Machine-learning model derived gene signature predictive of paclitaxel survival benefit in gastric cancer: results from the randomised phase III SAMIT trial.

OBJECTIVE: To date, there are no predictive biomarkers to guide selection of patients with gastric cancer (GC) who benefit from paclitaxel. Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) was a 2×2 factorial randomised phase III study in which patients with GC were randomised to Pac-S-1 (paclitaxel +S-1), Pac-UFT (paclitaxel +UFT), S-1 alone or UFT alone after curative surgery. DESIGN: The primary objective of this study was to identify a gene signature that predicts survival benefit from paclitaxel chemotherapy in GC patients. SAMIT GC samples were profiled using a customised 476 gene NanoString panel. A random forest machine-learning model was applied on the NanoString profiles to develop a gene signature. An independent cohort of metastatic patients with GC treated with paclitaxel and ramucirumab (Pac-Ram) served as an external validation cohort. RESULTS: From the SAMIT trial 499 samples were analysed in this study. From the Pac-S-1 training cohort, the random forest model generated a 19-gene signature assigning patients to two groups: Pac-Sensitive and Pac-Resistant. In the Pac-UFT validation cohort, Pac-Sensitive patients exhibited a significant improvement in disease free survival (DFS): 3-year DFS 66% vs 40% (HR 0.44, p=0.0029). There was no survival difference between Pac-Sensitive and Pac-Resistant in the UFT or S-1 alone arms, test of interaction p<0.001. In the external Pac-Ram validation cohort, the signature predicted benefit for Pac-Sensitive (median PFS 147 days vs 112 days, HR 0.48, p=0.022). CONCLUSION: Using machine-learning techniques on one of the largest GC trials (SAMIT), we identify a gene signature representing the first predictive biomarker for paclitaxel benefit. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry: C000000082 (SAMIT); ClinicalTrials.gov identifier, 02628951 (South Korean trial).

Feasibility of totally laparoscopic total gastrectomy in obese patients with gastric cancer.

PURPOSE: This study aimed to evaluate the short- and long-term outcomes in obese patients with gastric cancer undergoing totally laparoscopic total gastrectomy (TLTG) to clarify its feasibility in this population. METHODS: We examined 136 consecutive patients who underwent TLTG for gastric cancer (GC) between 2013 and 2018. A total of 45 patients with a body mass index (BMI) ≥ 25 kg/m2 were defined as the obese group (obese and overweight patients by the WHO classification), and 91 patients with a BMI < 25 kg/m2 were defined as the non-obese group. Short- and long-term outcomes were compared, and the correlation between obesity and postoperative complications was examined in patients who underwent TLTG. RESULTS: Although the operation time (min) was significantly longer in the obese group than in the non-obese group (329 vs 307, p = 0.002), there were no significant differences in the total volume of blood loss (mL) (118 vs 60, p = 0.059) or the rate of conversion to laparotomy between the two groups (2 vs 2, p = 0.466). Moreover, there was no significant difference in the incidence of postoperative complications between the two groups (16% vs 19%, p = 0.653). In the multivariate analysis, obesity was not identified as a risk factor for postoperative complications among patients who underwent TLTG. The rate of overall survival was not significantly different between the groups (p = 0.512). CONCLUSION: TLTG is feasible for obese Japanese patients with GC. To validate the results of the present study, it is necessary to conduct a prospective study of a large population of patients with GC.

Postoperative acute pancreatitis after pancreatic resection in patients with pancreatic ductal adenocarcinoma.

