Effects of trastuzumab emtansine on canine urothelial carcinoma cells in vitro and in vivo.

Urothelial carcinoma (UC) is the most common malignancy of the urinary tract in dogs and has aggressive behaviour. Although human epidermal growth factor receptor 2 (HER2) is a known therapeutic target with evidence in canine UC, the efficacy of anti-HER2 antibody drugs remains unknown. This study aimed to investigate the effects of anti-HER2 antibody drugs including trastuzumab and trastuzumab emtansine (T-DM1) on canine UC cell lines in vitro and in vivo. Four canine UC cell lines (Nene, TCCUB, Love, and Sora) were used. In western blotting, HER2 protein expression was observed in all the cell lines. Although both trastuzumab and T-DM1 showed dose-dependent growth inhibitory activity in the cell lines, T-DM1 showed much stronger activity than that of trastuzumab. In flow cytometry analyses with the canine UC cell line (Sora), T-DM1 but not trastuzumab significantly increased the percentages of early and late apoptotic cells in annexin V apoptotic assays and the sub-G1 phase fraction in cell cycle analyses. For the in vivo experiment, the canine UC cells (Sora) were subcutaneously injected into nude mice. Four days after inoculation, trastuzumab, T-DM1, or vehicle was administered intraperitoneally once a week for three times. Tumour volumes were significantly smaller in the T-DM1 group compared to the trastuzumab and vehicle control groups. These findings indicate that T-DM1 exerts a stronger antitumour effect than that of trastuzumab on canine UC cells in vitro and in vivo, possibly by inducing apoptosis due to DM1.

Surgical repair for a parahiatal hernia with an esophageal hiatal hernia: A case report and literature review.

INTRODUCTION AND IMPORTANCE: A parahiatal hernia (PH) is a rare diaphragmatic hernia (DH) adjacent to but separated from the esophageal hiatus. The surgical repair for PH needs primary suture closure or complicated hernioplasty and the addition of an anti-reflux procedure. This report describes a case of PH with a symptomatic esophageal hiatal hernia managed using three-dimensional (3D) laparoscopy. CASE PRESENTATION: A 65-year-old woman with back pain and breathlessness was referred to our hospital for a DH. Computed tomography showed a diaphragmatic defect on the left side of the esophageal hiatus. Upper gastrointestinal endoscopy and 24-hour esophageal impedance-pH monitoring showed a symptomatic esophageal hiatal hernia. Laparoscopic repair for both hernias was performed using 3D laparoscopy. The DH orifice was located in the left crus of the diaphragm, and it was separated from the esophageal hiatus. These findings showed that this DH was a PH. The PH was repaired with primary suturing, and a hiatoplasty was performed. Toupet fundoplication was performed with a 270° posterior wrap of the gastric fornix. The patient has remained asymptomatic a year after surgery without any complications. CLINICAL DISCUSSION: 3D laparoscopy provides significant advantages in surgeries requiring precise suturing. PH repairs require complex procedures, including mesh repair or suturing. Approximately 44 % of PH cases also necessitate fundoplication. 3D laparoscopy was useful for the present case. CONCLUSIONS: A rare PH and a symptomatic type 1 hiatal hernia were repaired with 3D laparoscopy, which is helpful for PH treatment in cases requiring complicated procedures.

Staged therapeutic surgery for progressive pulmonary regurgitation and pacemaker induced cardiomyopathy after the tetralogy of fallot repair.

BACKGROUND: Recently, improvements in the repair of tetralogy of Fallot have increased the need for reoperation in adulthood, and it's not rare that these reoperation candidates suffer from biventricular failure. However, there are no firm treatment guidelines, and each country, and even each facility, treats each case individually. CASE PRESENTATION: We report the successful staged treatment of pulmonary regurgitation and pacemaker-induced cardiomyopathy with biventricular failure in adulthood in a case of complete atrioventricular block after tetralogy of Fallot repair in childhood. We planned a staged therapeutic strategy with preoperative left ventricular volume reduction with medication, following surgical pulmonary valve replacement concomitant epicardial lead implantation on the lateral basal wall, placed just beneath the generator pocket through 3rd intercostal space. in addition to postoperative intervention with a defibrillator to adjust cardiac resynchronization therapy, resulted in improvement of symptoms. CONCLUSION: In a patient with biventricular failure after TOF repair, a staged treatment strategy involving medication, PVR, and CRT with a combination of epicardial and intravenous leads could be a useful treatment worth trying before heart transplantation.

