Ectopic pancreatic adenocarcinoma in Meckel's diverticulum: a case report.

BACKGROUND: Malignant neoplasms arising from Meckel's diverticulum are rare and an adenocarcinoma in Meckel's diverticulum originating from ectopic pancreatic tissue is even rarer. Herein, we report a patient with an ectopic pancreatic adenocarcinoma in Meckel's diverticulum who was successfully treated with surgery and chemotherapy. CASE PRESENTATION: A woman in her sixties presented to another hospital with abdominal pain. Plain computed tomography suggested an abdominal tumor and she was referred to our hospital. Enhanced computed tomography revealed a 23-mm low-density tumor in the abdominal cavity. Surgery was performed with a tentative diagnosis of a mesenteric tumor, such as a gastrointestinal stromal tumor, schwannoma, or lymphoma. First, we inspected the peritoneal cavity with a laparoscope. This revealed numerous nodules in the small bowel mesentery, suggesting peritoneal dissemination. A 20-mm-diameter white tumor was found in the small intestine and diagnosed as a small intestinal cancer. The small intestine was partially resected laparoscopically through a small skin incision. The patient's postoperative course was uneventful, and she was discharged on postoperative day 9. Pathological examination revealed well-differentiated adenocarcinoma in the small intestine. The tumor had developed from a sac-like portion protruding toward the serosal side and had a glandular structure lined with flattened atypical cells. Neither pancreatic acinar cells nor islets of Langerhans were evident, suggesting a Heinrich type 3 ectopic pancreas. The final diagnosis was an adenocarcinoma originating from an ectopic pancreas in Meckel's diverticulum. After a smooth recovery, the patient commenced chemotherapy for pancreatic cancer. CONCLUSIONS: We present a very rare case of ectopic pancreatic carcinoma in Meckel's diverticulum.

Effect of duration of adjuvant chemotherapy with S-1 (6 versus 12 months) for resected pancreatic cancer: the multicenter clinical randomized phase II postoperative adjuvant chemotherapy S-1 (PACS-1) trial.

BACKGROUND: Six-month adjuvant chemotherapy with S-1 is standard care for resected pancreatic cancer in Japan; however, the optimal duration has not been established. We aimed to evaluate the impact of duration of adjuvant chemotherapy with S-1. METHODS: We performed a multicenter, randomized, open-label, phase II study. Patients with histologically proven invasive pancreatic ductal carcinoma, pathological stage I-III, and no local residual or microscopic residual tumor were eligible. Patients were randomized 1:1 to receive 6- or 12-month adjuvant chemotherapy with S-1. The primary endpoint was 2-year overall survival (OS). Secondary endpoints were disease-free survival (DFS) and feasibility. RESULTS: A total of 170 patients were randomized (85 per group); the full analysis set was 82 in both groups. Completion rates were 64.7% (6-month group) and 44.0% (12-month group). Two-year OS was 71.5% (6-month group) and 65.4% (12-month group) (hazard ratio (HR): 1.143; 80% confidence interval CI 0.841-1.553; P = 0.5758). Two-year DFS was 46.4% (6-month group) and 44.9% (12-month group) (HR: 1.069; 95% CI 0.727-1.572; P = 0.6448). In patients who completed the regimen, 2-year DFS was 56.5% (6-month group) and 75.0% (12-month group) (HR: 0.586; 95% CI 0.310-1.105; P = 0.0944). Frequent (≥ 5%) grade ≥ 3 adverse events comprised anorexia (10.5% in the 6-month group) and diarrhea (5.3% vs. 5.1%; 6- vs. 12-month group, respectively). CONCLUSIONS: In patients with resected pancreatic cancer, 12-month adjuvant chemotherapy with S-1 was not superior to 6-month therapy regarding OS and DFS.

