Epidemiology, microbiology, and diagnosis of infection in diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome: A multicenter retrospective observational study.

AIMS: We investigated the characteristics of infection and the utility of inflammatory markers in diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic syndrome (HHS). METHODS: A multicenter, retrospective observational study in 21 acute-care hospitals was conducted in Japan. This study included adult hospitalized patients with DKA and HHS. We analyzed the diagnostic accuracy of markers including C-reactive protein (CRP) and procalcitonin (PCT) for bacteremia. Multiple regression models were created for estimating bacteremia risk factors. RESULTS: A total of 771 patients, including 545 patients with DKA and 226 patients with HHS, were analyzed. The mean age was 58.2 (SD, 19.3) years. Of these, 70 tested positive for blood culture. The mortality rates of those with and without bacteremia were 14 % and 3.3 % (P-value < 0.001). The area under the curve (AUC) of CRP and PCT for diagnosis of bacteremia was 0.85 (95 %CI, 0.81 to 0.89) and 0.76 (95 %CI, 0.60 to 0.92), respectively. Logistic regression models identified older age, altered level of consciousness, hypotension, and higher CRP as risk factors for bacteremia. CONCLUSIONS: The mortality rate was higher in patients with bacteremia than patients without it. CRP, rather than PCT, may be valid for diagnosing bacteremia in hyperglycemic emergencies. TRIAL REGISTRATION: This study is registered in the UMIN clinical trial registration system (UMIN000025393, Registered December 23, 2016).

High versus low chloride load in adult hyperglycemic emergencies with acute kidney injury: a multicenter retrospective cohort study.

Hyperglycemic emergencies frequently lead to acute kidney injury (AKI) and require treatment with large amount of intravenous fluids. However, the effects of chloride loading on this population have not yet been investigated. We conducted a multicenter, retrospective, cohort study in 21 acute-care hospitals in Japan. The study included hospitalized adult patients with diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic syndrome (HHS) who had AKI upon arrival. The patients were classified into high and low chloride groups based on the amount of chloride administered within the first 48 h of their arrival. The primary outcome was recovery from AKI; secondary outcome was major adverse kidney events within 30 days (MAKE30), including mortality and prolonged renal failure. A total of 390 patients with AKI, including 268 (69%) with DKA and 122 (31%) with HHS, were included in the study. Using the criteria of Kidney Disease Improving Global Outcomes, the severity of AKI in the patients was Stage 1 (n = 159, 41%), Stage 2 (n = 121, 31%), and Stage 3 (n = 110, 28%). The analysis showed no significant difference between the two groups in recovery from AKI (adjusted hazard ratio, 0.96; 95% CI 0.72-1.28; P = 0.78) and in MAKE30 (adjusted odds ratio, 0.91; 95% CI 0.45-1.76; P = 0.80). Chloride loading with fluid administration had no significant impact on recovery from AKI in patients with hyperglycemic emergencies.Trial Registration This study was registered in the UMIN clinical trial registration system (UMIN000025393, registered December 23, 2016).

Higher incidence of cholelithiasis with Roux-en-Y reconstruction compared with Billroth-I after laparoscopic distal gastrectomy for gastric cancer: a retrospective cohort study.

PURPOSE: Cholelithiasis occurs often after gastrectomy. However, no consensus has been established regarding the difference in the incidence of postgastrectomy cholelithiasis with different reconstruction methods. In this study, we examined the frequency of cholelithiasis after two major reconstruction methods, namely Billroth-I (B-I) and Roux-en-Y (R-Y) following laparoscopic distal gastrectomy (LDG) for gastric cancer. METHODS: Among 696 gastric cancer patients who underwent LDG between April 2000 and March 2017, after applying the exclusion criteria, 284 patients who underwent B-I and 310 who underwent R-Y were examined retrospectively. The estimated incidence of cholelithiasis was compared between the methods, and factors associated with the development of cholelithiasis in the gallbladder and/or common bile duct were investigated. RESULTS: During the median follow-up of 61.2 months, 52 patients (8.8%) developed cholelithiasis postgastrectomy; 12 patients (4.2%) after B-I and 40 (12.9%) after R-Y (p = 0.0002). Among them, choledocholithiasis was more frequent in patients who underwent R-Y (n = 11, 27.5%) vs. B-I (n = 1, 8.3%) (p = 0.0056). Univariate and multivariate analyses revealed that male sex, body mass index > 22.5 kg/m2, and R-Y reconstruction were significant predictors of the development of postLDG cholelithiasis. CONCLUSION: Regarding cholelithiasis development, B-I reconstruction should be preferred whenever possible during distal gastrectomy.

