Significance of Prediction Models for Post-Hepatectomy Liver Failure Based on Type IV Collagen 7s Domain in Patients with Hepatocellular Carcinoma.

Background: Previous studies have attempted to establish predictive models for post-hepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC) undergoing liver resection. However, a versatile and useful predictive model for PHLF remains to be developed. Therefore, we aimed to develop predictive models for PHLF based on type IV collagen 7s domain (7s collagen) in patients with HCC. Methods: We retrospectively collected data from 972 patients with HCC who had undergone initial curative liver resection between February 2000 and December 2020 at our hospital. Multivariate logistic regression analysis using a restricted cubic spline was performed to evaluate the effect of 7s collagen on the incidence of PHLF. A nomogram was developed based on 7s collagen. Results: PHLF grades B or C were identified in 104 patients (11%): 98 (10%) and 6 (1%) PHLF grades B and C, respectively. Multivariate logistic regression analysis revealed that the preoperative serum level of 7s collagen was significantly associated with a proportional increase in the risk of PHLF, which was confirmed in both laparoscopic and open liver resections. A nomogram was developed based on 7s collagen, with a concordance index of 0.768. The inclusion of 7s collagen values in the predictive model increased the predictive accuracy. Conclusion: The findings highlight the efficacy of the serum level of 7s collagen as a predictive factor for PHLF. Our novel nomogram using 7s collagen may be useful for predicting the risk of PHLF.

Poorly Differentiated Hepatocellular Carcinoma Cells Avoid Apoptosis by Interacting with T Cells via CD40-CD40L Linkage.

Hepatocellular carcinoma (HCC) was associated with increased soluble CD40 levels in a previous study. This study aimed to investigate CD40's role in liver tumor progression. CD40 levels were examined in HCC patient tissues and various HCC cell lines, and their interaction with CD4+T cells was studied. RNA sequencing analysis was performed to explore the mechanisms of CD40 induction. Poorly differentiated HCC tumor tissues exhibited high membrane-bound CD40 expression, in contrast to nontumor areas. Poorly differentiated HCC cell lines showed high expression of membrane-bound CD40 with low CD40 promoter methylation, which was opposite of well-differentiated ones. Solely modulating CD40 expression in HCC cells exerted no direct consequences on cell growth or appearance. Interestingly, HLFs co-cultured with activated (CD40 ligand+) CD4+ T cells increased CD40 levels and showed a modest 3.2% dead cells, then increased to 10.9% underwent preneutralizing CD40 condition, whereas preblocking both CD40 and integrin α5ß1 concomitantly caused only 1.9% cell death. RNA sequencing of co-cultured HLFs with activated CD4+ T cells revealed the up-regulation of interferon and immune-response pathways. Increased interferon-γ levels in the activated T-cell media stimulated the Janus kinase/signal transducer and activator of transcription 3 pathway, resulting in increased CD40 expression in HLF. Collectively, CD40 expression in poorly differentiated HCC cells prevents cell death by interacting with CD40 ligand in activated T cells. Targeting CD40 may represent a promising anticancer therapy.

Impact of Tumor Subclassifications for Identifying an Appropriate Surgical Strategy in Patients with Intrahepatic Cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is subclassified into small and large duct types. The impact of these subclassifications for identifying appropriate surgical strategies remains unclear. PATIENTS AND METHODS: This study included 118 patients with ICC who underwent liver resection. Based on the pathological examination results, the participants were divided into the small duct-type ICC group (n = 64) and large duct-type ICC group (n = 54). The clinicopathological features and postoperative outcomes were compared between the two groups to investigate the impact of subclassification for selecting appropriate surgical strategies. RESULTS: Ten patients in the small duct-type ICC group had synchronous or metachronous hepatocellular carcinoma. The large duct-type ICC group had higher proportions of patients who underwent major hepatectomy, extrahepatic bile duct resection, portal vein resection, and lymph node sampling or dissection than the small duct-type ICC group. The large duct-type ICC group had significantly higher incidences of lymph node metastasis/recurrence and pathological major vessel invasion than the other. The small duct-type ICC group exhibited significantly higher recurrence-free and overall survival rates than the large duct-type ICC group. Further, the large duct-type ICC group had a significantly higher incidence of lymph node metastasis/recurrence than the small duct-type ICC at the perihilar region group. CONCLUSIONS: Suitable surgical strategies may differ between the small and large duct-type ICCs. In patients with large duct-type ICCs, hepatectomy with lymph node dissection and/or biliary reconstruction should be considered, whereas hepatectomy without these advanced procedures can be suggested for patients with small duct-type ICCs.