DUPAN-2 as a Risk Factor of Early Recurrence After Curative Pancreatectomy for Patients With Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: Several patients with pancreatic ductal adenocarcinoma (PDAC) experience postoperative early recurrence (ER). We evaluated PDAC patients to identify the risk factors for postoperative ER (≤6 months), including preoperative serum DUPAN-2 level. METHODS: We retrospectively evaluated 74 PDAC patients who underwent pancreatectomy with curative intent. Clinicopathological factors including age, sex, body mass index, postoperative complications, pathological factors, preoperative C-reactive protein/albumin ratio, neutrophil/lymphocyte ratio, modified Glasgow prognostic score, preoperative tumor markers (carcinoembryonic antigen, carbohydrate antigen 19-9, SPAN-1, and DUPAN-2), and history of adjuvant chemotherapy were investigated. Early recurrence risk factors were determined using multivariate logistic regression analysis. RESULTS: Recurrence and ER occurred in 52 (70.3%) and 23 (31.1%) patients, respectively. Univariate analysis revealed that postoperative complications, C-reactive protein/albumin ratio ≥0.02, neutrophil/lymphocyte ratio ≥3.01, carbohydrate antigen 19-9 ≥ 92.3 U/mL, SPAN-1 ≥ 69 U/mL, DUPAN-2 ≥ 200 U/mL, and absence of adjuvant chemotherapy were significant risk factors for ER. In multivariate analysis, DUPAN-2 ≥ 200 U/mL (P = 0.04) and absence of adjuvant chemotherapy (P = 0.02) were identified as independent risk factors for ER. CONCLUSIONS: A higher level of preoperative DUPAN-2 was an independent risk factor for ER. For patients with high DUPAN-2 level, neoadjuvant therapies might be required to avoid ER.

Efficacy of laparoscopic liver resection for small hepatocellular carcinoma located in the posterosuperior segments: A multi-institutional study using propensity score matching by the Kyushu Study Group of Liver Surgery.

AIM: Laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) located in the posterosuperior segments (PS) have generally been considered more difficult than those for HCC in anterolateral segments (AL), but may be safe and feasible for selected patients with accumulated experience. In the present study, we investigated the effectiveness of LLR for single nodular HCCs ≤3 cm located in PS. METHODS: In total, 473 patients who underwent partial liver resection for single nodular HCCs ≤3 cm at the 18 institutions belonging to the Kyusyu Study Group of Liver Surgery from January 2010 to December 2018 were enrolled. The short-term outcomes of laparoscopic partial liver resection and open liver resection (OLR) for HCCs ≤3 cm, with subgroup analysis of PS and AL, were compared using propensity score-matching analysis. Furthermore, results were also compared between LLR-PS and LLR-AL. RESULTS: The original cohort of patients with HCC ≤3 cm included 328 patients with LLR and 145 with OLR. After matching, 140 patients with LLR and 140 with OLR were analyzed. Significant differences were found between groups in terms of volume of blood loss (median, 55 vs. 287 ml, p < 0.001), postoperative complications (0.71 vs. 8.57%, p = 0.003), and postoperative hospital stay (median, 9 vs. 14 days, p < 0.001). The results of subgroup analysis of PS were similar. Short-term outcomes did not differ significantly between LLR-PS and LLR-AL after matching. CONCLUSIONS: Laparoscopic partial resection could be the preferred option for single nodular HCCs ≤3 cm located in PS.

Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma.

BACKGROUND: Driver alterations may represent novel candidates for driver gene-guided therapy; however, intrahepatic cholangiocarcinoma (ICC) with multiple genomic aberrations makes them intractable. Therefore, the pathogenesis and metabolic changes of ICC need to be understood to develop new treatment strategies. We aimed to unravel the evolution of ICC and identify ICC-specific metabolic characteristics to investigate the metabolic pathway associated with ICC development using multiregional sampling to encompass the intra- and inter-tumoral heterogeneity. METHODS: We performed the genomic, transcriptomic, proteomic and metabolomic analysis of 39-77 ICC tumour samples and eleven normal samples. Further, we analysed their cell proliferation and viability. RESULTS: We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case exhibited neutral evolution, regardless of their tumour stage. Upregulation of BCAT1 and BCAT2 indicated the involvement of 'Val Leu Ile degradation pathway'. ICCs exhibit the accumulation of ubiquitous metabolites, such as branched-chain amino acids including valine, leucine, and isoleucine, to negatively affect cancer prognosis. We revealed that this metabolic pathway was almost ubiquitously altered in all cases with genomic diversity and might play important roles in tumour progression and overall survival. CONCLUSIONS: We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions.

Risk Factors of Complications from Central Bisectionectomy (H458) for Hepatocellular Carcinoma: A Multi-Institutional Single-Arm Analysis.