Clinical profile of patients with diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome in Japan: a multicenter retrospective cohort study.

INTRODUCTION: Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar syndrome (HHS) are life-threatening complications of diabetes mellitus. Their clinical profiles have not been fully investigated. METHODS: A multicenter retrospective cohort study was conducted in 21 acute care hospitals in Japan. Patients included were adults aged 18 or older who had been hospitalized from January 1, 2012, to December 31, 2016 due to DKA or HHS. The data were extracted from patient medical records. A four-group comparison (mild DKA, moderate DKA, severe DKA, and HHS) was performed to evaluate outcomes. RESULTS: A total of 771 patients including 545 patients with DKA and 226 patients with HHS were identified during the study period. The major precipitating factors of disease episodes were poor medication compliance, infectious diseases, and excessive drinking of sugar-sweetened beverages. The median hospital stay was 16 days [IQR 10-26 days]. The intensive care unit (ICU) admission rate was 44.4% (mean) and the rate at each hospital ranged from 0 to 100%. The in-hospital mortality rate was 2.8% in patients with DKA and 7.1% in the HHS group. No significant difference in mortality was seen among the three DKA groups. CONCLUSIONS: The mortality rate of patients with DKA in Japan is similar to other studies, while that of HHS was lower. The ICU admission rate varied among institutions. There was no significant association between the severity of DKA and mortality in the study population. TRIAL REGISTRATION: This study is registered in the UMIN clinical Trial Registration System (UMIN000025393, Registered 23th December 2016).

Radiofrequency Ablation Combined with Hepatic Artery Embolization Using a Tris-acryl Gelatin Microsphere for Colorectal Liver Metastases-Initial Experience.

Purpose: We aim to evaluate retrospectively the feasibility, safety, and initial therapeutic outcomes of radiofrequency ablation combined with hepatic artery embolization using a tris-acryl gelatin microsphere for colorectal liver metastases. Material and Methods: Six consecutive patients (4 men and 2 women) with median age of 68 years (range 57-78 years) underwent computed tomography fluoroscopy-guided radiofrequency ablation immediately after hepatic artery embolization using microspheres. This study evaluated tumor visibility on noncontrast-enhanced computed tomography immediately after hepatic artery embolization; analyzed local tumor progression; defined technical success as the coverage of the tumor by the ablative zone; and assessed adverse events based on Common Terminology Criteria for Adverse Events v5.0. Results: Ten tumors with median maximum diameter of 9 mm (range 5-52 mm) were treated in nine sessions. Eight tumors (80%, 8/10 tumors) were detected as high-attenuation nodules. One tumor was treated in two sessions because follow-up computed tomography revealed an insufficient ablative margin. Therefore, the primary and secondary technical success was 90% (9/10 tumors) and 100% (10/10 tumors), respectively. Grade 2 pneumothorax was observed in one session (11%, 1/9 sessions). No grade 3 or higher adverse event was observed. The local tumor progression rate was 20% (2/10 tumors) during the median follow-up of 14 months. Conclusions: Radiofrequency ablation following microsphere embolization may be a feasible, safe, and useful therapeutic option for controlling small colorectal liver metastases.

Combined endoscopic stenting and laparoscopic stent fixation for benign gastric tube stricture after esophagectomy: a case report.