Impact of frailty on long-term outcomes after liver resection for hepatocellular carcinoma in elderly patients: A prospective study.

BACKGROUND: sFrailty affects short-term outcomes after liver resection in elderly patients. However, frailty's effects on long-term outcomes after liver resection in elderly patients with hepatocellular carcinoma (HCC) are unknown. METHODS: This prospective, single-center study included 81 independently living patients aged ≥65 years scheduled to undergo liver resection for initial HCC. Frailty was evaluated according to the Kihon Checklist, a phenotypic frailty index." We investigated and compared postoperative long-term outcomes after liver resection between patients with and without frailty. RESULTS: Of the 81 patients, 25 (30.9%) were frail. The proportion of patients with cirrhosis, high serum alpha-fetoprotein level (≥200 ng/mL), and poorly differentiated HCC was higher in the frail group than in the nonfrail group (n = 56). Among the patients with postoperative recurrence, the incidence of extrahepatic recurrence was higher in the frail group than in the nonfrail group (30.8% vs. 3.6%, P = 0.028). Moreover, the proportion of patients who underwent repeat liver resection and ablation for recurrence who met the Milan criteria tended to be lower in the frail group than in the nonfrail group. Although there was no difference in disease-free survival between the two groups, the overall survival rate in the frail group was significantly worse than that in the nonfrail group (5-year overall survival: 42.7% vs. 77.2%, P = 0.005). Results of the multivariate analysis indicated that frailty and blood loss were independent prognostic factors for postoperative survival. CONCLUSION: Frailty is associated with unfavorable long-term outcomes after liver resection in elderly patients with HCC.

Laparoscopic and open minor liver resection for hepatocellular carcinoma with clinically significant portal hypertension: a multicenter study using inverse probability weighting approach.

BACKGROUND: Liver resection offers substantial advantages over open liver resection (OLR) for patients with hepatocellular carcinoma (HCC) in terms of reduced intraoperative blood loss and morbidity. However, there is limited evidence comparing the indications and perioperative outcomes with the open versus laparoscopic approach for resection. This study aimed to compare postoperative outcomes between patients undergoing laparoscopic liver resection (LLR) and OLR for HCC with clinically significant portal hypertension (CSPH). METHODS: A total of 316 HCC patients with CSPH (the presence of gastroesophageal varices or platelet count < 100,000/ml and spleen diameter > 12 cm) undergoing minor liver resection at eight centers were included in this study. To adjust for confounding factors between the LLR and OLR groups, an inverse probability weighting method analysis was performed. RESULTS: Overall, 193 patients underwent LLR and 123 underwent OLR. After weighting, LLR was associated with a lower volume of intraoperative blood loss and the incidence of postoperative complications (including pulmonary complications, incisional surgical site infection, and paralytic ileus) compared to the OLR group. The 3-, 5-, and 7-year postoperative recurrence-free survival rates were 39%, 26%, and 22% in the LLR group and 49%, 18%, and 18% in the OLR group, respectively (p = 0.18). And, the 3-, 5-, and 7-year postoperative overall survival rates were 71%, 56%, and 44% in the LLR group and 76%, 51%, 44% in the OLR group, respectively (p = 0.87). CONCLUSIONS: LLR for HCC patients with CSPH is clinically advantageous by lowering the volume of intraoperative blood loss and incidence of postoperative complications, thereby offering feasible long-term survival.