Delayed traumatic aortic valve perforation after blunt chest trauma.

BACKGROUND: Aortic valve perforation is a rare complication of blunt chest trauma. We report a case of delayed aortic insufficiency presenting several months after trauma. CASE PRESENTATION: A 17-year-old male presented to the emergency department with traumatic brain injuries and blunt chest trauma, but no evidence of cardiac injuries. Three months later, he developed acute heart failure due to severe aortic valve regurgitation with left ventricular dysfunction. A sizable tear in the right coronary cusp caused aortic insufficiency. He was treated successfully by surgical replacement with an aortic bioprosthesis. CONCLUSION: We reported a successful surgical case of valve replacement for delayed aortic valve perforation. Delayed valve perforation should be kept in mind after blunt chest trauma.

Enhanced expression of neopterin in valve tissue of bicuspid aortic stenosis.

Background: Aortic valve stenosis (AS) occurs in bicuspid aortic valve (BAV) patients at a relatively young age compared to tricuspid aortic valve (TAV) patients. However, the underlying cause of this phenomenon remains unknown. Neopterin, which is a by-product of the guanosine triphosphate (GTP) pathway, enhances the oxidative potential of reactive oxygen species. To clarify the role of neopterin in the aortic valve, we immunohistochemically studied the presence of neopterin in aortic valve specimens from patients with AS harboring either TAV or BAV. Methods: Frozen aortic valve samples were surgically obtained from 68 patients with severe AS with TAV (n=34) and BAV (n=34). Normal aortic valves were obtained from cadavers who died of non-cardiovascular causes as controls (n=9). Samples were immunohistochemically stained with antibodies against smooth muscle cells, macrophages, T lymphocytes, neopterin, and 4-hydroxy-2-nonenal (4-HNE). Results: Quantitative analysis showed that the percentage of macrophages, 4-HNE- and neopterin-positive macrophage score, and the number of T lymphocytes were significantly higher in BAV patients than in TAV patients (macrophages, P=0.013; T lymphocytes, P=0.011; neopterin, P<0.001; 4-HNE, P=0.008). Double immunostaining for neopterin and macrophages demonstrated that most neopterin-positive cells were macrophages in BAV patients. Conclusions: Neopterin accumulation in macrophages may increase oxidative stress and contribute to the early onset of AS in BAV.

Aortic Annular Enlargement with Modified Y-Incision Technique Devised from Preoperative Three-Dimensional Computed Tomography.

The Y-incision technique introduced by Dr. Bo Yang in 2021 is a very innovative technique that can enlarge the aortic annulus by two or more sizes without violating the left atrium or mitral valve. However, we encountered a case in which the left coronary artery ostium was located close to the left-non commissure. Therefore, we considered it would be dangerous to expand the incision to the left coronary annulus. We therefore devised a new technique that enlarges only the noncoronary annulus in an "L" fashion instead of a "Y" fashion. In performing this surgery, preoperative three-dimensional images were useful for understanding the anatomy when planning the aortic annular enlargement procedure. The L-incision technique can be a useful alternative method of aortic annulus enlargement.

Vascular access site complications after transfemoral transcatheter aortic valve implantation: a comparison of open and percutaneous puncture approaches.

Background: In transfemoral transcatheter aortic valve implantation (TF-TAVI), which approach has lower vascular access site complications between the open puncture (OP) and percutaneous puncture (PP) approaches is still controversial. Moreover, few studies have analyzed risk factors for vascular access site complications in TF-TAVI. This study aimed to compare vascular access site complications between the OP and PP approaches in patients undergoing TF-TAVI and access risk factors for vascular access site complications. Methods: Three hundred fifty-one patients who underwent TF-TAVI via the PP (n=251) and OP (n=100) were retrospectively examined. Results: Incidence of vascular access site complications was 7.0% in the OP group and 8.4% in the PP group (P=0.828). Two deaths from vascular access site complications occurred in the PP group. After performing inverse probability weighting (IPW), regression analysis showed that PP was associated with a significantly higher odds of vascular access site complications [odds ratio =2.033; 95% confidence interval (CI): 1.397-2.958; P<0.001]. Common femoral artery (CFA) depth (hazard ratio =1.04; 95% CI: 1.000-1.070; P=0.045) and sheath/CFA diameter ratio (hazard ratio =971; 95% CI: 22.6-41,700; P<0.001) were independent complication risk factors. In patients with CFA depth ≥35 mm, the incidence of vascular access site complications was higher with PP than OP. Sheath/CFA diameter ratio ≥0.9 was associated with increased risk of vascular injury with both approaches. Conclusions: The incidence of vascular access site complications in patients undergoing TF-TAVI was significantly lower with OP than PP after IPW. OP may be preferable when CFA depth is ≥35 mm. When the sheath/CFA diameter ratio is ≥0.9, approaches other than the TF approach should be considered.