BACKGROUND: There are several options for the treatment of gastrointestinal stricture, including endoscopic stent placement and bypass surgery. However, a benign stricture is difficult to manage in a reconstructed gastric tube in the thoracic cavity owing to the technical difficulty of bypass surgery, and the possibility of stent migration. CASE PRESENTATION: A 78-year-old woman was admitted to our hospital for treatment for her inability to eat. She had undergone video-assisted subtotal esophagectomy with retromediastinal gastric tube reconstruction 7 years earlier. At the current admission, there was a severely dilated gastric tube in the thoracic cavity with a soft stricture immediately anterior to the spine. Conservative therapy was ineffective; therefore, endoscopic stenting was performed. However, the stent migrated to the upper side of the stricture because the stricture was mild, and the stent was not fixed in the gastric tube. Next, endoscopic stent placement followed by laparoscopic stent fixation was performed. The stent was patent and worked well, and the patient's body weight increased. However, the stent collapsed 2 years later, with recurrence of symptoms. Stent-in-stent placement with an over-the-scope clip was performed, and the second stent was also patent and worked well. CONCLUSIONS: Laparoscopic stent fixation with endoscopic stent placement could be an effective option for patients with a benign stricture in the reconstructed gastric tube.

Minimally invasive distal pancreatectomy for pancreatic cancer: cranial-to-caudal approach with identification of Gerota's fascia (with video).

BACKGROUND: Although radical antegrade modular pancreatosplenectomy for pancreatic ductal adenocarcinoma (PDAC) has become the gold standard procedure in open distal pancreatectomy, there has been no gold standardized procedure for PDAC in minimally invasive distal pancreatectomy (MIDP). In this study, we analyzed our novel cranial-to-caudal approach (CC approach) for patients undergoing MIDP and provide a video clip illustrating the details of the CC approach. METHODS: Ninety-four patients who underwent MIDP with splenectomy between 2016 and 2021 were included in this study. The CC approach was performed in 23 (24.5%) of the 94 patients. The concept of the CC approach is easy identification of Gerota's fascia from the cranial side of the pancreas and secure tumor removal (R0 resection) wrapped by Gerota's fascia. The short- and long-term outcomes were compared between the CC and non-CC approaches. RESULTS: The median operation time and blood loss were similar between the two groups. The ratios of grade ≥ B postoperative pancreatic fistula and Clavien-Dindo grade ≥ III complications were also comparable. All patients in the CC approach group achieved R0 resection, and the R0 ratio was similar in the two groups (p = 0.345). The 2-year survival rate in CC and non-CC approach groups was 87.5% and 83.6%, respectively (p = 0.903). CONCLUSIONS: The details of the CC approach for MIDP were demonstrated based on an anatomical point of view. This approach has the potential to become a standardized approach for left-sided PDAC.

Tertiary lymphoid structures correlate with enhancement of antitumor immunity in esophageal squamous cell carcinoma.

BACKGROUND: Tertiary lymphoid structures (TLSs) are associated with a favorable prognosis in several cancers. However, the correlation between TLSs and outcomes of esophageal squamous cell carcinoma (ESCC) and the impact of TLSs on the tumor immune microenvironment (TIME) remain unknown. METHODS: We pathologically evaluated the significance of TLSs in ESCC focusing on TLS maturation using 180 ESCC specimens and performed single-cell RNA sequencing (scRNA-seq) using 14 ESCC tissues to investigate functional differences of immune cells according to TLS presence. RESULTS: TLS+ cases had better recurrence-free-survival (RFS) (p < 0.0001) and overall survival (OS) (p = 0.0016) compared with TLS- cases. Additionally, mature TLS+ cases had better RFS and OS compared with immature TLS+ cases (p = 0.019 and p = 0.015) and TLS- cases (p < 0.0001 and p = 0.0002). The scRNA-seq showed that CD8+ T cells in TLS+ tumors expressed high levels of cytotoxic signatures and antigen-presentation of dendritic cells (DCs) was enhanced in TLS+ tumors. Immunohistochemistry showed that the densities of tumor-infiltrating CD8+ T cells and DCs were significantly higher in TLS+ tumors than those in TLS- tumors. CONCLUSIONS: These data suggest the prognostic and functional significance of TLSs in ESCC and provides new insights into TLSs on the TIME.

Endoscopic stent placement with laparoscopic stent fixation in a patient with obstruction at a gastrojejunostomy anastomosis site.

