[A Case of Advanced Gastric Cancer with Pancreatic Invasion Completely Resected after Chemotherapy].

An 80-year-old man with severe anemia was found to have a circumferential type 3 lesion with obstruction in the gastric pylorus during upper gastrointestinal endoscopy. A contrast-enhanced CT scan of the abdomen showed severe invasion of the pancreatic head, and the diagnosis was gastric cancer L, Circ, cType 3, tub2, cT4b, N(+), M0, cStage ⅣA. The patient underwent laparoscopic gastrojejunostomy for gastrointestinal transit obstruction followed by 4 courses of SOX therapy as systemic chemotherapy. After chemotherapy, the invasion to the head of the pancreas was obscured, and pyloric gastrectomy and lymph node dissection were performed. The patient was recurrence-free as of 18 months after surgery. In this case, we performed gastric jejunal bypass surgery followed by chemotherapy with oral anticancer agents to achieve the downstaging of unresectable advanced gastric cancer with pancreatic invasion and pyloric stenosis in patients with poor general condition. As a result, the patient was able to undergo distal gastrectomy, which is one of the recommended multidisciplinary treatments.

Clinical Significance of Endoscopic Response Evaluation to Predict the Distribution of Residual Tumor after Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma.

PURPOSE: To appropriately adopt the organ preservation approach, including subsequent chemoradiotherapy (CRT) in patients who respond to neoadjuvant chemotherapy (NAC), the distribution of residual disease, including pathological lymph nodes (LNs) and recurrence site, needs to be recognized preoperatively. This study was designed to evaluate whether endoscopic response evaluation can predict residual tumor distribution. METHODS: Patients with esophageal squamous cell carcinoma who underwent transthoracic esophagectomy (TTE) were retrospectively reviewed. Endoscopic responder (ER) to NAC was defined according to primary tumor endoscopic findings. Recurrence-free survival (RFS), overall survival (OS), and residual tumor patterns were compared between groups. RESULTS: Of 193 patients, 40 (20%) were classified as ER. ERs showed significantly better RFS and OS. The pN location was found within the primary tumor and cN field in 88% of ERs, which was significantly higher than non-ERs at 63% (p = 0.004). Furthermore, the postoperative recurrence incidence in the distant organ was significantly lower in the ERs than the non-ERs (8%, 32%, respectively, p = 0.002). Residual disease, including postoperative initial recurrence, existed within the same field as the primary tumor and cN in 88% of ERs, significantly higher than 42% in the non-ERs (p < 0.001). CONCLUSIONS: Endoscopic response evaluation can preoperatively predict distribution of residual tumors after NAC, which could help radiation field selection in subsequent definitive CRT when patients prefer to omit TTE. Along with improvements in NAC response rate, this could facilitate organ preservation in patients who respond to NAC.

Safety and efficacy of apalutamide in Japanese patients with metastatic castration-sensitive prostate cancer receiving androgen deprivation therapy: Final report for the Japanese subpopulation analysis of the randomized, placebo-controlled, phase III TITAN study.

OBJECTIVES: The TITAN study is a randomized, double-blind, placebo-controlled, multinational trial that evaluated apalutamide with androgen deprivation therapy in patients with metastatic castration-sensitive prostate cancer. At the first interim analysis in the Japanese subpopulation (median follow-up 25.7 months), there was an improvement in overall survival and radiological progression-free survival with apalutamide versus placebo. Here, we report the final analysis results for the Japanese subpopulation. METHODS: Patients were randomized 1:1 to receive apalutamide 240 mg or placebo. After the first interim analysis, protocol treatment was unblinded, and crossover was allowed. Efficacy and safety were evaluated in the preplanned, event-driven final analysis. RESULTS: Fifty-one patients were Japanese (apalutamide n = 28; placebo n = 23). After a median follow-up of 46.0 months, the median overall survival was not reached neither in the apalutamide nor the placebo group; the hazard ratio was 0.45, favoring apalutamide, which was consistent with the overall population. Hazard ratios for time to cytotoxic chemotherapy (0.39), time to pain progression (0.87), and time to chronic opioid use (0.82) also favored apalutamide and were comparable with those of the overall population. Time to prostate-specific antigen progression and progression-free survival 2, respectively, was favored in the apalutamide group (0.21 and 0.44). Apalutamide was associated with higher incidences of rash and fracture in the Japanese subpopulation compared with the overall population. CONCLUSIONS: The efficacy of apalutamide with androgen deprivation therapy in Japanese patients was consistent with efficacy demonstrated in the overall population. No new safety concerns emerged with long-term follow-up.

