Results of a Phase II Study on the Use of Neoadjuvant Chemotherapy (FOLFIRINOX or GEM/nab-PTX) for Borderline-resectable Pancreatic Cancer (NUPAT-01).

OBJECTIVE: Given the frequent adverse events with multidrug chemotherapy, not only the survival benefit but also the feasibility of using neoadjuvant chemotherapy to treat pancreatic cancer need to be clarified. SUMMARY OF BACKGROUND DATA: Although the development of multidrug chemotherapy regimens has improved the survival outcomes of patients with unresectable pancreatic cancer, the benefits of these treatments in the neo-adjuvant setting remain controversial. METHODS: Patients with borderline-resectable pancreatic cancer were enrolled and randomly assigned to receive neoadjuvant chemotherapy with either FOLFIRINOX or gemcitabine with nab-paclitaxel (GEM/nab-PTX). After the completion of chemotherapy, patients underwent surgical resection when feasible. This study (NUPAT-01) was a randomized phase II trial, and the primary endpoint was the R0 resection rate. RESULTS: Fifty-one patients were enrolled in this study [FOLFIRINOX (n = 26) and GEM/nab-PTX (n = 25)]. A total of 84.3% (n = 43/51) of the patients eventually underwent surgery, and R0 resection was achieved in 67.4% (n = 33/ 51) of the patients. Adverse events (grade >3) due to neoadjuvant treatment were observed in 45.1% of the patients (n = 23/51), and major surgical complications occurred in 30.0% (n = 13/43), with no mortality noted. The intention-to-treat analysis showed that the 3-year overall survival rate was 54.7%, with a median survival time of 39.4 months, and a significant difference in overall survival was not observed between the FOLFIRINOX and GEM/nab-PTX groups. CONCLUSIONS: These results indicate that neoadjuvant chemotherapy with FOLFIRINOX or GEM/nab-PTX is feasible and well tolerated, achieving an R0 resection rate of 67.4%. The survival of patients was even found to be favorable in the intention-to-treat analysis.

Predicting Inchinkoto efficacy, in patients with obstructive jaundice associated with malignant tumors, through pharmacomicrobiomics.

Inchinkoto (ICKT) is a popular choleretic and hepatoprotective herbal medicine that is widely used in Japan. Geniposide, a major ingredient of ICKT, is metabolized to genipin by gut microbiota, which exerts a choleretic effect. This study investigates the relationship between stool genipin-producing activity and diversity of the clinical effect of ICKT in patients with malignant obstructive jaundice. Fifty-two patients with malignant obstructive jaundice who underwent external biliary drainage were included. ICKT was administered as three packets per day (7.5 g/day) for three days and 2.5 g on the morning of the fourth day. Stool samples were collected before ICKT administration and bile flow was monitored on a daily basis. The microbiome, genipin-producing activity, and organic acids in stools were analyzed. The Shannon-Wiener (SW) index was calculated to evaluate gut microbiome diversity. The stool genipin-producing activity showed a significant positive correlation with the SW index. Stool genipin-producing activity positively correlated with the order Clostridia (obligate anaerobes), but negatively correlated with the order Lactobacillales (facultative anaerobes). Moreover, stool genipin-producing activity was positively correlated to the concentration valeric acid, but negatively correlated to the concentration of lactic acid and succinic acid. The change of bile flow at 2 and 3 days after ICKT administration showed significant positive correlation with genipin-producing activity (correlation coefficient, 0.40 and 0.29, respectively, P < 0.05). An analysis of stool profile, including stool genipin-producing activity, may predict the efficacy of ICKT. Modification of the microbiome may be a target to enhance the therapeutic effect of ICKT.

Comparison between autologous and homologous blood transfusions in liver resection for biliary tract cancer: a propensity score matching analysis.