BACKGROUND: Palliative endoscopic stent placement may be considered in patients with malignant gastrointestinal obstruction. Stent migration is a potential complication, particularly for those placed at a surgical anastomosis or across a stricture caused by extra-alimentary tract factors. We report a patient with left renal pelvis cancer and gastrojejunostomy obstruction who underwent endoscopic stent placement and laparoscopic stent fixation. CASE PRESENTATION: A 60-year-old male with peritoneal dissemination of a left renal pelvis cancer was admitted for treatment of upper gastrointestinal obstruction. A laparoscopic gastrojejunostomy had been previously performed for cancer invasion of the duodenum. Imaging showed gastroduodenal dilation and impaired passage of contrast medium through the efferent loop of the gastrojejunostomy. Gastrojejunostomy anastomosis site obstruction due to dissemination of left renal pelvis cancer was diagnosed. Conservative treatment failed and endoscopic stent placement with laparoscopic stent fixation was performed. After surgery, the patient was able to tolerate oral intake and he was discharged without complications. The patient gained weight and was able to resume chemotherapy, indicating the procedure was effective. CONCLUSIONS: Endoscopic stent placement with laparoscopic stent fixation for malignant upper gastrointestinal obstruction appears effective in patients with a high risk of stent migration.

A left-sided approach for wide mobilization of the pancreas with complete dissection of the Treitz ligament (with video).

BACKGROUND: In recent years, the number of minimally invasive pancreatoduodenectomy (MIPD) has been increasing; however, the procedure has not been widely accepted due to its complexity and difficulty. We have developed a technique to mobilize the pancreas head using a left-sided approach with a focus on the complete dissection of the Treitz ligament. METHODS: This technique focuses on the secure mobilization of the pancreas head using a left-sided approach. First, the transverse mesocolon is flipped upward and the anterior side of the mesojejunum is excised to expose the first jejunal artery (1st JA) from the distal side to its origin. During the procedure, the left sides of the SMA and Treitz ligament are exposed. The Treitz ligament is retracted to the left side and dissected anteriorly. Thereafter, the jejunum is flipped to the right side and the retroperitoneum around the origin of the jejunum and duodenum is dissected to identify the inferior vena cava (IVC). The rest of the Treitz ligament is dissected posteriorly and complete resection of the Treitz ligament releases the limitation of duodenal immobility. Thereafter, dissection proceeds along the anterior wall of the IVC, and mobilization of the pancreas head is completed from the left side. RESULTS: A total of 75 consecutive patients underwent MIPD from April 2016 to July 2022. The median operation times of laparoscopic and robotic procedures were 528 min (356-757 min) and 739 min (492-998 min), respectively. The volume of blood loss during laparoscopic and robotic procedures was 415 g (60-4360 g) and 211 g (17-1950 g), respectively. There was no mortality in any of the cases. CONCLUSION: Mobilization of the pancreas head and left-sided approach using a caudal view will be a safe and useful technique for MIPD.

Neoadjuvant chemotherapy enhances anti-tumor immune response of tumor microenvironment in human esophageal squamous cell carcinoma.

Although chemotherapy has been an essential treatment for cancer, the development of immune checkpoint blockade therapy was revolutionary, and a comprehensive understanding of the immunological tumor microenvironment (TME) has become crucial. Here, we investigated the impact of neoadjuvant chemotherapy (NAC) on immune cells in the TME of human esophageal squamous cell carcinoma using single cell RNA-sequencing. Analysis of 30 fresh samples revealed that CD8+/CD4+ T cells, dendritic cells (DCs), and macrophages in the TME of human esophageal squamous cell carcinoma showed higher levels of an anti-tumor immune response in the NAC(+) group than in the NAC(-) group. Furthermore, the immune cells of the NAC(+) group interacted with each other resulting in enhanced anti-tumor immune response via various cytokines, including IFNG in CD8+/CD4+ T cells, EBI3 in DCs, and NAMPT in macrophages. Our results suggest that NAC potentially enhances the anti-tumor immune response of immune cells in the TME.

Single-cell transcriptome analysis reveals functional changes in tumour-infiltrating B lymphocytes after chemotherapy in oesophageal squamous cell carcinoma.