Apalutamide for metastatic, castration-sensitive prostate cancer in the Japanese population: A subgroup analysis of the randomized, double-blind, placebo-controlled phase 3 TITAN study.

OBJECTIVE: To evaluate the efficacy and safety of apalutamide + androgen deprivation therapy versus androgen deprivation therapy alone in Japanese patients with metastatic castration-sensitive prostate cancer from the phase 3, randomized, global TITAN study. METHODS: Men with metastatic castration-sensitive prostate cancer randomly (1:1) received 240 mg apalutamide + androgen deprivation therapy or matching placebo + androgen deprivation therapy. The primary efficacy endpoints were radiographic progression-free survival and overall survival. Secondary efficacy endpoints were time to cytotoxic chemotherapy, pain progression, chronic opioid use, and skeletal-related events. Safety was also assessed. RESULTS: Of the 1052 patients included in the TITAN study, 51 (4.85%) were Japanese (apalutamide group, n = 28; placebo group, n = 23). In all, 81.8% of patients in the apalutamide and 71.8% in the placebo group did not experience radiographic progression or death, and the hazard ratio for radiographic progression-free survival favored treatment with apalutamide (hazard ratio 0.712, 95% confidence interval 0.205-2.466; P = 0.59). At 24 months, 85.7% of patients in the apalutamide group and 81.5% in the placebo group were alive, and the hazard ratio for overall survival favored apalutamide (hazard ratio 0.840, 95% confidence interval 0.210-3.361; P = 0.805). In the interim analysis, the median radiographic progression-free survival and overall survival were not reached in the apalutamide group and time to cytotoxic chemotherapy was delayed following apalutamide treatment. The safety profile of apalutamide in the Japanese subpopulation was comparable with that of the global population, except for skin rash. CONCLUSIONS: The results of the present analyses suggest that apalutamide + androgen deprivation therapy in Japanese patients had favorable efficacy compared with androgen deprivation therapy alone, and these findings are comparable to those in the overall population. Apalutamide + androgen deprivation therapy can be considered as one of the therapeutic options for a broad spectrum of metastatic castration-sensitive prostate cancer regardless of prior treatment and disease extent in Japanese patients.

Verification of oncological local control for hand-assisted laparoscopic abdominal lymph node dissection in esophageal cancer surgery: a propensity score-matched analysis.

BACKGROUND: In esophageal cancer, long-term outcomes of minimally invasive surgery using endoscopic surgery are currently being verified. However, most trials have compared thoracic procedures; few studies have focused on the abdominal procedures, which are important for lymph node dissection in radical esophageal cancer surgery. Hand-assisted laparoscopic surgery (HALS) is a simple and minimally invasive procedure. Although HALS superiority in short-term outcomes has been reported, its oncological safety in esophageal cancer remains unclear. Therefore, we retrospectively evaluated oncological safety of HALS compared with that of conventional open laparotomy (OL) in radical surgery for thoracic and abdominal esophageal cancer. METHODS: We retrospectively analyzed the postoperative survival in 142 patients who underwent radical esophageal cancer surgery at our hospital between May 2012 and May 2017, with and without propensity score matching (PSM) between groups. RESULTS: Before PSM, OL (n = 65) and HALS (n = 77) groups differed significantly in overall survival (OS) (3-year OS rate: 74.2% and 87.3%, respectively; log-rank p = 0.040). Additionally, clinical abdominal lymph node metastasis (cALNM) independently predicted OS (p = 0.031). After PSM, the OL and HALS groups did not differ significantly in OS (3-year OS rate: 80.5% and 89.8%, respectively; log-rank p = 0.716). There was no statistically significant difference in abdominal-specific recurrence-free survival between the OL and HALS group before and after PSM. CONCLUSION: HALS may be a well-accepted procedure for radical esophagectomy in esophageal cancer, with oncological safety, including local control specific to the abdomen, comparable to that of the conventional OL.

Clinical outcomes of laparoscopic and endoscopic cooperative surgery for submucosal tumors on the esophagogastric junction: a retrospective single-center analysis.