INTRODUCTION: Postoperative pancreatic fistula (POPF) is one of the major critical complications after pancreatic resection. Recently, postoperative acute pancreatitis (POAP), a new concept for a pancreatic-specific complication following pancreatic resection, has been advocated, and its association with POPF has been reported. The present study examined the clinical features of POAP and identified the associations of POAP with POPF and other postoperative morbidities in pancreatic ductal adenocarcinoma (PDAC) patients undergoing pancreatic resection. METHODS: A total of 312 consecutive patients who underwent pancreatic resection for PDAC at our institution from 2013 to 2019 were enrolled in this study. POAP was defined as an elevated serum amylase level above the upper limit normal on postoperative day (POD) 0 or 1, based on Connor's definition. The severity of POPF was assessed by the International Study Group on Pancreatic Surgery definition. RESULTS: A total of 184 patients (58.9%) had POAP. POAP occurred in 58.5% of subtotal stomach-preserving pancreatoduodenectomy patients and 60% of distal pancreatectomy combined with splenectomy patients. The presence of POAP was significantly associated with the development of clinically relevant POPF, higher rates of severe morbidity, and a prolonged hospital stay after pancreatic resection. A multivariate analysis showed that the presence of POAP and elevated C-reactive protein levels on POD 3 were independent predictors of clinically relevant POPF after subtotal stomach-preserving pancreatoduodenectomy. CONCLUSIONS: POAP is associated with the development of POPF, higher rates of severe morbidity, and a prolonged hospital stay after pancreatic resection and is an independent risk factor for clinically relevant POPF after pancreatoduodenectomy. POAP represents an important indicator for planning treatment strategies to prevent serious complications, including POPF.

[Vascular Prosthesis Perforation Caused by a Stent Graft Inserted into the Innominate Artery after Total Aortic Arch Replacement].

The patient was a 60-year-old woman who underwent thoracoabdominal aorta replacement for type B aortic dissection three years ago and aortic root replacement and total aortic arch replacement due to asymptomatic type A aortic dissection two years previously. Her clinical course was uneventful until follow-up computed tomography (CT) disclosed anastomotic insufficiency in the innominate artery and left main coronary artery stenosis owing to hematoma. Emergent percutaneous coronary intervention and stent graft insertion into the innominate artery were performed successfully. Seven months later, however, CT scan revealed a perforation in the posterior wall of the artificial graft damaged by the edge of the implanted stent graft. The patient underwent open surgery and perforation of artificial graft was sutured and redundant stent graft edge was resected. Artificial graft damage by stent graft placement is rare to date, but may increase in the future in accordance with broader application of endovascular treatment.

[A Case of Pregnancy-Associated Breast Cancer Which Underwent Surgical Treatment during Pregnancy and Chemotherapy after Delivery].

CASE: A 37-year-old pregnant woman arrived at our hospital with an abnormal mammogram. MEDICAL HISTORY: Mammography performed in June 2018 revealed an abnormal shadow on the left breast. Cytology from the 6-mm tumor in the left upper-outer quadrant revealed a malignancy. At the same time, a transvaginal echo revealed cysts, and the patient was diagnosed at 5 weeks gestation. Needle biopsy revealed a luminal A-like cStage Ⅰ, cT1bN0M0 invasive ductal carcinoma (IDC). Tumor resection and sentinel lymph node biopsy were performed under local anesthesia at 12 weeks gestation, and post-delivery adjuvant therapy was planned. Histologic examination of the resected tumor revealed that it was HER2-positive( immunohistochemistry score 3+); therefore, we had to reconsider the use of trastuzumab and decided to administer it to the patient after childbirth. The patient gave birth by cesarean section, and weekly paclitaxel plus trastuzumab was initiated 7 months after surgery. The patient is currently alive without recurrence. DISCUSSION: We faced several difficulties during the treatment of this patient. Postoperative adjuvant therapy is recommended to be administered 8 weeks after the surgical resection of the tumor. However, in our case, given that the tumor was HER2-positive, we could administer adjuvant therapy with trastuzumab only after delivery. Although the prevalence of breast cancer in women below the age of 40 years in Japan is currently as low as 4-6%, the incidence of pregnancy-associated breast cancer is predicted to increase as the number of elderly primigravida increases due to later marriage.