BACKGROUND: This study aims to clarify the perioperative risk factors and short-term prognosis of central bisectionectomy (CB) for hepatocellular carcinoma (HCC). METHODS: Surgical data from 142 selected patients out of 171 HCC patients who underwent anatomical CB (H458) between 2005 and 2020 were collected from 17 expert institutions in a single-arm retrospective study. RESULTS: Morbidities recorded by the International Study Group of Liver Surgery (ISGLS) from grade BC post-hepatectomy liver failure (PHLF) and bile leakage (PHBL), or complications requiring intervention were observed in 37% of patients. A multivariate analysis showed that increased blood loss (iBL) > 1500 mL from PHLF (risk ratio [RR]: 2.79), albumin level < 4 g/dL for PHBL (RR, 2.99), involvement of segment 1, a large size > 6 cm, or compression of the hepatic venous confluence or cava by HCC for all severe complications (RR: 5.67, 3.75, 6.51, and 8.95, respectively) (p < 0.05) were significant parameters. Four patients (3%) died from PHLF. HCC recurred in 50% of 138 surviving patients. The three-year recurrence-free and overall survival rates were 48% and 81%, respectively. CONCLUSIONS: Large tumor size and surrounding tumor involvement, or compression of major vasculatures and the related iBL > 1500 mL were independent risk factors for severe morbidities in patients with HCC undergoing CB.

Essential amino acids as diagnostic biomarkers of hepatocellular carcinoma based on metabolic analysis.

Metabolomics, defined as the comprehensive identification of all small metabolites in a biological sample, has the power to shed light on phenotypic changes associated with various diseases, including cancer. To discover potential metabolomic biomarkers of hepatocellular carcinoma (HCC), we investigated the metabolomes of tumor and non-tumor tissue in 20 patients with primary HCC using capillary electrophoresis-time-of-flight mass spectrometry. We also analyzed blood samples taken immediately before and 14 days after hepatectomy to identify associated changes in the serum metabolome. Marked changes were detected in the different quantity of 61 metabolites that could discriminate between HCC tumor and paired non-tumor tissue and additionally between HCC primary tumors and colorectal liver metastases. Among the 30 metabolites significantly upregulated in HCC tumors compared with non-tumor tissues, 10 were amino acids, and 7 were essential amino acids (leucine, valine, tryptophan, isoleucine, methionine, lysine, and phenylalanine). Similarly, the serum metabolomes of HCC patients before hepatectomy revealed a significant increase in 16 metabolites, including leucine, valine, and tryptophan. Our results reveal striking differences in the metabolomes of HCC tumor tissue compared with non-tumor tissue, and identify the essential amino acids leucine, valine, and tryptophan as potential metabolic biomarkers for HCC.

Maximum Diameter of the Gallbladder Determined Presurgically Using Computed Tomography as a Risk Factor for Difficult Emergency Laparoscopic Cholecystectomy in Patients With Mild to Moderate Acute Cholecystitis.

BACKGROUND: Early or emergency laparoscopic cholecystectomy (LC) was recommended in the 2018 Tokyo Guidelines for patients with mild to moderate acute cholecystitis (AC). Although surgical difficulty is frequently encountered during these surgeries, risk factors for predicting surgical difficulties have not been fully investigated, especially based on computed tomography (CT) findings. MATERIALS AND METHODS: We investigated 72 patients who underwent emergency LC with mild (n=45) to moderate (n=27) AC. Patients who previously underwent presurgical percutaneous or endoscopic biliary drainage were excluded from this study. Difficult LC was defined using any of the following surgical factors: surgical duration ≥180 minutes, blood loss ≥300 g, or a conversion to open cholecystectomy. Subsequently, several presurgical clinical factors were analyzed, including sex, age at surgery, experience of the surgeon, interval between symptom onset and surgery, body mass index, diabetes history, presurgical white blood cell count, and C-reactive protein level. Moreover, stones in the cystic duct or perigallblader fluid and the maximum thickness and diameter of the gallbladders were evaluated via presurgical CT. Finally, logistic regression analysis was performed to compare the relationship between surgical difficulty and each clinical factor. RESULTS: The average age at surgery of the included patients was 60.3 (range: 25 to 88 y), surgical duration was 112.2 (range: 29 to 296 min), and surgical blood loss was 55.2 (range: 0 to 530 g). Furthermore, 4 (5.6%) had to undergo open cholecystectomy, whereas postsurgical complications occurred in 5 (6.9%) patients. In addition, the mean postsurgical admission duration was 7 (range: 3 to 63 d). Thus, 12 patients experienced difficult LC, whereas 60 experienced nondifficult LC. Of the evaluated clinical factors, patients who experienced difficult LC showed higher presurgical C-reactive protein levels (10.78 vs. 6.76 mg/dL, P =0.01) and wider gallbladder diameters (48.4 vs. 41.8 mm, P <0.01) than those who experienced nondifficult LC. By univariate logistic regression analysis, results also showed that patients with a maximum gallbladder diameter had a higher risk of experiencing difficulty during emergency LC ( P =0.02). Moreover, the gallbladder diameter's cutoff value was 43 mm after the receiver operating characteristic curve analysis. CONCLUSIONS: In patients with mild to moderate AC, emergency LC can safely be performed. However, performing LC might be technically difficult in patients with AC after the identification of severe gallbladder swelling during presurgical CT.