Midterm Results of Mitral Valve Repair Using Loop Technique With Simple Height Reduction of the Large Posterior Leaflet.

OBJECTIVE: Systolic anterior motion (SAM) is one of the most serious problems in mitral valve repair. Height reduction is a key procedure to solve SAM, and there are limited data on the surgical results of height reduction procedure. This study is to assess the effectiveness and midterm results of simple height reduction procedure for SAM in patients with severe mitral regurgitation (MR). METHODS: From 2008 to 2022, 50 patients underwent loop technique with an additional simple height reduction procedure for prevention of SAM. We examined the midterm results of patients with simple height reduction regarding recurrent MR and reoperation. The follow-up period ranged from 171 to 3,816 days (median, 883 days). RESULTS: There were 338 patients (87%) who underwent loop technique without height reduction and 50 patients (13%) who underwent loop technique with height reduction. After the height reduction procedure, SAM was prevented in 44 patients, and 6 patients needed volume loading to suppress SAM. Freedom from recurrence of moderate to severe or severe MR at 1, 3, and 5 years was 98%, 88%, and 88% in the height reduction group versus 98%, 96%, and 94% in the group with loop technique alone (P = 0.074). Receiver operating characteristic curves showed that a systolic dimension of 26 mm had a sensitivity of 75% and a specificity of 83% for predicting SAM after height reduction. CONCLUSIONS: Loop technique with simple height reduction was a simple, secure, and effective procedure to prevent SAM and recurrent significant MR in the midterm periods.

Podoplanin promotes cell proliferation, survival, and migration of canine non-tonsillar squamous cell carcinoma.

Podoplanin (PDPN) is a prognostic factor and is involved in several mechanisms of tumor progression in human squamous cell carcinoma (SCC). Canine non-tonsillar SCC (NTSCC) is a common oral tumor in dogs and has a highly invasive characteristic. In this study, we investigated the function of PDPN in canine NTSCC. In canine NTSCC clinical samples, PDPN overexpression was observed in 80% of dogs with NTSCC, and PDPN expression was related to ki67 expression. In PDPN knocked-out canine NTSCC cells, cell proliferation, cancer stemness, and migration were suppressed. As the mechanism of PDPN-mediated cell proliferation, PDPN knocked-out induced apoptosis and G2/M cell cycle arrest in canine NTSCC cells. These findings suggest that PDPN promotes tumor malignancies and may be a novel biomarker and therapeutic target for canine NTSCC.

Simultaneous Hydrostatic and Compressive Loading System for Mimicking the Mechanical Environment of Living Cartilage Tissue.

In vivo, articular cartilage tissue is surrounded by a cartilage membrane, and hydrostatic pressure (HP) and compressive strain increase simultaneously with the compressive stress. However, it has been impossible to investigate the effects of simultaneous loading in vitro. In this study, a bioreactor capable of applying compressive stress under HP was developed to reproduce ex vivo the same physical loading environment found in cartilage. First, a HP stimulation unit was constructed to apply a cyclic HP pressure-resistant chamber by controlling a pump and valve. A compression-loading mechanism that can apply compressive stress using an electromagnetic force was implemented in the chamber. The synchronization between the compression and HP units was evaluated, and the stimulation parameters were quantitatively evaluated. Physiological HP and compressive strain were applied to the chondrocytes encapsulated in alginate and gelatin gels after applying high HP at 25 MPa, which induced damage to the chondrocytes. It was found that compressive stimulation increased the expression of genes related to osteoarthritis. Furthermore, the simultaneous application of compressive strain and HP, which is similar to the physiological environment in cartilage, had an inhibitory effect on the expression of genes related to osteoarthritis. HP alone also suppressed the expression of osteoarthritis-related genes. Therefore, the simultaneous hydrostatic and compressive stress-loading device developed to simulate the mechanical environment in vivo may be an important tool for elucidating the mechanisms of disease onset and homeostasis in cartilage.

