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.

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.

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.

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.

ERAP2 is a novel target involved in autophagy and activation of pancreatic stellate cells via UPR signaling pathway.

BACKGROUND/OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is characterized by excessive desmoplasia and autophagy-dependent tumorigenic growth. Pancreatic stellate cells (PSCs) as a predominant stromal cell type play a critical role in PDAC biology. We have previously reported that autophagy facilitates PSC activation, however, the mechanism remains unknown. We investigated the mechanism of autophagy in PSC activation. METHODS: We compared gene expression profiles between patient-derived PSCs from pancreatic cancer and chronic pancreatitis using a microarray. The stromal expression of target gene in specimen of PDAC patients (n = 63) was analyzed. The effect of target gene on autophagy and activation of PSCs was investigated by small interfering RNAs transfection, and the relationship between autophagy and ER stress was investigated. We analyzed the growth and fibrosis of xenografted tumor by orthotopic models. RESULTS: In analysis of gene expression microarray, endoplasmic reticulum aminopeptidase 2 (ERAP2) upregulated in cancer-associated PSCs was identified as the target gene. High stromal ERAP2 expression is associated with a poor prognosis of PDAC patients. Knockdown of ERAP2 inhibited unfolded protein response mediated autophagy, and led to inactivation of PSCs, thereby attenuating tumor-stromal interactions by inhibiting production of IL-6 and fibronectin. In vivo, the promoting effect of PSCs on xenografted tumor growth and fibrosis was inhibited by ERAP2 knockdown. CONCLUSIONS: Our findings demonstrate a novel mechanism of PSCs activation regulated by autophagy. ERAP2 as a promising therapeutic target may provide a novel strategy for the treatment of PDAC.

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.

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.

New high-throughput screening detects compounds that suppress pancreatic stellate cell activation and attenuate pancreatic cancer growth.

BACKGROUND/OBJECTIVES: Pancreatic stellate cells (PSCs) are involved in abundant desmoplasia, which promotes cancer cell aggressiveness and resistance to anti-cancer drugs. Therefore, PSCs are suggested to be a promising therapeutic target by attenuating PSC activation to inhibit tumor-stromal interactions with pancreatic cancer cells. Here, we developed a screen to identify compounds that reduce the activity of PSCs and investigated the effect of candidates on pancreatic cancer. METHODS: Lipid droplet accumulation in PSCs was used to observe differences in PSC activity and a new high-throughput screening platform that quantified lipid droplets in PSCs was established. A library of 3398 Food and Drug Administration-approved drugs was screened by this platform. Validation assays were performed in vitro and in vivo. RESULTS: Thirty-two compounds were finally selected as candidate compounds by screening. These compounds decreased α-smooth muscle actin expression and inhibited autophagic flux in PSCs in vitro. Among the candidates, three drugs selected for validation assays inhibited the proliferation and migration of PSCs and invasion of cancer cells by disrupting tumor-stromal interactions. Production of extracellular matrix molecules was also decreased significantly by this treatment. In vivo testing in xenograft models showed that dopamine antagonist zuclopenthixol suppressed tumor growth; this suppression was significantly increased when combined with gemcitabine. CONCLUSIONS: A new screening platform that focused on the morphological features of PSCs was developed. Candidate drugs from this screening suppressed PSC activation and tumor growth. This screening system may be useful to discover new compounds that attenuate PSC activation.

High frequency of bone recurrence as an initial recurrence site after radical surgery in T1N3 gastric cancer: a propensity score matching analysis.

PURPOSE: T1 gastric cancer (GC) with seven or more metastatic lymph nodes is extremely rare, and very few clinical studies have been conducted to evaluate the clinicopathological features of their recurrence. METHODS: We retrospectively analyzed the outcomes of T1 GC and T2-4 GC patients who had multiple nodal metastases after radical surgery from 2006 to 2020. Propensity score matching was performed to compare the two groups of patients. RESULTS: After propensity score matching, 18 of 22 patients in the T1 group and 36 of 144 patients in the T2-4 group were selected. Recurrence occurred in six patients (33.3%) in the T1 group. In the T1 group, the most common site of initial recurrence was bone (15.0%). The prevalence of bone recurrence was significantly higher in the T1 group than in the T2-4 group (P = 0.02). The median interval time between radical surgery and bone recurrence was 24 months, and the median survival time after bone recurrence was 14 months. CONCLUSION: Bone recurrence was more frequently identified as an initial recurrence site in T1 GC cases with multiple metastases after radical surgery compared with that in T2-4 GC cases. Careful attention should be paid to postoperative bone recurrence in the long-term postoperative course of these patients.