The Impact of Pretherapeutic Naples Prognostic Score on Survival in Patients with Locally Advanced Esophageal Cancer.

BACKGROUND: Naples prognostic score (NPS) is a scoring system based on albumin, cholesterol concentration, lymphocyte-to-monocyte ratio, and neutrophil-to-lymphocyte ratio reflecting host systemic inflammation, malnutrition, and survival for several malignancies. This study was designed to assess the prognostic significance of NPS in patients with locally advanced esophageal squamous cell carcinoma (ESCC) and to compare its prognostic accuracy with that of other systemic inflammatory and nutritional index. METHODS: We retrospectively examined 165 patients with locally advanced ESCC who underwent neoadjuvant therapy followed by curative resection between January 2011 and September 2019. Patients were divided into three groups based on their NPS before neoadjuvant therapy (Group 0: NPS = 0; Group 1: NPS = 1-2; Group 2: NPS = 3-4). We compared the clinicopathological characteristics and survival rates among the groups. RESULTS: The 5-year recurrence-free survival (RFS) and overall survival (OS) rates were significantly different between the groups (P < 0.001). The NPS was superior to other systemic inflammatory and nutritional index for predicting prognoses, as determined using area under the curves (P < 0.05). Multivariate analysis demonstrated that the NPS was a significant predictor of poor RFS (Group 1: hazard ratio [HR] 1.897, P = 0.049; Group 2: HR 3.979, P < 0.001) and OS (Group 1: HR 2.152, P = 0.033; Group 2: HR 3.239, P = 0.006). CONCLUSIONS: The present study demonstrated that NPS was an independent prognostic factor in patients with locally advanced ESCC and more reliable and accurate than the other systemic inflammatory and nutritional index.

Outcomes for Minimally Invasive Follicular Thyroid Carcinoma in Relation to the Change in Age Stratification in the AJCC 8th Edition.

BACKGROUND: Completion total thyroidectomy with radioactive iodine (RAI) therapy is not uniformly recommended for minimally invasive follicular thyroid carcinomas (MI-FTCs) without distant metastasis, but may be considered for cases with a risk factor of recurrence, such as age ≥ 45 years. OBJECTIVE: The present study aimed to investigate the outcomes for patients with MI-FTC using a stratification age of 55 years. METHODS: The records of 478 patients with MI-FTC confirmed by surgical specimens at Ito Hospital from January 2005 to December 2014 were retrospectively reviewed. Twenty patients had distant metastasis at diagnosis and were subsequently classified as M1. RESULTS: Among the 478 patients with MI-FTC, univariate analysis identified that age ≥ 55 years (p = 0.002) and M1 (p < 0.001) were related to cause-specific survival. In 458 patients with M0 MI-FTC, male sex (p = 0.041), age ≥ 55 years (p = 0.001), and tumor size > 40 mm (p < 0.001) were related to poor disease-free survival (DFS) in univariate analysis. Multivariate analysis showed that age ≥ 55 years (p = 0.005) and tumor size > 40 mm (p = 0.005) were independent prognostic factors for DFS. The 10-year DFS rates of patients aged < 45 years, 45 years ≤ age < 55 years, and ≥ 55 years were 97.0%, 95.5%, and 86.4%, respectively. CONCLUSIONS: The change in the recommended age for completion total thyroidectomy with RAI, from 45 to 55 years, seemed reasonable.

The Prognostic Value of Lymph Node Ratio in Locally Advanced Esophageal Cancer Patients Who Received Neoadjuvant Chemotherapy.