Podoplanin Drives Amoeboid Invasion in Canine and Human Mucosal Melanoma.

Mucosal melanoma metastasizes at an early stage of the disease in human and dog. We revealed that overexpression of podoplanin in tumor invasion fronts (IF) was related to poor prognosis of dogs with mucosal melanoma. Moreover, podoplanin expressed in canine mucosal melanoma cells promotes proliferation and aggressive amoeboid invasion by activating Rho-associated kinase (ROCK)-myosin light chain 2 (MLC2) signaling. PDPN-ROCK-MLC2 signaling plays a role in cell-cycle arrest and cellular senescence escape as a mechanism for regulating proliferation. Podoplanin induces amoeboid invasion in the IFs of mouse xenografted tumor tissues, similar to canine mucosal melanoma clinical samples. We further identified that podoplanin expression was related to poor prognosis of human patients with mucosal melanoma, and human mucosal melanoma with podoplanin-high expression enriched gene signatures related to amoeboid invasion, similar to canine mucosal melanoma. Overall, we propose that podoplanin promotes canine and human mucosal melanoma metastasis by inducing aggressive amoeboid invasion and naturally occurring canine mucosal melanoma can be a novel research model for podoplanin expressing human mucosal melanoma. IMPLICATIONS: Podoplanin could be a new therapeutic target to restrict the metastatic dissemination of canine and human mucosal melanoma.

Tricuspid annular area and leaflets stretch are associated with functional tricuspid regurgitation - insights from three-dimensional transesophageal echocardiography.

BACKGROUND: The presence of functional tricuspid regurgitation (TR) is associated with mortality and morbidity. Although uniform management with a tricuspid annuloplasty ring is currently considered as a standard surgical procedure, high rates of residual TR despite annuloplasty are reported. Therefore, the identification of the TR mechanisms would be necessary to provide personalized treatment for each TR patient. METHODS: This study population consisted of 106 patients with mitral regurgitation (MR) who were scheduled for procedure. Transthoracic and transesophageal echocardiography were performed prior to mitral valve intervention. We performed three-dimensional quantitative assessment including tricuspid annular (TA) area and the distance between the three commissures of tricuspid valve. RESULTS: Significant TR, which is defined as moderate or greater TR, was detected in 23 (22%). TA area (P < 0.01), the distance of septal-leaflet length (SL) (P = 0.03) and posterior-leaflet length (PL) (p = 0.02) were significantly associated with significant TR, while TA diameter assessed by transthoracic echocardiography was not. When patients were divided into four groups according to SL and PL, the group with longer SL and PL had a significantly higher incidence of significant TR (P < 0.01). CONCLUSIONS: Greater stretch of the septal and posterior leaflet between commissures and larger TA area are associated with significant TR in patients with severe MR. In order to prevent TR recurrence, the intervention of the septal leaflet in tricuspid annuloplasty may be beneficial. The precise implement of three-dimensional transesophageal echocardiography of tricuspid valve is valuable for a personalized strategy of tricuspid annuloplasty.

Flexible Total Ring Annuloplasty With Continuous Wrapping Suture Considering the Anatomy and Histology of the Tricuspid Valve.