Influence of endoscopic resection on additional laparoscopic distal gastrectomy: a propensity score-matching analysis.

PURPOSE: There is no definite evidence of the feasibility and safety of laparoscopic distal gastrectomy (LDG) for patients who have undergone incomplete endoscopic resection (ER). We investigated the influence of ER prior to LDG by a propensity score matching analysis. METHODS: We retrospectively analyzed the outcomes of gastric cancer patients who underwent LDG with or without prior ER from 2000 to 2014. Propensity score matching was performed to compare the two groups of patients. RESULTS: After matching, 47 patients in the ER group and 94 patients in the non-ER group were selected from a total of 365 patients. A residual tumor was observed in 10 of 47 patients (21.3%). The mean number of dissected lymph nodes in the non-ER group (39.4 ± 14.5) was higher than that in the ER group (31.7 ± 13.5) (P = 0.003). However, other perioperative data, such as the operation time and blood loss volume were similar. The complication rate of the ER group (17.0%) and the non-ER group (9.6%) did not differ to a statistically significant extent (P = 0.2). Among these patients, 6 died during the 5-year follow-up period, but no patients showed signs of recurrence. CONCLUSION: ER prior to surgical resection showed no significant influence on postoperative complications or mortality. LDG can be safely performed to achieve radical resection after incomplete ER.

Subcutaneous fat area as a risk factor for extraction site incisional hernia following gastrectomy for gastric cancer.

PURPOSE: To identify the incidence of extraction site incisional hernia following gastrectomy for gastric cancer and its significant risk factors, including the subcutaneous fat area. METHODS: We reviewed data gathered prospectively on patients with gastric cancer, who underwent gastrectomy between 2008 and 2012 at Kyushu University Hospital, Fukuoka, Japan. The subcutaneous fat area (SFA) and visceral fat area (VFA) were measured using axial computed tomography at the level of the L4 and L3 transverse processes, and the L2-L3 intervertebral disc. The primary endpoint of the rate of extraction site incisional hernia was based on the computed tomography and clinical data including hospital follow-up reports. RESULTS: After applying the inclusion and exclusion criteria, 320 patients were included in this retrospective analysis: 3.1% (10/320) had extraction site incisional hernias after a mean follow-up of 11 months. Multivariate analysis revealed that age and the SFA were independent risk factors (age ≥ 70.5 years: P = .013, odds ratio: 9.116, 95% confidence interval 1.581-52.553; L4 SFA ≥ 124 cm2: P = .004, odds ratio: 13.752, 95% confidence interval 2.290-82.582). CONCLUSION: Age and the SFA were independent risk factors for extraction site incisional hernia in patients undergoing gastrectomy for gastric cancer.

Adipose tissue-derived stromal cells are sources of cancer-associated fibroblasts and enhance tumor progression by dense collagen matrix.

Although recent studies revealed that adipose tissue accelerates pancreatic tumor progression with excessive extracellular matrix, key players for desmoplasia in the adipose microenvironment remains unknown. Here, we investigated the roles of adipose tissue-derived stromal cells (ASCs) in desmoplastic lesions and tumor progression by in vitro and in vivo experiments. In a three-dimensional (3-D) organotypic fat invasion model using visceral fat from CAG-EGFP mice, GFP-positive fibroblastic cells infiltrated toward cancer cells. When tumor cells were inoculated into transplanted visceral fat pads in vivo, tumor weights and stromal components were enhanced compared to subcutaneous and orthotopic tumor cells inoculated without fat pads. Expression of αSMA in established human ASCs was lower compared to cancer associated fibroblasts, and the 3-D collagen matrices produced by ASCs cultured in cancer cell-conditioned medium changed from loose to dense structures that affected the motility of cancer cells. Microarray analyses revealed upregulation of S100A4 in ASCs, while S100A4-positive stromal cells were observed at extrapancreatic invasion sites of human pancreatic cancer. The present findings indicate that ASCs are recruited to extrapancreatic invasion sites and produce dense collagen matrices that lead to enhanced tumor progression. Both inhibition of ASCs recruitment and activation could lead to a novel antistromal therapy.

Autophagy Is Required for Activation of Pancreatic Stellate Cells, Associated With Pancreatic Cancer Progression and Promotes Growth of Pancreatic Tumors in Mice.