Application of Indocyanine Green Fluorescence Imaging for Tumor Localization during Robot-Assisted Hepatectomy.

The efficacy of indocyanine green (ICG) fluorescence imaging for visualizing hepatic tumors in robot-assisted hepatectomy (RAH) should be validated. This study included 30 consecutive patients with 33 collective tumors who underwent RAH. ICG was administered at a dose of 0.5 mg/kg before surgery. ICG fluorescence imaging was performed intraoperatively. In total, 28 patients with a combined total of 31 tumors underwent ICG fluorescence imaging. Further, 26 (84%) tumors were identified on hepatic surfaces prior to hepatic transection. The fluorescence signals of eight tumors were detected on hepatic raw surfaces during parenchymal dissection, thereby enabling surgeons to adjust the transection planes to ensure appropriate surgical margins. One patient with intrahepatic cholangiocarcinoma tested positive for cancer cells at the dissected stump of the bile duct. However, in all patients in whom ICG fluorescence imaging was used, negative surgical margins were achieved at the site of the dissected hepatic parenchyma. On the other hand, one of two patients with ICG contraindications had a positive surgical margin surrounding the dissected hepatic parenchyma. The median operative time and volume of blood loss were 259 (range: 124-594) min and 150 (range: 1-1150) mL, respectively. ICG fluorescence imaging facilitates the easy identification of hepatic tumors, even in RAH. Hence, it can be useful for confirming appropriate surgical margins.

Prognostic impact of postoperative infection after resection of biliary malignancy: A multicenter retrospective cohort study.

BACKGROUND: The aim of this study was to investigate the prognostic impact of postoperative infections in patients who underwent resection for biliary malignancy, including intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, distal cholangiocarcinoma, gallbladder carcinoma, and carcinoma of the ampulla of Vater. METHODS: This study was conducted in an 11-center retrospective cohort study. Patients with biliary tract cancer who underwent curative resection between April 2013 and March 2015 at 11 institutions in Japan were enrolled. We analyzed the prevalence of postoperative infection, infection-related factors, and prognostic factors. RESULTS: Of the total 290 cases, 33 were intrahepatic cholangiocarcinoma, 60 were perihilar cholangiocarcinoma, 120 were distal cholangiocarcinoma, 55 were gallbladder carcinoma, and 22 were carcinoma of the ampulla of Vater. Postoperative infectious complications, including remote infection, were observed in 146 patients (50.3%), and Clavien-Dindo ≥III in 115 patients (39.7%). Postoperative infections occurred more commonly in the patients who received pancreaticoduodenectomy and bile duct resection. Patients with infectious complications had a significantly poorer prognosis than those without (median overall survival 38 months vs 62 months, P = .046). In a diagnosis-specific analysis, although there was no correlation between infectious complications and overall survival in intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, distal cholangiocarcinoma, and carcinoma of the ampulla of Vater, infectious complications were a significantly poor prognostic factor in gallbladder carcinoma (P = .031). CONCLUSION: Postoperative infection after surgery for biliary tract cancer commonly occurred, especially in patients who underwent pancreaticoduodenectomy and bile duct resection. Postoperative infection is relatively associated with the prognosis of patients with biliary malignancy, especially gallbladder carcinoma.

Atezolizumab plus bevacizumab-induced intratumoral hemorrhage in a patient with rib metastasis from unresectable hepatocellular carcinoma.