BACKGROUND: The lymph node (LN) ratio (LNR) has been proposed as a sensitive prognosticator in patients with esophageal squamous cell carcinoma (ESCC), especially when the number of LNs harvested is insufficient. We investigated the association between the LNR and survival in patients with locally advanced ESCC who received neoadjuvant chemotherapy (NAC) and explored whether the LNR is a prognosticator in these patients when stratified by their response to NAC. METHODS: We retrospectively reviewed 199 locally advanced ESCC patients who received curative resection after NAC between January 2011 and December 2019. The predictive accuracy of the adjusted X-tile cut-off values for LNR of 0 and 0.13 was compared with that in the Union for International Cancer Control pathological N (UICC pN) categories. The association between survival rate and clinicopathological features was examined. RESULTS: Multivariate analysis identified that the LNR was an independent risk factor for recurrence-free survival [RFS; hazard ratio (HR) 6.917, p < 0.001] and overall survival (OS) (HR 4.998, p < 0.001). Moreover, even when stratified by response to NAC, the LNR was a significant independent risk factor for RFS and OS (p < 0.001). The receiver operating characteristic curves identified that the prognostic accuracy of the LNR tended to be better than that of the UICC pN factor in all cases and responders. CONCLUSION: The LNR had a significant prognostic value in patients with locally advanced ESCC, including in those who received NAC.

Evaluation of Lymph Node Staging Systems as Independent Prognosticators in Remnant Gastric Cancer Patients with an Insufficient Number of Harvested Lymph Nodes.

BACKGROUND: The lymph node (LN) ratio (LNR) and the log odds of positive LNs (LODDS) have been proposed as sensitive prognosticators in patients with primary gastric cancer, especially in patients with an insufficient number of harvested LNs. We investigated the association of LNR and LODDS with survival in patients with remnant gastric cancer (RGC) and explored whether these staging methods are prognostic factors in patients with an insufficient number of harvested LNs. METHODS: The present study retrospectively examined 95 patients with RGC who received gastrectomy between January 2000 and December 2018. The patients were classified according to the adjusted X-tile cutoff for LNR and LODDS. The association between survival rates and clinicopathological features was investigated. The predictive accuracy of the LNR and LODDS was compared with that of the Union for International Cancer Control pathological N factor. RESULTS: Multivariate analysis revealed that the LNR and LODDS were independent risk factors for recurrence-free survival (RFS) [hazard ratio (HR) 2.623, p = 0.020; HR 3.404, p = 0.004, respectively] and overall survival (OS) (HR 3.694, p = 0.003; HR 2.895, p = 0.022, respectively) in patients with RGC. Moreover, even in patients with 15 or fewer harvested LNs, only the LNR was a significant independent risk factor for RFS (HR 21.890, p < 0.001) and OS (HR 6.597, p = 0.002). The receiver operating characteristic curves revealed that the prognostic accuracy of the three methods was comparable (p > 0.05). CONCLUSION: LNR has significant prognostic value for patients with RGC, including those with an insufficient number of harvested LNs.

Fibulin-1 Integrates Subendothelial Extracellular Matrices and Contributes to Anatomical Closure of the Ductus Arteriosus.

OBJECTIVE: The ductus arteriosus (DA) is a fetal artery connecting the aorta and pulmonary arteries. Progressive matrix remodeling, that is, intimal thickening (IT), occurs in the subendothelial region of DA to bring anatomic DA closure. IT is comprised of multiple ECMs (extracellular matrices) and migrated smooth muscle cells (SMCs). Because glycoprotein fibulin-1 binds to multiple ECMs and regulates morphogenesis during development, we investigated the role of fibulin-1 in DA closure. Approach and Results: Fibulin-1-deficient (Fbln1-/-) mice exhibited patent DA with hypoplastic IT. An unbiased transcriptome analysis revealed that EP4 (prostaglandin E receptor 4) stimulation markedly increased fibulin-1 in DA-SMCs via phospholipase C-NFκB (nuclear factor κB) signaling pathways. Fluorescence-activated cell sorting (FACS) analysis demonstrated that fibulin-1 binding protein versican was derived from DA-endothelial cells (ECs). We examined the effect of fibulin-1 on directional migration toward ECs in association with versican by using cocultured DA-SMCs and ECs. EP4 stimulation promoted directional DA-SMC migration toward ECs, which was attenuated by either silencing fibulin-1 or versican. Immunofluorescence demonstrated that fibulin-1 and versican V0/V1 were coexpressed at the IT of wild-type DA, whereas 30% of versican-deleted mice lacking a hyaluronan binding site displayed patent DA. Fibulin-1 expression was attenuated in the EP4-deficient mouse (Ptger4-/-) DA, which exhibits patent DA with hypoplastic IT, and fibulin-1 protein administration restored IT formation. In human DA, fibulin-1 and versican were abundantly expressed in SMCs and ECs, respectively. CONCLUSIONS: Fibulin-1 contributes to DA closure by forming an environment favoring directional SMC migration toward the subendothelial region, at least, in part, in combination with EC-derived versican and its binding partner hyaluronan.