BACKGROUND: Laparoscopic and endoscopic cooperative surgery (LECS) technique for gastric submucosal tumor (SMT) has developed, but treatment of SMT on the esophagogastric junction (EGJ) remains technically difficult because excessive resection may result in postoperative transformation of the EGJ and cause stenosis, and intervention to lower esophageal sphincter may result in gastroesophageal reflux. The study aim was to evaluate the feasibility and safety of LECS for SMT on the EGJ. METHODS: Between September 2012 and December 2018, LECS was performed for 21 patients with SMTs on the EGJ. Fundoplication was performed after LECS according to the intraoperative findings for each case. The patients' backgrounds, operative outcomes, and follow-up data, including endoscopic findings of gastroesophageal reflux disease (GERD) and proton pomp inhibitor (PPI) use, were reviewed. RESULTS: In all 21 cases, LECS was completed with a mean operation time of 225 min, and a mean blood loss of 8.8 mL. All patients were alive without recurrence within the mean follow-up period of 30.5 months. Both GERD and PPI use tended to be less frequent when fundoplication was performed, although these differences were not statistically significant. (7.7% vs. 37.5%; P = 0.091, 23.1% vs. 50.0%; P = 0.204, respectively). CONCLUSIONS: We demonstrated the feasibility and safety of LECS for SMTs even on the EGJ. Fundoplication after LECS may be an approach for the prevention of postoperative reflux esophagitis. Future research is warranted to validate the efficacy of the addition of fundoplication.

Clinical outcomes of non-exposed endoscopic wall-inversion surgery for gastric submucosal tumors: long-term follow-up and functional results.

BACKGROUND AND AIMS: To avoid the risk of iatrogenic dissemination during procedures, we have developed a combined laparoscopic and endoscopic surgery with a nonexposure technique for resection of gastric tumors. The study aim was to evaluate the feasibility and safety of non-exposed endoscopic wall-inversion surgery (NEWS) for gastric submucosal tumors (SMTs). METHODS: Between August 2013 and February 2018, NEWS was performed for 42 patients with gastric SMTs ≤ 3 cm in diameter at our institution. We retrospectively investigated the patients' backgrounds, operative and perioperative outcomes, tumor pathological characteristics, and follow-up data. RESULTS: All tumors were resected with negative margins by NEWS. The median operation time was 198 min, and the median estimated blood loss was 5.0 mL. Adverse events occurred in one patient with pneumonia. All patients were alive without recurrence within the median follow-up period of 29.2 months. The average body weight loss rate was 0.3 ± 4.0%. No food residue was observed at endoscopic follow-up. CONCLUSIONS: On the basis of slight body weight loss and the absence of food residue observed in the postoperative endoscopy, NEWS appeared to be safe and feasible for gastric SMTs and to preserve function of the remnant stomach.

Impact of endoscopic resection on the choice of surgical procedure in patients with additional laparoscopic gastrectomy.

BACKGROUND: Additional surgery is recommended for patients with noncurative resection after endoscopic submucosal dissection (ESD) for early gastric cancer. Additional resection requires the excision of an area larger than that of the resected mucosa in ESD, which is larger than the lesion, with convergence of the gastric mucosa due to scarring. Thus, the selection of the surgical procedure for lesion removal in specific areas can be affected by ESD. This study therefore aimed to evaluate the impact of ESD on the selection of additional gastrectomy in patients with early gastric cancer in the boundary area between the upper third and middle third of the stomach (UM boundary region). METHODS: Between January 2013 and June 2018, laparoscopic gastrectomy was performed in 89 patients with cT1N0M0 gastric cancer located only in the UM boundary region. The patients' backgrounds and surgical and pathological results were retrospectively investigated. The predictive factors for performing laparoscopic distal gastrectomy (LDG) were evaluated by multivariate analysis. RESULTS: Among 89 patients, 23 patients underwent ESD before surgery. LDG was significantly less often performed in the ESD-surgery group than in the surgery-only group (34.8% vs. 72.7%; p = 0.003). Preoperative ESD was an independent negative predictor of LDG (odds ratio = 0.266; p = 0.025). CONCLUSIONS: Preoperative ESD has an impact on the selection of the type of additional gastrectomy, including reducing the conduct of LDG for early gastric cancer in the UM boundary region.

Effect of azygos arch preservation during thoracoscopic esophagectomy on facilitation of postoperative refilling.