Recently, combination therapy with atezolizumab, a humanized monoclonal antiprogrammed death ligand-1 antibody, and bevacizumab, has become available for treatment of unresectable hepatocellular carcinoma (HCC). We herein report a 73-year-old man with advanced stage HCC who developed fatigue during treatment with atezolizumab-bevacizumab combination therapy. Computed tomography identified intratumoral hemorrhage within the HCC metastasis to the right fifth rib metastasis of HCC, which was confirmed on emergency angiography of the right 4th and 5th intercostal arteries and some branches of the subclavian artery confirmed intratumoral hemorrhage, following which transcatheter arterial embolization (TAE) was performed to achieve hemostasis. He continued to receive atezolizumab-bevacizumab combination therapy after TAE, and no rebleeding was seen. Although uncommon, rupture and intratumoral hemorrhage in the HCC metastasis to the ribs can cause life-threatening hemothorax. However, to our knowledge, no previous cases of intratumoral hemorrhage in HCC during atezolizumab-bevacizumab combination therapy have been reported. This is the first report of intratumoral hemorrhage with the combination therapy of atezolizumab and bevacizumab, which was successfully controlled by TAE. Patients receiving this combination therapy should be observed for intratumoral hemorrhage, which can be managed by TAE if it does occur.

Efficacy and safety of tazobactam/ceftolozane in combination with metronidazole for intraabdominal infection in a hepato-biliary-pancreatic field in clinical practice.

INTRODUCTION: This single-center study evaluated the efficacy and safety of tazobactam/ceftolozane (TAZ/CTLZ) in combination with metronidazole for intraabdominal infection in a hepato-biliary-pancreatic field in clinical practice. METHODS: This study included 50 patients, including 35 with intraabdominal abscess or peritonitis, 5 with liver abscess, 4 with cholecystitis, and 6 with cholangitis with sepsis. Of the 50 patients, 29 received TAZ/CTLZ and metronidazole after a prior antibacterial therapy failure, including tazobactam/piperacillin, cefmetazole, and levofloxacin. Source control was performed in 36 patients. RESULTS: The clinical response could be evaluated in 49 patients. The clinical cure rate at end-of-therapy was 91.8% (45 of 49 patients) and that at test-of-cure was 89.6% (43 of 48 patients). Of 5 patients in whom clinical response at test-of-cure was a failure, 1 developed infectious disease during chemoradiotherapy for recurrent cancer and 4 after liver resection or pancreatoduodenectomy. Three of the 4 patients were associated with pancreatic juice leakage. Isolated pathogens were eradicated or presumably eradicated in 27 of 31 (87.1%) patients in whom microbiological response at test-of-cure could be evaluated. The response rate for AmpC-producing Enterobacteriaceae was 87.5%. Nausea was observed in two patients. Aspartate and alanine aminotransferase activities were increased in 3 of the 50 (6.0%) patients. The activities improved after the antibiotic discontinuation. CONCLUSIONS: This observational study demonstrated that TAZ/CTLZ in combination with metronidazole has a favorable effect without major drug-related adverse events for intraabdominal infection in the hepato-biliary-pancreatic field in clinical practice although the efficacy of TAZ/CTLZ may decrease in compromised patients.

Pancreaticoduodenectomy with celiac artery resection (PD-CAR) for unresctable locally advanced pancreatic ductal adenocarcinoma.

PURPOSE: Locally advanced pancreatic ductal adenocarcinoma (LA-PDAC) involving the celiac artery (CeA), the common hepatic artery and the gastroduodenal artery (GDA) is considered unresectable. We developed the novel procedure of pancreaticoduodenectomy with celiac artery resection (PD-CAR) for such LA-PDACs. METHODS: From 2015 to 2018, we performed curative pancreatectomy with major arterial resection for 13 LA-PDACs as a clinical study (UMIN000029501). Of those, four patients with pancreatic neck cancer involving the CeA and GDA were candidates for PD-CAR. Prior to surgery, blood flow alterations were performed to unify the blood flow to the liver, stomach, and pancreas, resulting in feeding from the cancer-free artery. During PD-CAR, arterial reconstruction of the unified artery was performed as needed. Based on the records of PD-CAR cases, we retrospectively analyzed the validity of the operation. RESULTS: R0 resection was achieved in all patients. Arterial reconstruction was performed in three patients. In another patient, the hepatic arterial flow was maintained by preserving of the left gastric artery. The mean operative time was 669 min, and the mean blood loss was 1003 ml. Although Clavien-Dindo classification III-IV postoperative morbidities occurred in three patients, no reoperations nor mortalities occurred. Although two patients died of cancer recurrence, one patient survived for 26 months without recurrence (died of cerebral infarction), and another is alive at 76 months without recurrence. CONCLUSION: PD-CAR, which enabled R0 resection and preservation of the residual stomach, pancreas, and spleen, provided acceptable postoperative outcomes.