BACKGROUND & AIMS: Pancreatic stellate cells (PSCs) change from a quiescent to activated state in the tumor environment and secrete extracellular matrix (ECM) molecules and cytokines to increase the aggressiveness of tumors. However, it is not clear how PSCs are activated to produce these factors, or whether this process can be inhibited. PSCs have morphologic and functional similarities to hepatic stellate cells, which undergo autophagy to promote fibrosis and tumor growth. We investigated whether autophagy activates PSCs, which promotes development of the tumor stroma and growth of pancreatic tumors in mice. METHODS: We used immunofluorescence microscopy and immunohistochemistry to analyze pancreatic tumor specimens from 133 patients who underwent pancreatectomy in Japan from 2000 to 2009. PSCs were cultured from pancreatic tumor tissues or tissues of patients with chronic pancreatitis; these were analyzed by immunofluorescence microscopy, immunoblots, quantitative reverse transcription polymerase chain reaction, and in assays for invasiveness, proliferation, and lipid droplets. Autophagy was inhibited in PSCs by administration of chloroquine or transfection with small interfering RNAs. Proteins were knocked down in immortalized PSCs by expression of small hairpin RNAs. Cells were transplanted into pancreatic tails of nude mice, and tumor growth and metastasis were quantified. RESULTS: Based on immunohistochemical analyses, autophagy was significantly associated with tumor T category (P = .018), histologic grade (P = .001), lymph node metastases (P < .001), stage (P = .009), perilymphatic invasion (P = .001), and perivascular invasion (P = .003). Autophagy of PSCs was associated with shorter survival times of patients with pancreatic cancer. PSC expression of microtubule-associated protein 1 light chain 3, a marker of autophagosomes, was associated with poor outcomes (shorter survival time, disease recurrence) for patients with pancreatic cancer (relative risk of shorter survival time, 1.56). Immunoblots showed that PSCs from pancreatic tumor samples expressed higher levels of markers of autophagy than PSCs from chronic pancreatitis samples. Inhibitors of autophagy increased the number of lipid droplets of PSCs, indicating a quiescent state of PSCs, and reduced their production of ECM molecules and interleukin 6, as well as their proliferation and invasiveness in culture. PSCs exposed to autophagy inhibitors formed smaller tumors in nude mice (P = .001) and fewer liver metastases (P = .018) with less peritoneal dissemination (P = .018) compared to PSCs not exposed to autophagy inhibitors. CONCLUSIONS: Autophagic PSCs produce ECM molecules and interleukin 6 and are associated with shorter survival times and disease recurrence in patients with pancreatic cancer. Inhibitors of PSC autophagy might reduce pancreatic tumor invasiveness by altering the tumor stroma.

Autophagy inhibition enhances antiproliferative effect of salinomycin in pancreatic cancer cells.

BACKGROUND: Salinomycin has cytotoxic effects on various types of malignancy and induces autophagy. However, it has not been clarified whether autophagy induced by salinomycin treatment has a protective or cytotoxic role. We investigated whether salinomycin affects autophagy in pancreatic cancer cells and whether autophagy induced by salinomycin treatment has a protective or cytotoxic role in these cells. METHODS: We investigated the effect of salinomycin using three pancreatic cancer cell lines. We investigated effect on proliferation and the CD133 positive fraction using flow cytometry. In addition, we monitored the change in autophagic activity after salinomycin treatment using fluorescent immunostaining, western blotting, and flow cytometry. Finally, knockdown of ATG5 or ATG7 by siRNA was used to investigate the impact of autophagy inhibition on sensitivity to salinomycin. RESULTS: Salinomycin suppressed the proliferation of pancreatic cancer cells in a concentration dependent manner, and reduced the CD133 positive fraction. Salinomycin enhanced autophagy activity in these cells in a concentration dependent manner. Autophagy inhibition made pancreatic cancer cells more sensitive to salinomycin. CONCLUSIONS: Our data provide the first evidence indicating that autophagy induced by salinomycin have a protective role in pancreatic cancer cells. A new therapeutic strategy of combining salinomycin, autophagy inhibitors, and anticancer drugs could hold promise for pancreatic cancer treatment.

Laparoscopic lateral pelvic lymph node dissection is achievable and offers advantages as a minimally invasive surgery over the open approach.