PURPOSE: In esophageal cancer surgery, the significance of preserving the azygos arch during thoracoscopic esophagectomy remains unknown. To determine the significance, we examined the difference in postoperative courses between patients who underwent an azygos arch-preserving technique and patients whose azygos arch had been dissected. METHODS: We retrospectively analyzed 119 patients with esophageal cancer who underwent thoracoscopic esophagectomy from January 2017 to December 2019. Statistical tests, including univariate or multivariate analyses and propensity score-matched analysis, were performed focusing on changes in fluid balance caused by the preservation of the azygos arch. RESULTS: The azygos arch was preserved in 65 patients and dissected in 54 patients. Urine output on postoperative day 2 was higher, and the IN-OUT balance on postoperative day 2 or accumulated IN-OUT balance up to postoperative day 2 tended to be lower in the azygos arch-preserving group than in the dissected group. The azygos arch-preserving technique did not affect the number of dissected mediastinal lymph nodes. CONCLUSION: The azygos arch-preserving technique during thoracoscopic esophagectomy facilitated postoperative refilling and avoided postoperative fluid excess. This technique might be a novel minimally invasive option for an otherwise highly invasive esophageal cancer surgery.

[A Case of Esophagogastric Junction(EGJ)Cancer for Which Pathological Complete Response(pCR)Was Obtained by Multidisciplinary Treatment].

We report the case of a 68-year-old male with EGJ cancer, who was treated with palliative radiotherapy for persistent bleeding, and for whom, pCR was ultimately obtained by chemotherapy. Chemotherapy was planned to treat the EGJ cancer with intramural metastasis of the esophagus, but anemia due to persistent bleeding from the tumor was noted. Even with frequent blood transfusions, the anemia was difficult to control. Palliative radiotherapy was performed at 30 Gy/10 Fr for hemostasis, followed by chemotherapy. After approximately 9 months of chemotherapy, reduction of the primary tumor, a metastatic lymph node, and disappearance of the intramural metastasis of the esophagus were noted, and conversion surgery was performed. In the final histopathological examination, pCR was obtained. Radiotherapy for persistent bleeding from advanced gastric cancer is a minimally invasive treatment, and therefore could be an effective treatment to enable chemother- apy without any loss of compliance.

Discrepancy Between the Clinical and Final Pathological Findings of Lymph Node Metastasis in Superficial Esophageal Cancer.

BACKGROUND: Recent advances in endoscopic examinations have resulted in the detection of a larger number of early esophageal cancers; however, there have been many cases with clinically negative but pathologically positive lymph node metastasis (LNM). In this study, we aimed to evaluate the discrepancy between the clinical and pathological diagnoses of LNM in patients with cT1a-MM/cT1b N0M0 esophageal cancer, and assess LNM size in these patients to clarify the presence of LNM that cannot be detected with current modalities. METHODS: This study included 50 patients who underwent surgery for cT1a-MM/cT1b N0M0 thoracic esophageal squamous cell carcinoma between January 2012 and November 2016 at our institution. The maximum size of involved LNs and metastatic nests were measured, and the distribution of LNM was investigated. RESULTS: Of the 50 patients, 13 (26%) had LNM on pathological examination. Lymphatic invasion was significantly more frequent in the LNM-positive group than in the LNM-negative group (p = 0.005). The median sizes of 28 involved LNs and metastatic nests were 3 and 1.6 mm, respectively. Of these LNs, 20 (71%) were classified as micrometastases (≤ 2 mm). The involved nodes were distributed across three fields. CONCLUSIONS: There was a discrepancy between the clinical and final pathological findings of LNM in patients with cT1a-MM/cT1b N0M0 esophageal cancer. The detection of involved nodes with current modalities in these patients was difficult because of the small size of LNM. Therefore, continued strong consideration for extended LN dissection is necessary in these patients to ensure appropriate diagnosis and treatment.

Thyroid and Parathyroid Functions After Pharyngo-Laryngo-Esophagectomy for Cervical Esophageal Cancer.