BACKGROUND: Tumour immune microenvironment is related with carcinogenesis and efficacy of immunotherapy. B cells play major roles in humoral immunity, but detailed functions of tumour-infiltrating B lymphocytes (TIL-Bs) are unknown. Therefore, our aim was to investigate the functional heterogeneity of TIL-Bs in oesophageal squamous cell carcinoma (ESCC) and lymph nodes (LNs) during chemotherapy. METHODS: Single-cell transcriptome analysis was performed on 23 specimens. We also performed immunohistochemical analysis of immunoglobulin κ C (IGKC), an antibody-secreting cell (ASC) marker, in 166 ESCC samples and evaluated the implication of IGKC in 2-year recurrence free survival (RFS) and 3-year overall survival (OS). RESULTS: A total of 81,246 cells were grouped into 24 clusters. We extracted B cell clusters based on canonical markers and identified 12 TIL-B subtypes in ESCC. We found that several functions, such as co-stimulation and CD40 signalling, were enhanced in TIL-Bs after chemotherapy. The proportion of naive B cells (NBCs) decreased and B cell activation genes were up-regulated in NBCs after chemotherapy. The proportion of ASCs in tumours increased with the loss of migratory abilities and antibody production in ASCs was promoted after chemotherapy. Differentially expressed genes up-regulated with chemotherapy in ASCs correlated with prolonged survival with oesophageal cancer (p = .028). In a metastatic LN, the ASC proportion increased and B cell differentiation was enhanced. In immunohistochemical analysis, RFS and OS of high IGKC expression cases were significantly better than those of low IGKC expression cases (RFS: p < .0001, OS: p < .0001). And in multivariable analysis, the expression of IGKC was an independent favourable prognostic factor for RFS (hazard ratio (HR): 0.23, 95% confidence interval (CI): 0.12-0.45, p < .0001) and OS (HR: 0.20, 95% CI: 0.086-0.47, p = .0002) in ESCC. CONCLUSIONS: Our findings provide novel insights for the heterogeneity of TIL-Bs during chemotherapy and will be useful to understand the clinical importance of TIL-Bs.

Clinical Experience of Percutaneous Radiofrequency Ablation Using an arfa RF ABLATION SYSTEMⓇ in Various Organs.

Purpose: To evaluate the feasibility, safety, and efficacy of radiofrequency (RF) ablation using an ablation system (arfa RF ABLATION SYSTEMⓇ; Japan Lifeline Co. Ltd.) for treating solid tumors in various organs. Material and Methods: Between October 2019 and August 2021, 80 patients (29 women, 51 men; median age, 70.0 yr) underwent 107 RF ablation sessions using the ablation system to treat 151 tumors in the liver (n = 86), lung (n = 51), adrenal gland (n = 4), pleura (n = 4), bone (n = 3), lymph node (n = 2), and kidney (n = 1). The maximum tumor diameter was 2-40 mm (median, 11 mm). This study evaluated technical success (defined as the completion of planned RF ablation), technique efficacy (defined as the complete tumor ablation on follow-up images), and adverse events. Local tumor progression in 146 curatively treated malignant tumors was evaluated. Results: The technical success rate was 100% (107/107). Ablation zones in two tumors were insufficient. Therefore, the primary technique efficacy rate was 98.1% (105/107). Grade 3 hepatic infarction (1.6%, 1/64) and grade 4 pleuritis (3.4%, 1/29) occurred respectively after liver and lung RF ablation. During the median follow-up period of 10.2 months (Interquartile range, 4.2 and 16.4 months), local tumor progression developed in two tumors (1.4%, 2/146). Conclusions: The arfa RF ABLATION SYSTEMⓇ is a feasible, safe, and effective RF ablation device for managing solid tumors in various organs.

Long-Term Neurological Outcome of Extracorporeal Cardiopulmonary Resuscitation for Out-of-Hospital Cardiac Arrest Patients With Nonshockable Rhythms: A Single-Center, Consecutive, Retrospective Observational Study.