Prognostic significance of intrahepatic lymphatic invasion in colorectal liver metastases.

BACKGROUND: Intrahepatic lymphatic invasion is an adverse prognostic factor after hepatectomy for colorectal liver metastases (CLMs). However, most patients in previous reports had liver resection before the era of FOLFOX/FIRI-based chemotherapy. METHODS: Forty-six patients who underwent hepatectomy for CLMs from 2004 to 2020 were evaluated. We histologically evaluated portal invasion, intrahepatic lymphatic invasion, and biliary invasion on hematoxylin-eosin slides. We also collected the following clinicopathologic factors: gender, age, timing, the number and maximum size of CLMs, preoperative tumor markers, neutrophil/lymphocyte ratio, location, and lymph node metastases of primary cancer, and chemotherapy after hepatectomy. A multivariate Cox proportional hazard model was used to define the relationship between overall (OS) or disease-free survival (DFS) and clinicopathologic factors. RESULTS: Histological invasions were portal invasion in 8 (17.4 %), intrahepatic lymphatic invasion in 6 (13.0 %), and biliary invasion in 5 (10.9 %). Chemotherapy for recurrence after hepatectomy (n = 29) was performed in 22 and 14 of those who received FOLFOX/FIRI-based chemotherapy. By multivariate analysis, the number of CLMs (p < 0. 01) and presence of intrahepatic lymphatic invasion (p = 0.02) were independent predictors of recurrence. The number of CLMs (p = 0.02) and prehepatectomy carcinoembryonic antigen level (p = 0.02), but not intrahepatic lymphatic invasion (p = 0.18), were independent predictors of survival using multivariate analysis. CONCLUSIONS: The presence of intrahepatic lymphatic invasion adversely affected patient's DFS, but not OS in patients with CLMs in the era of FOLFOX/FIRI chemotherapy. FOLFOX/FIRI-based chemotherapy might improve OS, even in patients with positive intrahepatic lymphatic invasion.

Elevated Preoperative DUPAN-2 Level Predicts Locoregional Recurrence After Pancreatectomy in Patients With Pancreatic Ductal Adenocarcinoma.

BACKGROUND/AIM: The diagnostic value of serum DUPAN-2 level has been reported; however, the relationship between preoperative DUPAN-2 level and recurrence pattern has not been fully investigated in pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: We retrospectively analyzed 50 patients with PDAC who underwent pancreatectomy. The relationships between clinicopathologic factors and site-specific disease-free survival (DFS) were analyzed using Cox proportional hazard and receiver operating characteristic (ROC) curve analyses. RESULTS: The tumor location was the pancreatic head in 31 patients and the body/tail in 19 patients. Of the 50 patients, 34 had recurrence (median DFS, 11 months). Fifteen patients had hematogenous recurrence, and 16 had locoregional recurrence. In multivariate analysis, adjuvant chemotherapy [p=0.01; odds ratio (OR)=8.10; 95% confidence interval (CI)=1.58-41.6] and venous invasion (p=0.01; OR=8.33; 95%CI=1.53-45.4) were significant factors for hematogenous recurrence-free survival, whereas the neutrophil-to-lymphocyte ratio (p=0.03; OR=2.57; 95%CI=1.10-5.98) and DUPAN-2 level (p<0.01; OR=1.00; 95%CI=1.000-1.002) were significant factors for locoregional recurrence-free survival. In ROC curve analysis, the area under the curve of DUPAN-2 level was 0.613 for hematogenous recurrence and 0.682 for locoregional recurrence. In the log-rank test, the hematogenous and locoregional recurrence-free survival rates of patients with higher DUPAN-2 levels were significantly worse than those with lower DUPAN-2 level. CONCLUSION: Elevation of preoperative DUPAN-2 level independently predicts locoregional recurrence after surgery. Patients with elevated preoperative DUPAN-2 level may benefit from neoadjuvant chemoradiation therapy to avoid postoperative locoregional recurrence.