BACKGROUND: Cervical esophageal cancer (CEC) patients whose larynx function cannot be preserved often undergo chemoradiotherapy, whereas those with residual or recurrent lesions undergo a pharyngo-laryngo-esophagectomy (PLE); however, some need to undergo a pharyngolaryngectomy with total esophagectomy (PLTE) for synchronous or metachronous esophageal cancer. We retrospectively evaluated the relationship between preoperative irradiation (or the extent of esophageal resection) and postoperative endocrine complications in CEC, including hypothyroidism and hypoparathyroidism. METHODS: The cancers of 35 (5.4%) of 678 esophageal cancer patients with esophagectomy treated in 2000-2017 were CECs. We also analyzed the 17 cases of CEC patients who underwent PLE with thyroid lobectomy-11 with irradiation before PLE and 6 without irradiation. Seven patients underwent a PLTE. RESULTS: Hypothyroidism and hypoparathyroidism occurred in 14 and 12 patients, respectively. The hypothyroidism rate was significantly higher in patients with irradiation versus those without irradiation (100% vs. 50%; p = 0.010), and the hypoparathyroidism rate was significantly higher in the PLTE versus non-PLTE patients (100% vs. 50%; p = 0.026). The mean levothyroxine dosage was 1.60 µg/kg/day in the PLE patients post-irradiation. CONCLUSIONS: Irradiation appears to be a risk factor for hypothyroidism after PLE with thyroid lobectomy, while PLTE might have some effect on hypoparathyroidism. Due to vocal function loss, PLE patients may experience symptoms from endocrine complications. Levothyroxine treatment soon after PLE for post-irradiation patients and patients requiring as-needed calcium or vitamin D supplementation based on biochemical hypocalcemia for PLE (especially PLTE), may be effective in preventing symptomatic endocrine complications.

Potential for local resection with sentinel node basin dissection for early gastric cancer based on the distribution of primary sites.

BACKGROUND: Based on the sentinel node (SN) concept, function-preserving surgery with SN basin dissection (SNBD) can be performed for SN-negative early gastric cancers. Particularly, a resection area can be minimized when the SN basin and primary site are closely localized. The aim of this study was to compare probabilities of being candidates for local resection with SNBD based on tumor location among patients with early gastric cancer. METHODS: We retrospectively analyzed 358 patients who underwent surgery with SN mapping for gastric cancer in our institution from November 1999 to April 2014. The proportion of patients who had a localized single basin and the distributions of the SN basins and primary sites were investigated. Patients with single basin drainage excluding remote sentinel node basin were considered as candidates for local resection with SNBD. RESULTS: Of the 358 patients, 191 (53%) patients were considered eligible for local resection with SNBD. Patients with tumors located in the upper third of the stomach were more likely candidates for local resection than those with tumors in other locations (upper third, 68%; middle third, 50%; and lower third, 51%), whereas patients with tumors located in the anterior wall were less likely candidates than those with tumors other locations (anterior wall, 31%; posterior wall, 58%; greater curvature, 55%; and lesser curvature, 57%). CONCLUSION: We found that > 50% of the patients indicated for SN navigation surgery, particularly those with tumors in the upper third of the stomach, potentially could undergo partial resection with SNBD.

Conversion surgery for gastric remnant cancer with liver metastasis after nivolumab combination chemotherapy achieving pathological complete response: a case report and literature review.

BACKGROUND: Nivolumab combination chemotherapy has recently emerged as a potential first-line treatment for patients with unresectable or metastatic gastric cancer (GC). Further research has indicated that R0 resection by conversion surgery could be an effective treatment strategy to improve overall survival. However, there have been limited reports on the successful application of conversion surgery following combination chemotherapy achieving pathological complete response (pCR) in cases of advanced gastric remnant cancer with liver metastasis. Here, we present a case of long-term survival in a patient who underwent this treatment. CASE PRESENTATION: A 54-year-old man was initially referred to our department for treatment of stage III (cT3N1M0) gastric cancer where he underwent laparoscopic distal gastrectomy and D2 lymph node dissection. After a year of uneventful follow-up, the patient was diagnosed with a tumor in the gastric remnant combined with liver metastasis, resulting in a diagnosis of stage IV (cT3N0M1) gastric remnant cancer. Subsequently, the patient was treated with four cycles of TS-1, Oxaliplatin, and Nivolumab as the first-line regimen. Remarkably, both the remnant tumor and liver metastasis exhibited significant shrinkage, and no new lesions were found. Given this response, conversion surgery was performed to achieve complete resection of the remnant gastric cancer and liver metastasis, followed by laparoscopic remnant gastrectomy and partial hepatectomy. Pathological examination revealed the absence of residual carcinoma cells and lymph node metastases. Postoperatively, the patient was treated with adjuvant chemotherapy with S-1 for 1 year, and survived without recurrence for 18 months after conversion surgery. CONCLUSIONS: Nivolumab combination chemotherapy shows promise as a clinically beneficial treatment approach for gastric remnant cancer with liver metastasis, particularly when pCR can be achieved following conversion surgery.