Excessive EP4 Signaling in Smooth Muscle Cells Induces Abdominal Aortic Aneurysm by Amplifying Inflammation.

OBJECTIVE: Excessive prostaglandin E2 production is a hallmark of abdominal aortic aneurysm (AAA). Enhanced expression of prostaglandin E2 receptor EP4 (prostaglandin E receptor 4) in vascular smooth muscle cells (VSMCs) has been demonstrated in human AAAs. Although moderate expression of EP4 contributes to vascular homeostasis, the roles of excessive EP4 in vascular pathology remain uncertain. We aimed to investigate whether EP4 overexpression in VSMCs exacerbates AAAs. Approach and Results: We constructed mice with EP4 overexpressed selectively in VSMCs under an SM22α promoter (EP4-Tg). Most EP4-Tg mice died within 2 weeks of Ang II (angiotensin II) infusion due to AAA, while nontransgenic mice given Ang II displayed no overt phenotype. EP4-Tg developed much larger AAAs than nontransgenic mice after periaortic CaCl2 application. In contrast, EP4fl/+;SM22-Cre;ApoE-/- and EP4fl/+;SM22-Cre mice, which are EP4 heterozygous knockout in VSMCs, rarely exhibited AAA after Ang II or CaCl2 treatment, respectively. In Ang II-infused EP4-Tg aorta, Ly6Chi inflammatory monocyte/macrophage infiltration and MMP-9 (matrix metalloprotease-9) activation were enhanced. An unbiased analysis revealed that EP4 stimulation positively regulated the genes binding cytokine receptors in VSMCs, in which IL (interleukin)-6 was the most strongly upregulated. In VSMCs of EP4-Tg and human AAAs, EP4 stimulation caused marked IL-6 production via TAK1 (transforming growth factor-ß-activated kinase 1), NF-κB (nuclear factor-kappa B), JNK (c-Jun N-terminal kinase), and p38. Inhibition of IL-6 prevented Ang II-induced AAA formation in EP4-Tg. In addition, EP4 stimulation decreased elastin/collagen cross-linking protein LOX (lysyl oxidase) in both human and mouse VSMCs. CONCLUSIONS: Dysregulated EP4 overexpression in VSMCs promotes inflammatory monocyte/macrophage infiltration and attenuates elastin/collagen fiber formation, leading to AAA exacerbation.

Short-term results of a phase II study of preoperative docetaxel/cisplatin/S-1 therapy for locally advanced gastric cancer.