Identification of microRNA-96-5p as a postoperative, prognostic microRNA predictor in nonviral hepatocellular carcinoma.

AIM: The microRNA (miR) clusters miR-183/96/182 and miR-217/216a/216b are significantly upregulated in nonviral hepatocellular carcinoma (NBNC-HCC). Here, we investigate the impact of each member of these clusters on the clinical outcome of NBNC-HCC and analyze the antitumor effects of miR-96-5p. METHODS: The association between recurrence-free survival of 111 NBNC-HCC patients and the levels of miR-183-5p, miR-96-5p, miR-182-5p, miR-217-5p, miR-216a-5p, and miR-216b-5p in tumor and adjacent tissues was investigated. The impact of miR-96-5p on apoptosis and invasion of a hepatoma cell line, HepG2, was investigated by cell counting, Transwell assay, and flow cytometry, respectively. RESULTS: MicroRNA-183-5p, miR-96-5p, miR-182-5p, miR-217-5p, and miR-216b-5p were significantly upregulated in tumor tissues compared to the adjacent tissues (p = 0.0005, p = 0.0030, p = 0.0002, p = 0.0011, and p = 0.0288, respectively). By multivariate Cox regression analysis, high tumor/adjacent ratios of miR-182-5p (p = 0.007) and miR-217-5p (p = 0.008) were associated with poor recurrence-free survival. In contrast, a low tumor/adjacent ratio of miR-96-5p (p < 0.001) was associated with poor recurrence-free survival. It suggested that further upregulation of miR-96-5p in tumors might have an inhibitory effect on recurrence. Transfection of miR-96-5p mimic significantly induced apoptosis of HepG2 cells, in association with downregulation of Nucleophosmin 1 (NPM1) and a decrease of phosphorylated AKT protein. Interestingly, simultaneous knockdown of the NPM1 and AKT genes induced apoptosis. MicroRNA-96-5p also suppressed proliferation and invasion, which inhibited epithelial-to-mesenchymal transition of HCC cells. CONCLUSION: MicroRNA-96-5p as a tumor suppressor would be valuable to stratify NBNC-HCC patients at high risk of recurrence.

Prognostic significance of preoperative PNI and CA19-9 for pancreatic ductal adenocarcinoma: A multi-institutional retrospective study.

BACKGROUND: The aim of this study was to investigate the clinical value of nutritional and immunological prognostic scores as predictors of outcomes and to identify the most promising scoring system for patients with pancreatic ductal adenocarcinoma (PDAC) in a multi-institutional study. METHODS: Data were retrospectively collected for 589 patients who underwent surgical resection for PDAC. Prognostic analyses were performed for overall (OS) and recurrence-free survival (RFS) using tumor and patient-related factors, namely neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, Prognostic Nutritional Index (PNI), Glasgow Prognostic Score (GPS), modified GPS, C-reactive protein-to-albumin ratio, Controlling Nutritional Status score, and the Geriatric Nutritional Risk Index. RESULTS: Compared with PDAC patients with high PNI values (≥46), low PNI (<46) patients showed significantly worse overall survival (OS) (multivariate hazard ratio (HR), 1.432; 95% CI, 1.069-1.918; p = 0.0161) and RFS (multivariate HR, 1.339; 95% CI, 1.032-1.736; p = 0.0277). High carbohydrate antigen 19-9 (CA19-9) values (≥450) were significantly correlated with shorter OS (multivariate HR, 1.520; 95% CI, 1.261-2.080; p = 0.0002) and RFS (multivariate HR, 1.533; 95% CI, 1.199-1.961; p = 0.0007). Stratification according to PNI and CA19-9 was also significantly associated with OS and RFS (log rank, P < 0.0001). CONCLUSIONS: Our large cohort study showed that PNI and CA19-9 were associated with poor clinical outcomes in PDAC patients following surgical resection. Additionally, combining PNI with CA19-9 enabled further classification of patients according to their clinical outcomes.

A totally extraperitoneal approach for endoscopic resection of a congenital prepubic sinus through the pubic symphysis.