Apalutamide and Goserelin for Androgen Receptor-Positive Salivary Gland Carcinoma: A Phase II Nonrandomized Clinical Trial, YATAGARASU.

PURPOSE: To assess the efficacy and safety of apalutamide plus goserelin for androgen receptor (AR)-positive unresectable or recurrent/metastatic salivary gland carcinoma. PATIENTS AND METHODS: This trial was an open-label, single-arm, multicenter phase II study. Patients with histologically confirmed unresectable or recurrent/metastatic salivary gland carcinoma with AR expression were included. The primary endpoint was the overall response rate (ORR) according to RECIST v1.1 by an independent central radiology review in the first 24 response-evaluable (RE) patients who had been observed at least 24 weeks from study initiation (primary RE patients). The efficacy was to be declared when at least 8 of the 24 primary RE patients responded. RESULTS: A total of 31 patients were enrolled. In the first 24 primary RE patients with a median follow-up of 7.4 months, confirmed ORR by independent central radiology review was 25.0% [6/24 patients; 95% confidence interval, 9.8%-46.7%; P = 0.11 (one-sided)], which did not meet the predefined criteria of efficacy. Clinical benefit rate (ORR + rate of stable disease for at least 24 weeks) and median progression-free survival were 50.0% and 7.4 months, respectively. Both median duration of response and overall survival were not reached. Exploratory analyses showed a better ORR of 54.5% (6/11) in patients with AR positivity ≥70% and no history of prior systemic therapy. Grade 3 or higher treatment-emergent adverse events were reported in 35.5% (11/31), which included skin rash, anemia, leukopenia, and cancer pain. CONCLUSIONS: Although this study did not meet the predefined efficacy criteria, apalutamide plus goserelin showed clinically meaningful efficacy in a subset of patients with AR-positive salivary gland carcinoma and safety consistent with prior experience in prostate cancer.

P53 Activation Promotes Maturational Characteristics of Pluripotent Stem Cell-Derived Cardiomyocytes in 3-Dimensional Suspension Culture Via FOXO-FOXM1 Regulation.

BACKGROUND: Current protocols generate highly pure human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in vitro that recapitulate characteristics of mature in vivo cardiomyocytes. Yet, a risk of arrhythmias exists when hiPSC-CMs are injected into large animal models. Thus, understanding hiPSC-CM maturational mechanisms is crucial for clinical translation. Forkhead box (FOX) transcription factors regulate postnatal cardiomyocyte maturation through a balance between FOXO and FOXM1. We also previously demonstrated that p53 activation enhances hiPSC-CM maturation. Here, we investigate whether p53 activation modulates the FOXO/FOXM1 balance to promote hiPSC-CM maturation in 3-dimensional suspension culture. METHODS AND RESULTS: Three-dimensional cultures of hiPSC-CMs were treated with Nutlin-3a (p53 activator, 10 µM), LOM612 (FOXO relocator, 5 µM), AS1842856 (FOXO inhibitor, 1 µM), or RCM-1 (FOXM1 inhibitor, 1 µM), starting 2 days after onset of beating, with dimethyl sulfoxide (0.2% vehicle) as control. P53 activation promoted hiPSC-CM metabolic and electrophysiological maturation alongside FOXO upregulation and FOXM1 downregulation, in n=3 to 6 per group for all assays. FOXO inhibition significantly decreased expression of cardiac-specific markers such as TNNT2. In contrast, FOXO activation or FOXM1 inhibition promoted maturational characteristics such as increased contractility, oxygen consumption, and voltage peak maximum upstroke velocity, in n=3 to 6 per group for all assays. Further, by single-cell RNA sequencing of n=2 LOM612-treated cells compared with dimethyl sulfoxide, LOM612-mediated FOXO activation promoted expression of cardiac maturational pathways. CONCLUSIONS: We show that p53 activation promotes FOXO and suppresses FOXM1 during 3-dimensional hiPSC-CM maturation. These results expand our understanding of hiPSC-CM maturational mechanisms in a clinically-relevant 3-dimensional culture system.