BACKGROUND: A multi-institutional phase II study was conducted to evaluate the efficacy and safety of preoperative docetaxel, cisplatin and S-1 therapy in marginally resectable advanced gastric cancer. METHODS: Patients with macroscopic type 4, large macroscopic type 3 and bulky lymph node metastasis received two cycles of preoperative docetaxel, cisplatin and S-1 therapy (docetaxel 40 mg/m2 and cisplatin 60 mg/m2 on day 1, and S-1 80 mg/m2 for 14 days, every 4 weeks). The primary endpoint was the pathological response rate, with an expected value of 65%. RESULTS: Thirty-one patients were enrolled in this study. The pathological response rate was 54.8%, and it was higher than the threshold value but lower than the expected rate. The R0 resection rate was 93.5%. The frequencies of grade 3-4 toxicities during docetaxel, cisplatin and S-1 therapy were 41.9% for neutropenia, 6.5% for febrile neutropenia and 32.3% for nausea/vomiting. Grade 2 and 3 surgical morbidities occurred in 23.3 and 6.7% of the patients, respectively. CONCLUSIONS: Preoperative docetaxel, cisplatin and S-1 therapy was feasible in terms of chemotherapy-related toxicities and surgical morbidity, but the effect did not achieve the expected value. The association between the pathological response rate and survival will be evaluated in the final analysis of this clinical trial.

Short-Term Outcomes from a Randomized Screening Phase II Non-inferiority Trial Comparing Omentectomy and Omentum Preservation for Locally Advanced Gastric Cancer: the TOP-G Trial.

BACKGROUND: Omentectomy is considered an essential part of curative gastrectomy for locally advanced gastric cancer (GC), albeit without solid evidence. We conducted a randomized phase II trial (the TOP-G trial) comparing omentectomy and omentum preservation for gastric cancer. This report describes the short-term findings regarding the trial's secondary endpoints. METHODS: The trial protocol was submitted to the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/ : UMIN000005421). The key eligibility criteria were histologically confirmed cT2-4a and N0-2 gastric adenocarcinoma. Short-term surgical outcomes, including morbidity and mortality, were compared between the omentectomy group (group A, control arm) and the omentum-preserving surgery group (group B, test arm). All procedures were performed via an open approach. Based on a non-inferiority margin of 7%, statistical power of 0.7, and type I error of 0.2, the sample size was set to 250 patients. RESULTS: A total of 251 patients were eligible and randomized (group A: 125 patients, group B: 126 patients) between April 2011 and October 2018. After excluding patients who had peritoneal metastasis or laparotomy history, safety outcomes were analyzed for 247 patients. Group A had a significantly longer median operation time (225 min vs. 204 min, p = 0.022) and tended to have greater median blood loss (260 mL vs. 210 mL p = 0.073). The incidences of morbidity were similar and < 10% in both groups (8% vs. 9%, p = 1.000). There was no mortality in either group. CONCLUSIONS: Operative risk was generally similar between omentectomy and omentum-preserving surgery for locally advanced gastric cancer.

Detection of EGFR mutation of pulmonary adenocarcinoma in sputum using droplet digital PCR.

BACKGROUND: It is still unclear whether epidermal growth factor receptor (EGFR) mutation of primary lung adenocarcinoma can be detected on sputum samples. This study aimed to examine EGFR mutations of primary lung adenocarcinoma in sputum samples using droplet digital polymerase chain reaction (ddPCR) and compare it with an EGFR mutation in surgically resected lung cancer. METHODS: Sputum was prospectively collected from the patients before complete resection of the primary lung cancer at Kanagawa Cancer Center from September 2014 to May 2016. ddPCR was performed to detect EGFR exon 21 L858R point mutation (Ex21) and EGFR exon 19 deletion mutation (Ex19) in sputum samples from patients with lung adenocarcinoma. The concordance of EGFR mutation status in sputum samples and tumors in surgically resected specimen was evaluated for each positive and negative cytology group. RESULTS: One hundred and eighteen patients with primary lung adenocarcinoma provided sputum samples. Sputum cytology was positive in 13 patients (11.0%). ddPCR detected two cases of Ex21 and two cases of Ex19 in sputum cytology positive cases. Compared to surgically resected specimens, the sensitivity, specificity, and positive predictive value of EGFR mutation (Ex19 and Ex21) detection were 80.0%, 100%, and 100%, respectively, in sputum cytology positive cases. In contrast, the sensitivity, specificity, and positive predictive value of EGFR mutation (Ex19 and Ex21) detection were 3.1%, 100%, and 100%, respectively, in sputum cytology negative cases. CONCLUSIONS: EGFR mutations in primary lung adenocarcinoma can be detected with high sensitivity in sputum samples if sputum cytology is positive.