BACKGROUND: It remains unclear whether preoperative blood donation is truly beneficial in liver surgery. The aim of this study was to compare surgical outcomes between patients receiving autologous and homologous transfusions during liver resection for biliary tract cancer (BTC). METHODS: Patients who underwent hepatectomy for BTC were retrospectively reviewed (2006-2017). Patients who deposited autologous blood and underwent resection without homologous blood transfusion intraoperatively (Autologous group) were compared with non-depositing patients who required homologous transfusion during hepatectomy (Homologous group). Propensity score matching analyses were performed to adjust the data for the baseline characteristics of both groups. RESULTS: During the study period, 359 patients were included in the Autologous group, and 105 patients were in the Homologous group. The postoperative maximum total bilirubin (T-Bil) levels and the incidence of postoperative liver failure were significantly higher in the Homologous group than in the Autologous group. After propensity score matching, postoperative maximum T-Bil levels were significantly higher in the Homologous group, whereas the incidence of postoperative liver failure was comparable between the two groups; between-group differences were not observed for the remaining major complications, hospital stays and mortality. CONCLUSION: Although autologous blood transfusion may minimize postoperative hyperbilirubinemia, it may not decrease the risk for mortality or morbidities following hepatectomy for BTC.

Loss of trefoil factor 1 inhibits biliary regeneration but accelerates the hepatic differentiation of progenitor cells in mice.

Although the regeneration of the adult liver depends on hepatic progenitor cells (HPCs), many uncertainties regarding hepatic regeneration in the injured liver remain. Trefoil factor family 1 (TFF1), a secretory protein predominantly expressed in the gastrointestinal tract, is responsible for mucosal restitution. Here, we investigated the role of TFF1 in liver regeneration using a mouse model of hepatic injury (choline-deficient ethionine-supplemented diet and carbon tetrachloride administration) and genetically engineered mice (TFF1 knockout (TFF1-/-)). Immunohistochemistry analysis of human liver samples revealed TFF1 expression in the hepatocytes close to ductular reaction and the regenerating biliary epithelium in injured liver. The number of cytokeratin 19 (CK19)-positive bile ducts was significantly decreased in the TFF1-/- mice after liver injury. Notch pathway in the TFF1-/- mice was also downregulated. HPCs in the control mice differentiated into biliary cells (CK19+/SRY HMG box 9 (SOX9)+) more frequently. In contrast, HPCs in the TFF1-/- mice more frequently differentiated into a hepatic lineage (alpha fetoprotein+/SOX9+) after acute liver damage. Hepatocyte proliferation was upregulated, and the liver weight was increased in TFF1-/- mice in response to chronic liver damage. Thus, TFF1 is responsible for liver regeneration after liver injury by promoting HPC differentiation into a biliary lineage and inhibiting HPC differentiation into a hepatic lineage.

Does the intestinal microenvironment have an impact on the choleretic effect of inchinkoto, a hepatoprotective herbal medicine?

AIM: The choleretic effects of inchinkoto (ICKT), a hepatoprotective herbal medicine, are variable among patients. This study sought to investigate the correlation between the choleretic effects of ICKT and the intestinal microenvironment in patients with biliary obstruction. METHODS: Patients with biliary obstruction who underwent external biliary drainage were enrolled. The concentrations of total bilirubin and bile acid in the bile, and genipin, a major active ingredient of ICKT, in the bloodstream before and after ICKT treatment were measured. Feces were collected from the patients to determine bacterial count and organic acid concentrations. RESULTS: Samples from 37 patients were collected and analyzed. The serum concentration of genipin increased 3 h after ICKT treatment and showed a positive correlation with the percent changes of biliary concentrations of bile acid, total bilirubin, and direct bilirubin. Serum genipin concentration also showed a positive correlation with the fecal concentrations of representative obligate anaerobes such as the Clostridium leptum subgroup, Bacteroides fragilis group, Bifidobacterium, and the Atopobium cluster. In sharp contrast, so-called harmful bacteria such as Clostridium difficile, Enterobacteriaceae, and Enterococcus showed a negative correlation with the concentration of genipin. Genipin concentration after ICKT administration showed a positive correlation with the fecal concentration of short chain fatty acids such as propionic acid and butyric acid, and a negative correlation with the fecal concentration of lactic acid. CONCLUSIONS: The absorption of genipin was variable among patients. This variability may be associated with the fecal microenvironment profile and partly explain the variable choleretic effects of ICKT among patients.

Inhibition of Toll-like receptor 4 ameliorates experimental postischemic injury in the cholestatic liver through inhibition of high-mobility group box protein b1 (HMGB1) signaling.