Surgical Treatment of a Defect Recurring 22 Years after Closure of an Inferior Sinus Venosus Defect: A Case Report.

BACKGROUND: Residual shunt after closure of an inferior sinus venosus defect (ISVD) is a rare complication with a high rate of reintervention. CASE PRESENTATION: Here, we report a rare case of a recurrent defect identified 22 years after closure of an ISVD. The defect (25 × 10 mm) was located at the inferior vena cava-right atrial junction and was closed directly when the patient was 5 years of age. No residual shunt was detected and follow-up was discontinued at age 12 years. However, a residual atrial septal defect shunt was detected incidentally at age 27 years. During the second surgery, the lower end of the original defect was opened and then closed with an expanded polytetrafluoroethylene patch. CONCLUSIONS: Because of the high rate of reintervention for residual shunt after ISVD closure, patch closure was selected as a better option to reduce tension at the inferior-posterior border. Patients with this profile should be followed closely, at least during childhood, including by echocardiography.

Tissue-embedded stretchable nanoelectronics reveal endothelial cell-mediated electrical maturation of human 3D cardiac microtissues.

Clinical translation of stem cell therapies for heart disease requires electrical integration of transplanted cardiomyocytes. Generation of electrically matured human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is critical for electrical integration. Here, we found that hiPSC-derived endothelial cells (hiPSC-ECs) promoted the expression of selected maturation markers in hiPSC-CMs. Using tissue-embedded stretchable mesh nanoelectronics, we achieved a long-term stable map of human three-dimensional (3D) cardiac microtissue electrical activity. The results revealed that hiPSC-ECs accelerated the electrical maturation of hiPSC-CMs in 3D cardiac microtissues. Machine learning-based pseudotime trajectory inference of cardiomyocyte electrical signals further revealed the electrical phenotypic transition path during development. Guided by the electrical recording data, single-cell RNA sequencing identified that hiPSC-ECs promoted cardiomyocyte subpopulations with a more mature phenotype, and multiple ligand-receptor interactions were up-regulated between hiPSC-ECs and hiPSC-CMs, revealing a coordinated multifactorial mechanism of hiPSC-CM electrical maturation. Collectively, these findings show that hiPSC-ECs drive hiPSC-CM electrical maturation via multiple intercellular pathways.

Effect of aqueous olanexidine versus alcohol-based chlorhexidine for surgical skin antisepsis on incidence of surgical site infections in gastrointestinal surgery: multicentre randomised controlled clinical trial (OEDO trial) protocol.

INTRODUCTION: Surgical site infections (SSIs) are among the most common nosocomial infections in surgery patients. Two types of preparations, povidone-iodine and chlorhexidine-alcohol, are commonly used in preoperative antiseptic procedures worldwide. However, there are inconsistencies among international guideline recommendations concerning skin antiseptics. This trial aimed to evaluate the superiority of olanexidine, which reduced SSI rates more than povidone-iodine in our previous randomised trial, over chlorhexidine-alcohol in clean-contaminated surgery. METHODS AND ANALYSIS: This multicentre randomised controlled clinical trial will compare two antiseptics (1.5% olanexidine and 1.0% chlorhexidine-alcohol) to prevent SSI in clean-contaminated gastrointestinal surgeries with surgical wounds. On providing consent, patients aged <18 years will be included. The primary outcome will be the postoperative 30-day overall SSI rate, while the secondary outcomes will be the postoperative 30-day superficial incisional SSI rate, deep incisional SSI rate, organ/space SSI rate, positive bacterial wound culture rate, cultured bacterial strains, rates of intervention-related toxicity and allergic events (eg, erythema, pruritus, dermatitis and other symptoms of allergy around the region disinfected by the antiseptic during surgery), rate of reoperations due to SSI, medical economic effect indicators (based on health insurance claims) and hospital duration. The Mantel-Haenszel method will be used to estimate the adjusted risk ratio and its 95% CI for the primary analysis, which will compare the treatment effects. ETHICS AND DISSEMINATION: The protocol was approved by the Institutional Review Board of Keio University School of Medicine and subsequently by the board of each participating site. Participant recruitment began in January 2023. The final results will be published in medical journals after international peer review. TRIAL REGISTRATION NUMBER: UMIN000049712.