OBJECTIVE: About half of tricuspid valves (TVs) have 2 posterior leaflets, and the fibrous tissue of the tricuspid annulus is poor. Considering the anatomy and histology of the TV, we devised a secure ring annuloplasty technique. We herein report the outcomes of our continuous wrapping suture annuloplasty technique using a flexible total ring. METHODS: We used a Tailor™ ring (Abbott, Chicago, IL, USA) as a full ring. The mark on the left side of the ring was fixed to the anteroseptal commissure, and the midpoint of the ring's markers was fixed at the center of the septal leaflet annulus. Using a continuous suture, all stitches were passed around the annuloplasty ring without penetration. One suture from the anteroseptal commissure ran toward the left side and another from the midpoint of the septal leaflet annulus ran toward the right, leading to annuloplasty without TV deformation. RESULTS: Eighty patients underwent TV repair with this technique. The tricuspid regurgitation (TR) score in all patients improved from 1.9 ± 0.7 to 0.8 ± 0.4 (P < 0.001) at 3 years postoperatively. The TR score of TVs with 2 posterior leaflets also improved from 1.9 ± 0.7 to 0.6 ± 0.4 after the operation and was unchanged during follow-up. The median follow-up period was 1.3 (0.5 to 2.0) years, and no patients required TV reoperation. The 3-year survival rate was 93%, and the 3-year rate of freedom from pacemaker implantation was 95%. CONCLUSIONS: The continuous wrapping suture technique using a flexible total ring is a useful procedure without TV deformation even when 2 posterior leaflets are present.

Impact of cystatin C-derived glomerular filtration rate in patients undergoing transcatheter aortic valve implantation.

Background: Chronic kidney disease (CKD) impacts prognosis in patients undergoing transcatheter aortic valve implantation (TAVI). While estimated glomerular filtration rate (eGFR) calculated from serum creatinine [eGFR (creatinine)] is affected by body muscle mass which reflects frailty, eGFR calculated from serum cystatin C [eGFR (cystatin C)] is independent of body composition, resulting in better renal function assessment. Methods: This study included 390 consecutive patients with symptomatic severe aortic stenosis (AS) who underwent TAVI, and measured cystatin C-based eGFR at discharge. Patients were divided into two groups, with or without CKD estimated with eGFR (cystatin C). The primary endpoint of this study was the 3-year all-cause mortality after TAVI. Results: The median patient age was 84 years, and 32.8% patients were men. Multivariate Cox regression analysis indicated that eGFR (cystatin C), diabetes mellitus, and liver disease were independently associated with 3-year all-cause mortality. In the receiver-operating characteristic (ROC) curve, the predictive value of eGFR (cystatin C) was significantly higher than that of eGFR (creatinine). Furthermore, Kaplan-Meier estimates revealed that 3-year all-cause mortality was higher in the CKD (cystatin C) group than that in the non-CKD (cystatin C) group with log-rank p = 0.009. In contrast, there was no significant difference between the CKD (creatinine) and non-CKD (creatinine) groups with log-rank p = 0.94. Conclusions: eGFR (cystatin C) was associated with 3-year all-cause mortality in patients who underwent TAVI, and it was superior to eGFR (creatinine) as a prognostic biomarker.

Diagnosis of unicuspid aortic valve after loss of consciousness during cesarean section: A case report.

Loss of consciousness is a rare but potentially serious complication of delivery by cesarean section under spinal anesthesia. Here, we report the case of a pregnant woman with unicuspid aortic valve that was incidentally diagnosed during aortic valve replacement after transient loss of consciousness during cesarean section.

Mitral valve repair with patch augmentation for atrial functional mitral regurgitation complicated with giant left atrium.

OBJECTIVE: We aimed to assess the results of posterior leaflet augmentation with an autologous pericardial patch in atrial functional mitral regurgitation. METHODS: Data of 16 patients with atrial functional mitral regurgitation who underwent posterior leaflet patch augmentation for mitral valve repair were retrospectively analyzed. This procedure was applied to a short posterior leaflet with a height of < 10 mm in P2. The median age was 72.5 [67.8-78.3] years. Preoperative New York Heart Association functional class was II in 7 (43.8%) and III or IV in 9 (56.2%) patients. Mitral regurgitation was moderate in 2 (12.5%) and severe in 14 (87.5%) patients. RESULTS: Operative mortality occurred in 1 (6.2%) patient due to cerebral infarction. One patient required valve replacement because of patch perforation early after operation. Mitral regurgitation was reduced to less than mild in 15 (93.8%) patients and less than trivial in 11 (68.8%) patients (P < 0.01) postoperatively. As for mid-term results, New York Heart Association functional class improved to I or II in 12 (75%) patients (P < 0.01). Two cases of thrombotic complication were observed. Remote recurrent regurgitation occurred in one case due to small patch size. The 3-year free rate of valve-related morbidity and regurgitation recurrence was 65.6% and 87.1%, respectively. The 5-year survival rate was 93.8%. CONCLUSIONS: Pericardial patch augmentation in atrial functional mitral regurgitation leads to good survival and mitral regurgitation recurrence-free rates. Steady anticoagulation and the use of larger patches would be necessary to reduce thrombotic complications and recurrent MR.