BACKGROUND: A congenital prepubic sinus (CPS) is a rare congenital anomaly in which a duct remnant extends from the skin opening near the pubic symphysis to various parts and the lesions are mostly located in the preperitoneal space. The totally extraperitoneal (TEP) approach is an operational method that provides a good field of view for the preperitoneal space. We report the CPS through the pubic symphysis in which complete resection was achieved by a TEP approach. TEP approach was minimally invasive and achieved satisfactory cosmetic outcome. CASE PRESENTATION: We herein report the case of a 13-year-old boy with a fistula opening near the dorsal penis. He was admitted to our hospital due to fever and lower abdominal pain. Abdominal ultrasonography and computed tomography revealed an abscess inside a fistula lumen on the posterior surface of the rectus abdominis muscles in the midline of the lower abdomen. Under a diagnosis of CPS, which was located in the preperitoneal space, endoscopic resection was performed by a totally extraperitoneal approach. After making an umbilical incision, the rectus abdominis muscle was excised outward to expose the preperitoneal space. A single-port system was placed in the preperitoneal space. Three 5-mm-port trocars were inserted. As the preperitoneal cavity was expanded, a sinus connecting to the pubic symphysis was confirmed. The pubic symphysis did not connect with the bladder. Because the fistula was penetrated with the pubic symphysis, the remaining caudal fistula was removed from the body surface with a small spindle-shaped incision around the fistula opening. Finally, the sinus was completely resected, with confirmation from both the cranial side and dorsal side of the pubic symphysis. We were able to perform complete resection of the CPS with good visibility and without any peritoneal damage. There were no intraoperative complications. His postoperative course was uneventful during the 1-year follow-up. CONCLUSIONS: The TEP approach may be feasible for the resection of a CPS and may allow safe and secure resection due to good visibility, even in pediatric patients.

The novel driver gene ASAP2 is a potential druggable target in pancreatic cancer.

Targeting mutated oncogenes is an effective approach for treating cancer. The 4 main driver genes of pancreatic ductal adenocarcinoma (PDAC) are KRAS, TP53, CDKN2A, and SMAD4, collectively called the "big 4" of PDAC, however they remain challenging therapeutic targets. In this study, ArfGAP with SH3 domain, ankyrin repeat and PH domain 2 (ASAP2), one of the ArfGAP family, was identified as a novel driver gene in PDAC. Clinical analysis with PDAC datasets showed that ASAP2 was overexpressed in PDAC cells based on increased DNA copy numbers, and high ASAP2 expression contributed to a poor prognosis in PDAC. The biological roles of ASAP2 were investigated using ASAP2-knockout PDAC cells generated with CRISPR-Cas9 technology or transfected PDAC cells. In vitro and in vivo analyses showed that ASAP2 promoted tumor growth by facilitating cell cycle progression through phosphorylation of epidermal growth factor receptor (EGFR). A repositioned drug targeting the ASAP2 pathway was identified using a bioinformatics approach. The gene perturbation correlation method showed that niclosamide, an antiparasitic drug, suppressed PDAC growth by inhibition of ASAP2 expression. These data show that ASAP2 is a novel druggable driver gene that activates the EGFR signaling pathway. Furthermore, niclosamide was identified as a repositioned therapeutic agent for PDAC possibly targeting ASAP2.

Prognostic Significance of PD-1, PD-L1 and CD8 Gene Expression Levels in Gastric Cancer.

