complication in patients with liver dysfunction. We recently provided an experimental lung injury model in mouse with common bile duct ligation. In this study, we aimed to characterize the pathologic and biochemical features of lung tissues in common bile duct ligation mice using a proteomic approach. METHODS: Common bile ducts of BALB/c mice, 8 weeks of age, were ligated operatively. CD31-expressing pulmonary cells were sorted with immunomagnetic microbeads, and protein profiles were examined by 2-dimensional gel electrophoresis. Based on the results of protein identification, immunohistochemistry and quantitative reverse transcription polymerase chain reaction were carried out in pulmonary and hepatic tissues. RESULTS: Two-dimensional gel electrophoresis revealed 3 major inflammation-associated proteins exhibiting considerable increases in the number of CD31-positive pulmonary cells after common bile duct ligation. Mass spectrometry analysis identified these proteins as SerpinB1a (48 kDa), ANXA1 (46 kDa), and S100A9 (16 kDa). Furthermore, the 3 proteins were more highly expressed in dilated pulmonary blood vessels of common bile duct ligation mice, in which neutrophils and monocytes were prominent, as shown by immunohistochemistry. More importantly, SerpinB1a mRNA and protein were significantly upregulated in the liver, whereas S100A9 and ANXA1 mRNA and protein were upregulated in the lungs, as shown by quantitative reverse transcription polymerase chain reaction and Western blotting. CONCLUSION: We identified 3 proteins that were highly expressed in the lung after common bile duct ligation using a proteomics-based approach.

A case of biatrial drainage of the right superior vena cava.

Biatrial drainage of the right superior vena cava resulting from a sinus venosus defect is a rare congenital malformation. It can result in severe desaturation although a sinus venosus defect usually presents as a left-to-right shunt. A male baby was noted to have cyanosis while nursing and was referred to us for medical treatment on his second day of life. Echocardiography showed that most of the blood flowing through the superior vena cava drained into the left atrium. He underwent successful surgery to correct this defect at the age of 2 years.

Aortic Coarctation 28 Days after an Arterial Switch Operation in a Neonate.

Aortic coarctation rarely occurs after an arterial switch operation for D-transposition of the great arteries with intact ventricular septum. We report the case of a neonate patient in whom aortic coarctation developed 28 days after an uncomplicated arterial switch operation. Preoperatively, the aorta was noted to have an irregular shape, but there was no pressure gradient across the lesion. The patient underwent successful reoperation to correct the coarctation. We hope that our report raises awareness of a rare early complication after arterial switch operation with intact ventricular septum, and the need to carefully monitor the aortic isthmus in patients who have aortic irregularities, even in the absence of a pressure gradient.

Aortopulmonary collateral arteries: a rare complication after arterial switch operation for transposition of the great arteries.

Collateral vascular arteries from the descending aorta to the pulmonary arteries are uncommon after arterial switch operation. Here, we report the case of a baby girl treated with coil embolization for abnormal blood flow from the descending aorta to the pulmonary arteries after arterial switch operation. A baby girl weighing 1324 g was delivered at 32 weeks 4 days of gestation, and she had D-transposition of the great arteries and a ventricular septal defect. She underwent nitrogen inhalation to reduce pulmonary blood flow before arterial switch operation. After the operation, she presented with left heart failure due to the presence of abnormal blood flow from the descending aorta to the pulmonary arteries, and she was successfully treated with coil embolization. After the treatment, her condition improved dramatically, and she was discharged without any complications.

V-ATPase-dependent luminal acidification is required for endocytic recycling of a yeast cell wall stress sensor, Wsc1p.

Wsc1p is a major cell wall sensor protein localized at the polarized cell surface. The localization of Wsc1p is maintained by endocytosis and recycling from endosomes back to the cell surface, but changes to the vacuole when cells are subjected to heat stress. Exploiting this unique property of Wsc1p, we screened for yeast single-gene deletion mutants exhibiting defects in Wsc1p trafficking. By expressing 3GFP-tagged Wsc1p in mutants with deleted genes whose function is related to intracellular trafficking, we identified 5 gene groups affecting Wsc1p trafficking, impaired respectively in endocytic internalization, multivesicular body sorting, the GARP complex, endosomal maturation/vacuolar fusion, and V-ATPase. Interestingly, deletion of the VPH1 gene, encoding the V(o) subunit of vacuolar-type H(+)-ATPase (V-ATPase), led to mis-localization of Wsc1p from the plasma membrane to the vacuole. In addition, disruption of other V-ATPase subunits (vma mutants) also caused defects of Wsc1p trafficking and vacuolar acidification similar to those seen in the vph1Δ mutant. Moreover, we found that deletion of the VPS26 gene, encoding a subunit of the retromer complex, also caused a defect in Wsc1p recycling and mis-localization of Wsc1p to the vacuole. These findings clarified the previously unidentified Wsc1p recycling pathway and requirement of V-ATPase-dependent luminal acidification for Wsc1p recycling.

Localization and functional requirement of yeast Na+/H+ exchanger, Nhx1p, in the endocytic and protein recycling pathway.

Acidification of the lumen of intracellular organelles is important for post-transcriptional processing, endosomal maturation, receptor recycling, and vesicle trafficking, being regulated by an intricate balance between H+ influx through vacuolar-type H+-ATPase and efflux through ion channels and transporters, such as the Na+/H+ exchanger (NHE). The eukaryotic NHE family comprises two major subgroups, one residing in the plasma membrane and the other in intracellular organelles. While mammalian intracellular NHE isoforms are localized to various organelles, including the mid-trans-Golgi compartments, early and late endosomes, and recycling endosomes, Nhx1p, the sole NHE in yeast, has been reported to be localized predominantly to the late endosomal/prevacuolar compartment. Here, using live cell imaging, we demonstrated that Nhx1p is localized to the trans-Golgi network compartments, late endosomes, and recycling endosomes, similar to mammalian intracellular NHE isoforms. Loss of Nhx1p led to accumulation of components of the retromer and endosomal sorting complex required for transport complexes, but not trans-Golgi compartments, in aberrant prevacuolar compartments. Importantly, Nhx1p was also required for recycling of the plasma membrane vesicle SNAP receptor Snc1p. These observations suggest that Nhx1p plays an important role in regulation of the luminal pH of various intracellular organelles, and that this regulation is critical for the protein recycling pathway as well as the endocytic pathway.