Deep Learning Model Based on Contrast-Enhanced Computed Tomography Imaging to Predict Postoperative Early Recurrence after the Curative Resection of a Solitary Hepatocellular Carcinoma.

We aimed to develop the deep learning (DL) predictive model for postoperative early recurrence (within 2 years) of hepatocellular carcinoma (HCC) based on contrast-enhanced computed tomography (CECT) imaging. This study included 543 patients who underwent initial hepatectomy for HCC and were randomly classified into training, validation, and test datasets at a ratio of 8:1:1. Several clinical variables and arterial CECT images were used to create predictive models for early recurrence. Artificial intelligence models were implemented using convolutional neural networks and multilayer perceptron as a classifier. Furthermore, the Youden index was used to discriminate between high- and low-risk groups. The importance values of each explanatory variable for early recurrence were calculated using permutation importance. The DL predictive model for postoperative early recurrence was developed with the area under the curve values of 0.71 (test datasets) and 0.73 (validation datasets). Postoperative early recurrence incidences in the high- and low-risk groups were 73% and 30%, respectively (p = 0.0057). Permutation importance demonstrated that among the explanatory variables, the variable with the highest importance value was CECT imaging analysis. We developed a DL model to predict postoperative early HCC recurrence. DL-based analysis is effective for determining the treatment strategies in patients with HCC.

Development of intraductal papillary neoplasm of the bile duct in patients with occupational cholangiocarcinoma.

This study aimed to investigate the clinicopathological findings of intraductal papillary neoplasm of the bile duct (IPNB) in patients with occupational cholangiocarcinoma caused by exposure to 1,2-dichloropropane and/or dichloromethane to elucidate the development of IPNB to cholangiocarcinoma. The clinicopathological findings of 17 IPNB lesions according to the size (1.5-20 mm in diameter) and their comparison between type 1 (n = 9) and type 2 IPNBs (n = 8) were investigated. An IPNB of <5 mm in size was classified as micro IPNB (n = 7), while those ≥5 mm in size were classified as ordinary IPNB (n = 10). Both types 1 and 2 IPNBs were observed in micro IPNB, and their proportions were not different between micro and ordinary IPNBs. The clinicopathological characteristics of types 1 and 2 IPNBs were fundamentally similar to those previously reported. IPNB with invasive carcinoma was only found in ordinary IPNB although the proportions of low-grade and high-grade epithelium were not different between micro IPNB and ordinary IPNB. All IPNB exhibited γH2AX and S100P, indicating the occurrence of DNA injury and malignant transformation in micro and ordinary IPNBs. These results indicate that the carcinogens may induce micro IPNB with types 1 or 2 at the initiation and then develop ordinary IPNB with types 1 or 2, subsequently, progressing to IPNB with invasive carcinoma in patients with occupational cholangiocarcinoma.

Surgical Outcomes for Hepatocellular Carcinoma in Patients with Child-Pugh Class B: a Retrospective Multicenter Study.