INTRODUCTION: Anti-programmed cell death 1 (PD-1) therapies have shown promising clinical activity against gastric cancer (GC). We evaluated the clinical significance of immune-related gene expression in GC tissues to better understand the tumor immune microenvironment. METHODS: PD-1, PD-1 ligand 1 (PD-L1) and CD8 mRNA levels and clinicopathological factors, including survival, were examined by quantitative RT-PCR in 155 GC patients who underwent surgery. PD-1 and PD-L1 expression in tumor tissue from 24 GC patients was investigated by immunohistochemical analysis. RESULTS: PD-1, PD-L1 and CD8 mRNA levels were significantly lower in tumor tissue than in normal tissue (p < 0.0001, p < 0.05, and p < 0.0001). GC patients with low PD-1, PD-L1 and CD8 mRNA levels had significantly poorer overall survival (OS) than those with high PD-1, PD-L1 and CD8 mRNA levels, respectively (p < 0.001, p < 0.01 and p < 0.05). Low PD-1, PD-L1 and CD8 mRNA levels were more significantly associated with poor prognosis in undifferentiated-type GC patients than in differentiated-type GC patients (PD-1: differentiated p = 0.0071 vs. undifferentiated p = 0.0024; PD-L1: p = 0.6527 vs. p < 0.0001; CD8: p = 0.4465 vs. p < 0.05). Multivariate analysis showed that lymph node metastasis, peritoneal dissemination, distant metastasis, low PD-1 mRNA levels and low CD8 mRNA levels were independent prognostic factors for worse OS (low PD-1 mRNA level: OR 2.16, 95% CI 1.10-4.58, p < 0.05; low CD8 mRNA level: OR 2.55, 95% CI 1.12-6.90, p < 0.05). PD-1 and PD-L1 mRNA levels in immune cells were significantly associated with PD-1 and PD-L1 protein levels (both p < 0.05), respectively. CONCLUSIONS: PD-1, PD-L1 and CD8 mRNA levels may reflect antitumor immunity in GC, and low PD-1 and CD8 mRNA levels are potential predictive biomarkers for poor prognosis in GC patients who underwent surgery.

Effect of epigenetic modulation on cancer sphere.

Background : Cancer stem cell properties are highly relevant to the biology of treatment-resistant cancers. Epigenetic modification regulates gene expressions by chromatin remodeling during malignant transformation. The aim of this study was to elucidate the possible strategy for cancer stem cells focusing on epigenetic modification. Methods : We made cancer sphere from HepG2 cells, and we added Histone deacetylase (HDAC) inhibitor, valproic acid to cancer sphere. And we compared methylation status and the gene expression between normal HepG2 and cancer sphere groups, and between cancer sphere and sphere with HDAC inhibitor treatment groups. Results : Valproic acid (VPA) cancelled this spheroid formation. In comparison between normal HepG2 and cancer sphere, the number of methylation status changes more than 0.1 of beta level was 826 probes, and we could isolate some epithelial-mesenchymal transition (EMT) related genes. And VPA reduced the expressions of EMT related genes in sphere with RT-PCR. On the other hand, in comparison between cancer sphere and sphere with VPA treatment, we detected 29 probe of methylation status change, and VPA reduced the expressions of Bcl-6 in sphere. Conclusions : HDAC inhibitor affected the methylation status of cancer stem cells. Histone-acetylation might overcome treatmet-resistant cancer through the regulation of cancer stem cell. J. Med. Invest. 67 : 70-74, February, 2020.

Reduction of T-Box 15 gene expression in tumor tissue is a prognostic biomarker for patients with hepatocellular carcinoma.

Genome-wide analysis is widely applied to detect molecular alterations during oncogenesis and tumor progression. We analyzed DNA methylation profiles of hepatocellular carcinoma (HCC), and investigated the clinical role of most heypermethylated of tumor, encodes T-box 15 (TBX15), which was originally involved in mesodermal differentiation. We conducted a genome-wide analysis of DNA methylation of tumor and non-tumor tissue of 15 patients with HCC, and revealed TBX15 was the most hypermethylated gene of tumor (Beta-value in tumor tissue = 0.52 compared with non-tumor tissue). Another validation set, which comprised 58 HCC with radical resection, was analyzed to investigate the relationships between tumor phenotype and TBX15 mRNA expression. TBX15 mRNA levels in tumor tissues were significantly lower compared with those of nontumor tissues (p < 0.0001). When we assigned a cutoff value = 0.5-fold, the overall survival 5-year survival rates of the low-expression group (n = 17) were significantly shorter compared with those of the high-expression group (n = 41) (43.3% vs. 86.2%, p = 0.001). Multivariate analysis identified low TBX15 expression as an independent prognostic factor for overall and disease-free survival. Therefore, genome-wide DNA methylation profiling indicates that hypermethylation and reduced expression of TBX15 in tumor tissue represents a potential biomarker for predicting poor survival of patients with HCC.

Perioperative serum and urine metabolome analyses in patients with hepatocellular carcinoma undergoing partial hepatectomy.