BACKGROUND: Data on extracorporeal cardiopulmonary resuscitation (ECPR) in patients with out-of-hospital cardiac arrest (OHCA) and initially nonshockable rhythms are limited. OBJECTIVE: This study aimed to evaluate the long-term neurological outcomes of ECPR for patients with OHCA and initially nonshockable rhythms. METHODS: In this single-center, consecutive, retrospective, observational study, patients with OHCA and initially nonshockable rhythms who underwent ECPR between January 2012 and December 2017 were included. All patients with refractory cardiopulmonary arrest were transported while undergoing conventional CPR and received ECPR on arrival in the emergency department. We retrospectively collected characteristics at admission and neurological outcomes at the last visit or telephone interview. Cerebral performance category (CPC) scales 1 and 2 were defined as good neurological outcomes and CPC scales 3, 4, and 5 were defined as poor neurological outcomes. RESULTS: Of the 39 patients included in this study, 32 died in the hospital and only 7 survived. There were 4, 0, 0, 3, and 32 patients with CPC 1, 2, 3, 4, and 5, respectively. The proportion of good neurological outcomes for all patients was 10.3% (95% CI 2.9-24.2%) and 14.3% (95% CI 4.0-32.7%) for patients with pulseless electrical activity. No patients with asystole had a good neurological outcome. Median follow-up period was 1052 days (interquartile range 116-1589 days) for those who survived to discharge. CONCLUSIONS: Approximately 10% of initially nonshockable patients with OHCA, generally considered to be a poor prognosis, could acquire good neurological outcomes when they underwent ECPR with our indications.

Lymphangiography as a Treatment for Refractory Congenital Chylothorax Due to RASopathies: A Report of Two Cases.

In this study, we report two cases in which intranodal lymphangiography helped improve congenital chylothorax due to RASopathies. We performed lymphangiography after conservative treatments failed to improve chylothorax in an 8-year-old girl with cardiofaciocutaneous syndrome and a 2-month-old boy with Noonan syndrome. Inguinal lymph nodes were punctured with 25-gauge needles under ultrasonographic guidance, and 4 and 1 mL of iodized oil were injected, respectively, showing a backflow of iodized oil into the lungs. Chylothorax had improved in both patients after nodal lymphangiography. However, the second child experienced worsening of disease-associated extremity edema and died of sepsis 4 months later.

Use of Microballoon Catheter in Transarterial Ethanol Embolization of Renal Angiomyolipoma: A Retrospective Comparative Study with Historical Control?

Purpose: To clarify the utility of microballoon catheter in renal arterial ethanol embolization of renal angiomyolipoma (AML). Material and Methods: A total of 20 patients (15 women, 5 men) with median age of 45 years (39-60 years) underwent embolization to treat 22 AMLs. A mixture of ethanol and iodized oil was injected into the feeding arteries of 13 tumors using balloon occlusion (the balloon embolization group) with a microballoon catheter and 9 tumors without using balloon occlusion (the non-balloon embolization group). Changes in the maximum tumor diameter, tumor volume, and adverse events were evaluated. Result: The median baseline maximum tumor diameters and volumes were 6.3 cm and 61.4 cm3 in the balloon embolization group, and 4.6 cm and 40.1 cm3 in the non-balloon embolization group, respectively. Tumor enhancement disappeared on postembolization angiography in all cases. All tumors shrunk after embolization. There were no statistically significant differences in the percent decrease in the maximum tumor diameter and volume at 10-12 month between balloon occlusion group (31.5% and 67.9%) and control group (34.8% and 62.6%). Fever was significantly more frequent when balloon occlusion was used: 38% vs. 0% (p = 0.03). No major complication was observed in either patient group. Conclusions: Balloon occlusion may not affect tumor shrinkage when embolizing AMLs with a mixture of ethanol and lipiodol.

Clinical impact of remnant lymphatic invasion on the recurrence of esophageal squamous cell carcinoma after esophagectomy with neoadjuvant chemotherapy.