BACKGROUNDS: Liver resection for hepatocellular carcinoma (HCC) in patients with Child-Pugh class (CPC) B increases the incidence of postoperative complication and in-hospital death and decreases the disease-free survival (DFS) and overall survival (OS) compared with those with CPC A. Conversely, some selected patients possibly gained benefits for liver resection. METHODS: Clinical records of 114 patients with CPC B who underwent liver resection for HCC were retrospectively reviewed. The risk of postoperative complications (Clavien-Dindo classification grade of ≥ II), postoperative recurrence, and death was analyzed. RESULTS: Postoperative complications occurred in 36 patients (31.6%), and 2 died within 90 days postoperatively due to the liver and respiratory failure, respectively. Multivariate analysis indicated that albumin-bilirubin (ALB) grade III and extended operation time were found as independent risk factors for postoperative complications. The DFS and OS rates at 3/5 years after liver resection were 30.8%/25.3% and 68.4%/48.9%, respectively. Multivariate analysis indicated that the extended blood loss, high α-fetoprotein (AFP) level (≥ 200 ng/mL), and Barcelona Clinic Liver Cancer stage C were found to be independent risk factors for postoperative recurrence. The high AFP level was also an independent prognostic factor for OS. Patients with high AFP levels had postoperative recurrence within 2 years and a higher number of extrahepatic recurrences than those with low AFP levels (< 200 ng/mL). CONCLUSION: For patients with HCC with CPC B who were scheduled for liver resection, ALBI grade III and high AFP level should be considered as unfavorable outcomes after liver resection.

Increasing incidence and severity of post-hepatectomy adhesion around the liver may be influenced by the hepatectomy-related operative procedures.

BACKGROUND: The incidence of postoperative adhesions is directly correlated with the difficulty level of repeat hepatectomies. However, the incidence, location, and severity of postoperative adhesions in relation to hepatectomy-related operative procedures are yet unclear. METHODS: First hepatectomy-induced hard dense adhesions were evaluated from the surgical records and/or videos of 168 patients who underwent second hepatectomies. RESULTS: The incidence of postoperative hard dense adhesions around the liver was significantly associated with locations, such as the hepatic cut surface, dissected areas around the liver, and peri-incision peritoneum, and hepatectomy-related operative procedures, such as Pringle maneuver and cholecystectomy. The incidence of hard dense adhesions after dissection was higher around the right liver than in the left infraphrenic space. Further, the incidence of hard dense adhesions around the hepatoduodenal ligament or Morison pouch was greater than 30% even in patients who did not undergo Pringle maneuver, cholecystectomy, or hepatorenal ligament dissection. Although the incidence of hard dense adhesions of the peritoneum around the incision was higher after open hepatectomy than after laparoscopic hepatectomy, adhesion barrier use reduced the incidence of such adhesions in patients after open hepatectomy. CONCLUSION: Hepatectomy-related operative procedures such as peri-hepatic dissection, Pringle maneuver and cholecystectomy are directly associated with postoperative hard dense adhesions. However, the incidence of postoperative hard dense adhesions around the hepatoduodenal ligament and Morison pouch was high even when the above-mentioned operative procedures were not performed. These findings may help inform clinical decisions regarding the indications and sites for adhesion barrier use during hepatectomies.

Recent evidence for subcutaneous drains to prevent surgical site infections after abdominal surgery: A systematic review and meta-analysis.

BACKGROUND: Surgical site infections (SSIs) increase mortality, hospital stays, additional medical treatment, and medical costs. Subcutaneous drains prevent SSIs in gynecological and breast surgeries; however, their clinical impact in abdominal surgery remains unclear. AIM: To investigate whether subcutaneous drains were beneficial in abdominal surgery using a systematic review and meta-analysis. METHODS: The database search used PubMed, MEDLINE, and the Cochrane Library. The following inclusion criteria were set for the systematic review: (1) Randomized controlled trial studies comparing SSIs after abdominal surgery with or without subcutaneous drains; and (2) Studies that described clinical outcomes, such as SSIs, seroma formation, the length of hospital stays, and mortality. RESULTS: Eight studies were included in this meta-analysis. The rate of total SSIs was significantly lower in the drained group (54/771, 7.0%) than in the control group (89/759, 11.7%), particularly in gastrointestinal surgery. Furthermore, the rate of superficial SSIs was slightly lower in the drained group (31/517, 6.0%) than in the control group (49/521, 9.4%). No significant differences were observed in seroma formation between the groups. Hospital stays were shorter in the drained group than in the control group. CONCLUSION: Subcutaneous drains after abdominal surgery prevented SSIs and reduced hospital stays but did not significantly affect seroma formation. The timing of drain removal needs to be reconsidered in future studies.