BACKGROUND: Laparoscopic lateral pelvic lymph node dissection (LPLD) is a minimally invasive alternative to open surgical therapy for advanced low rectal cancer patients. This study assessed potential risk factors for lateral pelvic lymph node metastasis (LPLM) and evaluated the feasibility and oncological safety of laparoscopic LPLD compared with the conventional open approach. METHODS: We retrospectively reviewed the clinical records of 90 patients with advanced low rectal cancer who underwent LPLD following total mesorectal excision at Kyushu University Hospital between January 2001 and July 2014. We compared the clinicopathological features between the patients with and without LPLM and the surgical outcomes between patients who underwent laparoscopic LPLD (LL) and open LPLD (OL). RESULTS: Fourteen (15.6 %) patients had LPLM. Univariate analysis revealed that undifferentiated cancer, positive lymphatic invasion, >50 % circumferential cancer extent, mesorectal lymph node metastases (MLM), and distant metastasis were associated with LPLM. In the multivariate analysis, MLM was the only independent risk factor for LPLM. Forty-six (51.1 %) patients underwent LL, and 44 (48.9 %) patients underwent OL. The mean surgical duration was longer in the LL group than in the OL group (641.0 vs. 312.0 min, P < 0.001). The LL group also had less hemorrhage (252.0 vs. 815.0 mL, P < 0.001) and a shorter hospital stay (22.9 vs. 29.1 days, P = 0.04) than the OL group. The mean number of harvested lateral pelvic lymph nodes was larger in the LL group than in the OL group (19.5 vs. 15.8, P < 0.05). The morbidity rate and overall survival (3-year OS: 94.7 vs. 82.9 %, P = 0.25) did not differ between the two groups. CONCLUSIONS: Patients with advanced low rectal cancer presenting MLM are good candidates for LPLD. Laparoscopic LPLD enables retrieval of more lymph nodes and may be acceptable for the treatment of advanced low rectal cancer.

[A Case of Primary Peritoneal Cancer Successfully Treated with Debulking Surgery and Postoperative Chemotherapy].

A 52-year-old woman with abdominal pain and a feeling of incomplete evacuation visited a local clinic. Enlargement of the right ovary was detected, and the patient was referred to the gynecological department of our hospital. CT and MRI revealed a round-shaped mass, 8 cm in diameter, with cystic and solid components in the Douglas pouch. The patient underwent a laparotomy under the diagnosis of ovarian cancer. Intraoperatively, both the ovaries appeared normal and the tumor strongly adhered to the rectum and uterus. An exploratory laparotomy was performed; the tumor was identified as unresectable, and the patient was referred to our department after the surgery. PET-CT revealed nodules in the liver and peritoneum, in addition to the main tumor. Gastrointestinal endoscopy and immunohistochemical examination of a needle biopsy of the main tumor did not lead to the identification of the primary lesion. Thus, debulking surgery was performed to alleviate the patient's complaints. Histologically, the tumor was diagnosed as a primary peritoneal clear cell carcinoma. One month after surgery, multiple liver metastases and swelling of the peritoneal lymph nodes occurred. Six courses of dose-dense TC therapy were administered, and the patient achieved a complete response. At 8 months after surgery, the patient is still alive without tumor recurrence.

TAK1 Promotes an Immunosuppressive Tumor Microenvironment through Cancer-Associated Fibroblast Phenotypic Conversion in Pancreatic Ductal Adenocarcinoma.

PURPOSE: We aim to clarify the precise function of Transformed growth factor-beta 1 activated kinase-1 (TAK1) in cancer-associated fibroblasts (CAFs) within human pancreatic ductal adenocarcinoma (PDAC) by investigating its role in cytokine-mediated signaling pathways. EXPERIMENTAL DESIGN: The expression of TAK1 in pancreatic cancer was confirmed by TCGA data and human pancreatic cancer specimens. CAFs from freshly resected PDAC specimens were cultured and used in a three-dimensional model for direct and indirect co-culture with PDAC tumors to investigate TAK1 function. Additionally, organoids from KPC (LSL-K-RasLSLG12D/+; LSL-p53R172H/+; Pdx1-Cre) mice were mixed with CAFs and injected subcutaneously into C57BL/6 mice to explore in vivo functional interactions of TAK1. RESULTS: TCGA data revealed significant upregulation of TAK1 in PDAC, associating with a positive correlation with the T-cell exhaustion signature. Knockdown of TAK1 in CAFs decreased the iCAF signature and increased the myCAF signature both in vitro and in vivo. The absence of TAK1 hindered CAF proliferation, blocked several inflammatory factors via multiple pathways associated with immunosuppression, and hindered EMT, outgrowth in vitro in spheroid co-cultures with PDAC cells. Additionally, TAK1 inhibitor restrained tumor growth, increased CD4+ and CD8+ T cell abundance, and reduced immunosuppressive cells present in vivo. CONCLUSIONS: Blocking the TAK1+CAF phenotype leads to the conversion of protumorigenic CAFs to antitumorigenic CAFs. This highlights TAK1 as a potential therapeutic target, particularly in CAFs, and represents a novel avenue for combined immunotherapy in PDAC.

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).

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, 0.81-0.89) and 0.76 (95 %CI, 0.60-0.92), 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).