BACKGROUND: The objective of this study was to elucidate whether the inhibition of Toll-like receptor 4 attenuates liver injury ischemia/reperfusion in the cholestatic liver. METHOD: Rats were assigned into sham, bile duct ligation, sham ischemia/reperfusion (ischemia/reperfusion after laparotomy), and bile duct ligation ischemia/reperfusion (ischemia/reperfusion after bile duct ligation) groups. In some rats, TAK-242, an inhibitor of Toll-like receptor 4, was administered 15 minutes before ischemia/reperfusion. We measured intrahepatic Toll-like receptor 4 expression, serum hepatic marker expression, liver necrosis, gene expression of inflammation-associated factors, and serum high-mobility group box protein b1 levels. RESULTS: Intrahepatic Toll-like receptor 4 expression was significantly greater in the bile duct ligation group than in the sham group. Toll-like receptor 4 expression was further increased after ischemia/reperfusion in bile duct ligation ischemia/reperfusion groups. The levels of serum hepatic markers were significantly greater in both the sham ischemia/reperfusion and bile duct ligation ischemia/reperfusion groups than in the groups without ischemia/reperfusion. Liver necrosis was greater in the bile duct ligation group than in the sham group and was further increased in the bile duct ligation ischemia/reperfusion group. Genomic expression of inflammation-associated factors was also significantly greater in the bile duct ligation ischemia/reperfusion group than in the sham group. Serum high-mobility groups box protein b1 levels were greater in the bile duct ligation ischemia/reperfusion group than in the sham group (28.1 ng/ml versus 9.2 ng/ml, P = .011) and the bile duct ligation group (28.1 ng/ml versus 10.6 ng/ml, P = .017). These changes in the bile duct ligation ischemia/reperfusion group were significantly attenuated by preconditioning with TAK242. CONCLUSIONS: Toll-like receptor 4 inhibition has a potential to minimize severe injury after ischemia/reperfusion in the cholestatic liver through inhibition of high-mobility groups box protein b1.

Prediction of Early Recurrence After Curative Resection of Colorectal Liver Metastasis and Subsequent S-1 Chemotherapy.

BACKGROUND: S-1, an oral 5-fluorouracil (5-FU)-based medicine that combines tegafur, gimeracil and oteracil potassium is commonly used as an adjuvant chemotherapeutic drug for the treatment of colorectal cancer. PATIENTS AND METHODS: We enrolled 53 patients who underwent curative resection for colorectal cancer and liver metastasis (synchronous, n=24; metachronous, n=29). The subsequent adjuvant chemotherapy with oral S-1 administration was initiated within 56 days after liver resection. Recurrence was evaluated by imaging studies, that were performed during the first year after liver resection. Of the 53 patients, 25 who did not recur within 1 year were defined as being in the no-recurrence (NREC) group and the remaining 18 patients were defined as being in the early-recurrence (EREC) group. There were no significant differences in gene expression profiling for drug resistance and metabolism between the NREC group and the EREC group. RESULTS: In synchronous liver metastasis, there was no significant difference in early recurrence between serum carcinoembryonic antigen (CEA) ≤5 ng/ml and serum CEA >5 ng/ml (8/24 vs. 16/24, respectively). In metachronous liver metastasis, the early recurrence rate was significantly higher in patients with CEA >5 ng/ml compared to patients with CEA ≤5 ng/ml (15/29 vs. 14/29, p=0.05). The expression of cytochrome P450 2C19 (CYP2C19) and ATP-binding cassette, sub-family B member 1 (ABCB1) were significantly lower in the EREC group (6/15) compared to the NREC group (9/15) in colorectal cancer with metachronous liver metastasis and with serum CEA >5 ng/ml. CONCLUSION: Although the exact reason for down-regulation of these genes in the group with poor prognosis is unknown, the information obtained in this study may be useful in clinical practice for colorectal cancer.

A case of mucinous carcinoma of the breast that demonstrated a good pathological response to neoadjuvant chemotherapy despite a poor clinical response.

A 30-year-old woman presented with a right breast tumor. Mucinous carcinoma was diagnosed by core needle biopsy (T2: 5 cm N1 M0). Despite receiving a neoadjuvant anthracycline and taxane regimen, the patient demonstrated no clinical response (NC). Based on the patient's strong preference, we performed breast-conserving surgery. On histological examination, we observed widespread mucus and a few viable malignant cells, a Grade 2 therapeutic response. Neither optimal management procedures nor guidelines for chemotherapy for primary mucinous carcinoma of the breast have been established. It is a reasonable assumption, however, that discordance between the clinical response and therapeutic response to neoadjuvant chemotherapy may occur in cases of mucinous carcinoma.