For stage II and III esophageal squamous cell carcinoma (ESCC), neoadjuvant chemotherapy (NAC) followed by esophagectomy is recommended in the Japanese guidelines for the diagnosis and treatment of esophageal cancer. However, recurrence of ESCC is common regardless of the NAC regimen and surgical method, and NAC demonstrates limited efficacy against recurrence. Therefore, the present study was conducted to identify risk factors of recurrence of ESCC with surgery after NAC. The outcomes of 51 patients who underwent esophagectomy for ESCC after NAC from 2010 to 2017 at Kyushu University Hospital were retrospectively analyzed. A total of 52 patients with ESCC without NAC followed by esophagectomy from 2001 to 2017 were selected for comparison. Among patients who underwent NAC followed by surgery, only lymphatic invasion (LY; hazard ratio, 2.761; 95% CI, 1.86-6.43, P=0.018) was an independent factor significantly associated with 3-year recurrence-free survival in the multivariate analysis. In patients with pathologic lymph node metastasis (pN) and no LY after NAC, there was significantly less recurrence compared with patients with pN and LY (P=0.0085), whereas in patients without LY after NAC, the presence of pN was not significantly associated with recurrence (P=0.2401). There were significantly fewer LY (+) patients in the NAC (+) group (P=0.0158) compared with those in the NAC (-) group. The presence of LY was an independent risk factor for recurrence of ESCC after esophagectomy following NAC. Overall, adjuvant treatment after surgery may be required in cases with remnant LY after NAC.

Potential therapeutic targets discovery by transcriptome analysis of an in vitro human gastric signet ring carcinoma model.

BACKGROUND: Loss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development. METHODS: To investigate novel therapeutic targets for gastric SRCC, we engineered an E-cadherin-deficient SRCC model in vitro using a human gastric organoid (hGO) with CDH1 knockout (KO). RESULTS: CDH1 KO hGO cells demonstrated distinctive morphological changes similar to SRCC and high cell motility. RNA-sequencing revealed up-regulation of matrix metalloproteinase (MMP) genes in CDH1 KO hGO cells compared to wild type. MMP inhibitors suppressed cell motility of CDH1 KO hGO cells and SRCC cell lines in vitro. Immunofluorescent analysis with 95 clinical gastric cancer tissues revealed that MMP-3 was specifically abundant in E-cadherin-aberrant SRCC. In addition, CXCR4 molecules translocated onto the cell membrane after CDH1 KO. Addition of CXCL12, a ligand of CXCR4, to the culture medium prolonged cell survival of CDH1 KO hGO cells and was abolished by the inhibitor, AMD3100. In clinical SRCC samples, CXCL12-secreting fibroblasts showed marked infiltration into the cancer area. CONCLUSIONS: E-cadherin deficient SRCCs might gain cell motility through upregulation of MMPs. CXCL12-positive cancer-associated fibroblasts could serve to maintain cancer-cell survival as a niche. MMPs and the CXCL12/CXCR4 axis represent promising candidates as novel therapeutic targets for E-cadherin-deficient SRCC.

Subtypes in pancreatic ductal adenocarcinoma based on niche factor dependency show distinct drug treatment responses.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma in which microenvironmental (niche) factors promote PDAC progression. In mouse models, reduction of the stroma increased the proportion of poorly differentiated PDAC with a worse prognosis. Here, we aimed to clarify the effects of stroma on PDAC that may define the PDAC phenotype and induce distinct therapeutic responses. METHODS: The molecular features of PDAC based on differentiation grade were clarified by genome and transcriptome analysis using PDAC organoids (PDOs). We identified the dependency on niche factors that might regulate the differentiation grade. A three-dimensional co-culture model with cancer-associated fibroblasts (CAFs) was generated to determine whether CAFs provide niche factors essential for differentiated PDAC. PDOs were subtyped based on niche factor dependency, and the therapeutic responses for each subtype were compared. RESULTS: The expression profiles of PDOs differed depending on the differentiation grade. Consistent with the distinct profiles, well differentiated types showed high niche dependency, while poorly differentiated types showed low niche dependency. The three-dimensional co-culture model revealed that well differentiated PDOs were strongly dependent on CAFs for growth, and moderately differentiated PDOs showed plasticity to change morphology depending on CAFs. Differentiated PDOs upregulated the expression of mevalonate pathway-related genes correlated with the niche dependency and were more sensitive to simvastatin than poorly differentiated PDOs. CONCLUSIONS: Our findings suggest that CAFs maintain the differentiated PDAC phenotype through secreting niche factors and induce distinct drug responses. These results may lead to the development of novel subtype-based therapeutic strategies.