Does the Endoscopic Surgical Skill Qualification System improve patients' outcome following laparoscopic surgery for colon cancer? A multicentre, retrospective analysis with propensity score matching.

BACKGROUND: This study aimed to investigate the short-term and oncological impact of the Endoscopic Surgical Skill Qualification System (ESSQS) by the Japan Society for Endoscopic Surgery on the operator performing laparoscopic surgery for colon cancer. METHODS: This retrospective cohort study was based on medical records from a multicentre database. A total of 417 patients diagnosed with stage II/III colon and rectosigmoid cancer treated with curative resection were divided into two groups according to whether they were operated on by qualified surgeons (Q group, n=352) or not (NQ group, n=65). Through strict propensity score matching, 98 cases (49 in each group) were assessed. RESULTS: Operative time was significantly longer in the NQ group than in the Q group (199 vs. 168 min, p=0.029). The amount of blood loss, post-operative complications, and duration of hospitalisation were similar between both groups. No mortality was observed. One conversion case was seen in the NQ group. The 3-year recurrence-free survival rate was 86.6% in the NQ group and 88.2% in the Q group, which was not statistically significant (log-rank p=0.966). CONCLUSION: Direct operation by ESSQS-qualified surgeons contributed to a shortened operation time. Under an organised educational environment, almost equivalent safety and oncological outcomes are expected regardless of the surgeon's qualifications.

Brachiocephalic artery dissection is a marker of stroke after acute type A aortic dissection repair.

OBJECTIVE: Postoperative stroke is a serious unsolved complication after acute type A aortic dissection (ATAAD) repair. We investigated the incidence and risk factors of stroke, and hypothesized that dissection of supra-aortic vessels is an important risk factor of this morbidity. METHODS: Between 2012 and 2019, 202 (56% men, median age 68 years) patients with ATAAD underwent surgical repair. Clinical data, image findings, method of circulatory support, and repair technique were retrospectively investigated to explore the risk factor of postoperative stroke. RESULTS: Of the 202 patients, operative mortality was 6% and the incidence of postoperative stroke was 12% (n = 25). Brachiocephalic artery (BCA) dissection was associated with a higher risk of stroke (odds ratio, 3.89; 95% confidence interval, 1.104-13.780; p = .035) having no relation to the presence or absence of left common carotid artery dissection. Preoperative malperfusion syndrome, circulatory arrest time, isolated cerebral perfusion time, repair technique (total arch replacement), and femoral artery perfusion alone were not related to the incident rate of postoperative stroke. Stroke occurred in both hemispheres, regardless of the laterality of carotid artery dissection. CONCLUSION: BCA dissection was an independent risk factor of stroke after ATAAD repair.

A novel method for isolating lymphatic endothelial cells from lymphatic malformations and detecting PIK3CA somatic mutation in these isolated cells.

PURPOSE: Tissue disaggregation and the cell sorting technique by surface markers has played an important role in isolating lymphatic endothelial cells (LECs) from lymphatic malformation (LM). However, this technique may have the drawback of impurities or result in isolation failure because it is dependent on surface marker expressions, the heterogeneity of which has been found in the lymphatic system. We developed a novel method for isolating LM-LECs without using whole tissue disaggregation. METHODS: Seven LM surgical specimens were collected from seven patients with LMs. LM-LECs were detached from the LM cyst wall by "lumen digestion" and irrigating the cystic cavity with trypsin, and maintained in culture. RESULTS: The cells formed a monolayer with a cobblestone-like appearance. Immunohistochemistry and quantitative RT-PCR of these cells revealed high expression of lymphatic-specific genes, confirming their identity as LM-LECs. The whole-exome sequencing and PIK3CA sequencing of these cells revealed somatic mutations in PIK3CA in all cases. CONCLUSIONS: We established a novel technique for isolating LM-LECs from LM tissue by "lumen digestion" without whole-tissue disaggregation. The limited incorporation of non-LM LECs in the isolate in our method could make it an important tool for investigating the heterogeneity of gene expression as well as mutations in LM-LECs.