Comparison of clinicopathological characteristics between resected ampullary carcinoma and carcinoma of the second portion of the duodenum.

BACKGROUND: Few studies compared the oncological and biological characteristics between ampullary carcinoma (AC) and cancer of the second portion of the duodenum (DC-II), although both tumors arise from anatomically close locations. AIM: To elucidate differences in clinicopathological characteristics, especially the patterns of lymph node metastasis (LNM), between AC and DC-II. METHODS: This was a retrospective cohort study of 80 patients with AC and 27 patients with DC-II who underwent pancreaticoduodenectomy between January 1998 and December 2018 in two institutions. Clinicopathological factors, LNM patterns, and prognosis were compared between the two groups. RESULTS: The patients with AC and DC-II did not exhibit significant differences in 5-year overall survival (66.0% and 67.1%, respectively) and 5-year relapse-free survival (63.5% and 62.2%, respectively). Compared to the patients with DC-II, the rate of preoperative biliary drainage was higher (P = 0.042) and the rates of digestive symptoms (P = 0.0158), ulcerative-type cancer (P < 0.0001), large tumor diameter (P < 0.0001), and advanced tumor stage (P = 0.0019) were lower in the patients with AC. The LNM rates were 27.5% and 40.7% in patients with AC and DC-II, respectively, without significant difference (P = 0.23). The rates of LNM to hepatic nodes (N-He) and pyloric nodes (N-Py) were significantly higher in patients with DC-II than in those with AC (metastasis to N-HE: 18.5% and 5% in patients with DC-II and AC, respectively; P = 0.0432; metastasis to N-Py: 11.1% and 0% in patients with DC-II and AC, respectively; P = 0.0186). CONCLUSION: Although there were no significant differences in the prognosis and recurrence rates between the two groups, metastases to N-He and N-Py were more frequent in patients with DC-II than in those with AC.

Prognostic impact of postoperative infection in patients with pancreatic cancer: A multicenter cohort study.

BACKGROUND: Postoperative infection after pancreatectomy in patients with pancreatic cancer often leads to poor prognosis. The aim of this study was to determine the prognostic effect of postoperative infection in patients with pancreatic cancer. METHODS: A multicenter cohort study was performed using a common database of patients with pancreatic cancer who underwent curative pancreatic resections between April 2013 and March 2015 at 15 high-volume centers in Japan. The rate of postoperative infection was determined, and patient demographic characteristics, clinicopathologic factors, and prognostic factors for overall survival were analyzed. RESULTS: Of the 462 eligible patients who underwent curative pancreatectomy, postoperative infection occurred in 141 patients (31%), including 114 surgical site infections (25%), 50 remote infections (11%), and 23 combined infections (5%). Risk factors for postoperative infection included high body mass index, nondiabetes, and longer operation time. In the survival analysis, patients with postoperative infection had significantly worse overall survival than patients without postoperative infection. The median survival times were 21.9 and 33.0 months (P = .023), respectively, for patients with and without postoperative infection. According to the multivariate analysis for overall survival, lack of adjuvant therapy (P = .002), but not postoperative infection (P = .829), predicted poor prognosis. The multivariate analysis revealed that postoperative infection (P < .001) was an independent risk factor for lack of adjuvant therapy. CONCLUSION: Postoperative infection in patients with pancreatic cancer may indirectly worsen the prognosis by preventing timely adjuvant therapy.

Cancer cells produce liver metastasis via gap formation in sinusoidal endothelial cells through proinflammatory paracrine mechanisms.