OBJECTIVES: Perioperative nutritional management is essential for early recovery after liver surgery. The aim of this study was to assess changes in amino acid levels in serum and urine after hepatectomy. METHODS: Serum samples were collected from 16 patients with hepatocellular carcinoma before and 1, 3, and 14 d after hepatectomy (S0, S1, S3, and S14, respectively). Spot urine samples were collected before and 3 d after the hepatectomy (U0 and U3). Metabolites in the serum and urine were analyzed. RESULTS: Compared with S0, insulin levels significantly increased in the S1 and S3 samples. Valine levels significantly decreased in S1 and S14, and leucine levels significantly decreased in S14. Phenylalanine levels significantly increased in S1 and S3, and tyrosine levels significantly increased in S1. The Fischer ratio (branched-chain/aromatic amino acids) significantly decreased in S1 and S3. In multiple regression analysis, changes in serum taurine levels were related to the white blood cell count in S1 and S3, and inversely related to alanine aminotransferase levels in S14. Changes in serum glutamine levels were negatively related to C-reactive protein levels in S3. Serum glutamine levels decreased in S3 and S14, and tended to increase in U3, suggesting a deficiency of glutamate resulting from the invasive surgical procedure. CONCLUSIONS: These findings highlight the usefulness of metabolome analysis for characterizing perioperative patterns after liver resection. The observed amino acid pattern, including the reduction in Fischer ratio, underscores the need for specialized nutritional support.

Prognostic Significance of Preoperative Controlling Nutritional Status (CONUT) Score in Patients Undergoing Hepatic Resection for Hepatocellular Carcinoma: A Multi-institutional Study.

BACKGROUND: The Controlling Nutritional Status (CONUT) score is an objective tool that is widely used to assess the nutritional status in patients, including those with cancer. The relationship between the CONUT score and prognosis in patients who have undergone hepatic resection has not been evaluated in a multi-institutional study. METHODS: Data were retrospectively collected for 2461 consecutive patients with hepatocellular carcinoma (HCC) who had undergone hepatic resection with curative intent at 13 institutions between January 2004 and December 2015. Patients were assigned to two groups: preoperative CONUT scores ≤ 3 (low CONUT score) and ≥ 4 (high CONUT score). Clinicopathological characteristics, surgical outcomes, and long-term survival were compared using propensity score matching analysis. RESULTS: Of the 2461 patients, 540 (21.9%) had high (≥ 4) and 1921 (78.1%) had low (≤ 3) preoperative CONUT scores. Overall, a high CONUT score was significantly associated with older age, female sex, low body mass index, low serum albumin, high serum total bilirubin, low lymphocyte count, low serum cholesterol, shorter prothrombin time, higher indocyanine green retention test at 15 min, Child-Pugh B (vs. A), liver cirrhosis, minor resection, shorter operation time, massive blood loss, blood transfusion, and postoperative complications. After propensity score matching, a higher CONUT score was significantly associated with poor overall survival (OS) and recurrence-free survival (RFS) using multivariate analysis. CONCLUSIONS: This retrospective, multi-institutional analysis showed that, in patients who undergo curative hepatectomy for HCC, the preoperative CONUT score is predictive of worse OS and RFS, even after propensity score matching analysis.

Accurate Estimation of Functional Liver Volume Using Gd-EOB-DTPA MRI Compared to MDCT/99mTc-SPECT Fusion Imaging.

BACKGROUND/AIM: We assessed the utility of dynamic magnetic resonance imaging (MRI) with gadoxetate-ethoxybenzyl-diethylenetriamine penta-aceticpenta-acetic acid (Gd-EOB-DTPA) (EOB-MRI) for estimating functional liver volume compared to 99mTc-galactosyl albumin single-photon-emission computed tomography (99mTc-GSA SPECT). PATIENTS AND METHODS: Regional functional liver volume (left lateral, medial, right anterior, right posterior) of 58 hepatectomized patients was assessed using EOB-MRI and 99mTc-GSA SPECT, and compared to the actual liver volume with MDCT-3D volumetry. RESULTS: 99mTc-GSA SPECT found a significantly lower functional volume of the left lateral section than the actual volume found by MDCT-3D volumetry (p=0.003) and EOB-MRI (p<0.001). Functional liver volume of right anterior section found with 99mTc-GSA SPECT was significantly higher than that found by MDCT-3D volumetry (p=0.04), despite no differences in asialoglycoprotein receptor 1 (ASGR1) or ATP-dependent organic anion transporting polypeptide 1 (OATP) expression between the left lateral and right anterior sections. CONCLUSION: 99mTc-GSA SPECT might underestimate the function of the left lobe and overestimate that of the right lobe. Therefore, EOB-MRI could be better for estimating the true regional functional liver reserve.