Evaluating the effect of high-density measurement mode on patient-specific quality assurance for head and neck cancer with ArcCHECK.

The high-density measurement (HDm) mode of the ArcCHECK device can achieve a twofold resolution enhancement compared to the standard measurement (Sm) mode. The aim of this study was to evaluate the effect of HDm on the gamma passing rate (GPR) for the patient-specific quality assurance (PSQA) in head and neck cancer. We retrospectively evaluated 30 patients who underwent volumetric modulated arc therapy (VMAT) for head and neck cancer. Absolute gamma analysis was performed on Sm and HDm data. We also investigated correlations between the modulation complexity score for VMAT (MCSv) and differences in the GPR between the two measurement modes. The global GPR of Sm and HDm was 81.0% ± 8.4% and 82.6% ± 7.6% for the 2%/2 mm criterion, 94.0% ± 4.1% and 94.9% ± 3.6% for the 3%/2 mm criterion, and 96.6% ± 2.4% and 97.0% ± 2.4% for the 3%/3 mm criterion, respectively. HDm slightly improved GPR (p < 0.01) for the 2%/2 mm criterion. Differences in GPR between Sm and HDm for the 2%/2 mm, 3%/2 mm, and 3%/3 mm criteria were 1.6% ± 3.0%, 0.8% ± 2.0%, and 0.4% ± 1.2%, respectively. No correlation was identified between the MCSv and the difference in GPR between Sm and HDm. Despite an improvement in GPR with HDm, the difference in GPR between Sm and HDm was approximately 2% even when the tighter criteria were used. Moreover, the change in the GPR between Sm and HDm did not depend on plan complexity. Thus, the effect of HDm on GPR is limited for the PSQA in VMAT for head and neck cancer.

Patch augmentation vs. valve replacement for patients with atrial functional mitral regurgitation and long-standing atrial fibrillation.

Background: Long-standing atrial fibrillation is associated with atrial functional mitral regurgitation (AFMR) with atriogenic tethering. We compared the outcomes of patch augmentation (PA) and valve replacement (VR) for AFMR. Methods: We retrospectively compared the data of 16 patients who underwent PA for AFMR with the data of 15 patients who underwent VR between 2008 and 2021. Patients with a left ventricular ejection fraction (LVEF) of <50% were excluded. We also performed atrial plication and left appendage closure if the patients had no weak atrial wall that led to severe bleeding. Results: The median age was 72.5 and 76.0 years in the PA and VR groups, respectively. The PA group had a longer cardiopulmonary bypass time (206 vs. 172 min, P=0.012). Although there were no differences in hospital morbidity and mortality between the PA and VR groups, one patient underwent reoperation for patch perforation in the PA group. The overall 3-year survival rate was 93.8% and 100% in the PA and VR groups, respectively (P=0.878). The 3-year rate of freedom from major adverse cardiac events was 75.0% and 53.6% in the PA and VR groups, respectively (P=0.181). Three and six patients were readmitted for congestive heart failure in the PA and VR groups, respectively. Two patients in the PA group developed severe recurrent regurgitation, including one patient who required reoperation. No patients in the VR group required reoperation. The postoperative left atrial volume index (LAVI) was associated with thromboembolic events (P=0.016). Conclusions: PA may achieve comparable outcomes to those of VR for AFMR. Operative procedures should be chosen based on each patient's background. Atrial reduction could be considered to prevent thromboembolic events.

A Novel Ring Knot Pusher With Closed Triangle Tip for Minimally Invasive Cardiac Surgery.

We created a novel ring-type knot pusher with a closed triangle tip, wherein the thread is never detached from the knot pusher head during the ligation process. This knot pusher has a small head and is suitable for complex fields, such as the subvalvular apparatus of the mitral valve, allowing the surgeons to observe the knot itself. Considering that the thread passes through the inner corner of the triangle during the tying-down process without swinging inside the triangle, this knot pusher allows for a stable and secure ligation.