Intracellular gap (iGap) formation in liver sinusoidal endothelial cells (LSECs) is caused by the destruction of fenestrae and appears under pathological conditions; nevertheless, their role in metastasis of cancer cells to the liver remained unexplored. We elucidated that hepatotoxin-damaged and fibrotic livers gave rise to LSECs-iGap formation, which was positively correlated with increased numbers of metastatic liver foci after intrasplenic injection of Hepa1-6 cells. Hepa1-6 cells induced interleukin-23-dependent tumor necrosis factor-α (TNF-α) secretion by LSECs and triggered LSECs-iGap formation, toward which their processes protruded to transmigrate into the liver parenchyma. TNF-α triggered depolymerization of F-actin and induced matrix metalloproteinase 9 (MMP9), intracellular adhesion molecule 1, and CXCL expression in LSECs. Blocking MMP9 activity by doxycycline or an MMP2/9 inhibitor eliminated LSECs-iGap formation and attenuated liver metastasis of Hepa1-6 cells. Overall, this study revealed that cancer cells induced LSEC-iGap formation via proinflammatory paracrine mechanisms and proposed MMP9 as a favorable target for blocking cancer cell metastasis to the liver.

Liver Cancer Study Group of Japan Clinical Practice Guidelines for Intrahepatic Cholangiocarcinoma.

This paper presents the first version of clinical practice guidelines for intrahepatic cholangiocarcinoma (ICC) established by the Liver Cancer Study Group of Japan. These guidelines consist of 1 treatment algorithm, 5 background statements, 16 clinical questions, and 1 clinical topic, including etiology, staging, pathology, diagnosis, and treatments. Globally, a high incidence of ICC has been reported in East and Southeast Asian countries, and the incidence has been gradually increasing in Japan and also in Western countries. Reported risk factors for ICC include cirrhosis, hepatitis B/C, alcohol consumption, diabetes, obesity, smoking, nonalcoholic steatohepatitis, and liver fluke infestation, as well as biliary diseases, such as primary sclerosing cholangitis, hepatolithiasis, congenital cholangiectasis, and Caroli disease. Chemical risk factors include thorium-232, 1,2-dichloropropane, and dichloromethane. CA19-9 and CEA are recommended as tumor markers for early detection and diagnostic of ICC. Abdominal ultrasonography, CT, and MRI are effective imaging modalities for diagnosing ICC. If bile duct invasion is suspected, imaging modalities for examining the bile ducts may be useful. In unresectable cases, tumor biopsy should be considered when deemed necessary for the differential diagnosis and drug therapy selection. The mainstay of treatment for patients with Child-Pugh class A or B liver function is surgical resection and drug therapy. If the patient has no regional lymph node metastasis (LNM) and has a single tumor, resection is the treatment of choice. If both regional LNM and multiple tumors are present, drug therapy is the first treatment of choice. If the patient has either regional LNM or multiple tumors, resection or drug therapy is selected, depending on the extent of metastasis or the number of tumors. If distant metastasis is present, drug therapy is the treatment of choice. Percutaneous ablation therapy may be considered for patients who are ineligible for surgical resection or drug therapy due to decreased hepatic functional reserve or comorbidities. For unresectable ICC without extrahepatic metastasis, stereotactic radiotherapy (tumor size ≤5 cm) or particle radiotherapy (no size restriction) may be considered. ICC is generally not indicated for liver transplantation, and palliative care is recommended for patients with Child-Pugh class C liver function.

Nivolumab for treating patients with occupational cholangiocarcinoma.

Tanaka et al. previously reported a case in which nivolumab for recurrent occupational cholangiocarcinoma resulted in complete response persisting for 26 months after discontinuation. Afterward, in that clinical trial, nivolumab was administered to two patients for recurrence. Both patients achieved complete response, suggesting that nivolumab is effective for occupational cholangiocarcinoma.