Implementation of a beating heart system for training in off-pump and minimally invasive coronary artery bypass.

BACKGROUND: Several training devices have been developed to train anastomotic skills in off-pump coronary artery bypass grafting (OPCAB). However, assessment of trainees' improvement remains challenging. The goal of this study was to develop a new practical scoring chart and investigate its reliability and utility for anastomotic skills in OPCAB and minimally invasive direct coronary artery bypass (MIDCAB). METHODS: A training device was used, which included a beating heart model installed in a dedicated box. A soft plastic tube was used as the left anterior descending artery, and a porcine ureter was used as the left internal mammary artery. Five cardiac surgery fellows (Fellows, > 5 year of surgical experience) and five residents or medical students (Residents, ≤ 5 year of surgical experience) were enrolled for this study. Before and after training, skills were evaluated using a scoring chart that took into account anastomotic time, leakage, shape, flow measurement, and self-estimation. RESULTS: Mean total score of all trainees was 15.4 ± 4.0 at pre-training and 18.5 ± 2.4 at post-training (P = 0.05). Before training, there was a significant difference in the total score between Fellows and Residents (18.6 ± 2.2 vs 12.2 ± 2.4 points, P = 0.002), which disappeared after training (19.4 ± 2.5 vs 17.6 ± 2.2 points, P = 0.262). Residents benefitted from training with improvements in their time, total score, score for time, score for flow and subtraction score; however, these effects were not seen in Fellows. The most evident training effect was improvement of self-estimation, which was also seen in Fellows. CONCLUSIONS: Residents were most likely to derive benefit from these training models with regard to both efficiency and quality. Training models seem to have an important role in making surgeons feel more comfortable with the procedure.

[A Long‒Term Survival Case of Advanced Rectal Cancer with Liver and Lung, Para‒Aortic Lymph Nodes Metastasis That Responded to Multidisciplinary Therapy].

The patient was a 59‒year‒old woman. In 2005, she underwent low anterior resection plus D2 dissection for rectal cancer (pT4aN2aM0, pStage Ⅲb). In 2007, she underwent hepatic S8 subsegment resection for liver metastasis. After that, FOLFIRI therapy was performed as chemotherapy for recurrence of the right upper lung lobe and para‒aortic lymph node(PALN). CR was once obtained in both(of)PALN and lung, but PALN re‒expansion and left ovary enlargement were observed in 2009, and resection of PALN plus left ovariectomy was performed. Histological examination showed PALNs were metastases from rectal cancer and the ovary was benign. Eleven years after the first operation, she stayed alive without recurrence.

[Postoperative Relapse of Combined Large‒Cell Neuroendocrine Carcinoma of the Lung with a Remarkable Transient Response to Amrubicin Monotherapy in an Elderly Patient-A Case Report].

An 86‒year‒old man with chronic kidney disease underwent surgical resection for combined large‒cell neuroendocrine carcinoma of the left lower lobe of the lung(pT2aN1M0, stage ⅡB). Five months later, multiple liver and bone metastases and mediastinal lymph node recurrence were detected. After 9 courses of amrubicin monotherapy(32 mg/m2 for 3 consecutive days), his tumor marker levels normalized, and radiological examination revealed a complete tumor response. Adverse events occurred, but they were tolerable except a decrease in the neutrophil count. The patient remained in good condition for several months but died of tumor relapse 22 months after the initial recurrence. Amrubicin monotherapy was considered to be one of the treatment choices for recurrent large‒cell neuroendocrine carcinoma of the lung in elderly patients.